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Entry
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- *607542 - POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 1; KCNQ1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*607542</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/607542">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000053918;t=ENST00000155840" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=3784" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607542" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000053918;t=ENST00000155840" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000218,NM_001406836,NM_001406837,NM_001406838,NM_001406839,NM_181798" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000218" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607542" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=06341&isoform_id=06341_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/KCNQ1" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/2076880,2198822,2465515,2465531,2961249,3953683,3953684,5042385,5042386,6166005,16877662,31711384,32479525,32479527,109730525,116488845,116488847,119622922,119622923,119622924,119622925,119622926,158254668,2241236898,2241236947,2241237015,2241237053" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P51787" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=3784" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000053918;t=ENST00000155840" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=KCNQ1" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=KCNQ1" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+3784" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/KCNQ1" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:3784" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/3784" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr11&hgg_gene=ENST00000155840.12&hgg_start=2445008&hgg_end=2849105&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:6294" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:6294" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/kcnq1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607542[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607542[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/KCNQ1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000053918" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=KCNQ1" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=KCNQ1" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=KCNQ1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://databases.lovd.nl/genomed/home.php?select_db=KCNQ1" title="Zhejiang University Center for Genetic and Genomic Medicine (ZJU-CGGM)" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Zhejiang University Center…</a></div><div style="margin-left: 0.5em;"><a href="http://www.fsm.it/cardmoc/" title="Gene Connection for the Heart" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Gene Connection for the He…</a></div><div style="margin-left: 0.5em;"><a href="http://www.ssi.dk/graphics/html/lqtsdb/lqtsdb.htm" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Long QT Syndrome Database</a></div><div style="margin-left: 0.5em;"><a href="https://research.cchmc.org/LOVD2/home.php?select_db=KCNQ1" title="CCHMC - Human Genetics Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">CCHMC - Human Genetics Mut…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=KCNQ1&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA223" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:6294" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:108083" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/KCNQ1#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:108083" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/3784/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002332/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=3784" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00002235;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-061214-5" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:3784" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=KCNQ1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 20852007<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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607542
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 1; KCNQ1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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KVLQT1<br />
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POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, MEMBER 9; KCNA9<br />
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KCNA8
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=KCNQ1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KCNQ1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/11/82?start=-3&limit=10&highlight=82">11p15.5-p15.4</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:2445008-2849105&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">11:2,445,008-2,849,105</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
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<a href="/clinicalSynopsis/table?mimNumber=192500,607554,220400,192500,609621" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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View Clinical Synopses
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</a>
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<tbody>
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<span class="mim-font">
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<a href="/geneMap/11/82?start=-3&limit=10&highlight=82">
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11p15.5-p15.4
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</a>
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<span class="mim-font">
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{Long QT syndrome 1, acquired, susceptibility to}
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<span class="mim-font">
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<a href="/entry/192500"> 192500 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<tr>
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<span class="mim-font">
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Atrial fibrillation, familial, 3
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<td>
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<span class="mim-font">
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<a href="/entry/607554"> 607554 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Jervell and Lange-Nielsen syndrome
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<span class="mim-font">
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<a href="/entry/220400"> 220400 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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<tr>
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<span class="mim-font">
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Long QT syndrome 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/192500"> 192500 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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<tr>
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<td>
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<span class="mim-font">
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Short QT syndrome 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/609621"> 609621 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/607542" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/607542" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Present in all eukaryotic cells, their diverse functions include maintaining membrane potential, regulating cell volume, and modulating electrical excitability in neurons. The delayed rectifier function of potassium channels allows nerve cells to efficiently repolarize following an action potential. In Drosophila, 4 sequence-related K+ channel genes--Shaker, Shaw, Shab, and Shal--have been identified. Each has been shown to have a human homolog (<a href="#15" class="mim-tip-reference" title="Chandy, K. G., Williams, C. B., Spencer, R. H., Aguilar, B. A., Ghanshani, S., Tempel, B. L., Gutman, G. A. <strong>A family of three mouse potassium channel genes with intronless coding regions.</strong> Science 247: 973-975, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2305265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2305265</a>] [<a href="https://doi.org/10.1126/science.2305265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2305265">Chandy et al., 1990</a>; <a href="#43" class="mim-tip-reference" title="McPherson, J. D., Wasmuth, J. J., Chandy, K. G., Swanson, R., Dethlefs, B., Chandy, G., Wymore, R., Ghanshani, S. <strong>Chromosomal localization of 7 potassium channel genes. (Abstract)</strong> Cytogenet. Cell Genet. 58: 1979, 1991."None>McPherson et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2305265" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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<div>
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<br />
|
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</div>
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</div>
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<div>
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<a id="cloning" class="mim-anchor"></a>
|
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>Using positional cloning methods, <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> identified a gene, which they called KVLQT1, within the critical region for long QT syndrome-1 locus (LQT1; <a href="/entry/192500">192500</a>) on chromosome 11. KVLQT1 is strongly expressed in the heart and encodes a protein with structural features of a voltage-gated potassium channel. The longest open reading frame of the KVLQT1 cDNA spans 1,645 bp. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#65" class="mim-tip-reference" title="Sanguinetti, M. C., Curran, M. E., Zou, A., Shen, J., Spector, P. S., Atkinson, D. L., Keating, M. T. <strong>Coassembly of K(v)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel.</strong> Nature 384: 80-83, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900283</a>] [<a href="https://doi.org/10.1038/384080a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8900283">Sanguinetti et al. (1996)</a> identified an apparently full-length human cDNA clone for KVLQT1. This clone predicted a 581-amino acid protein. Northern blot analysis detected a single 3.2-kb mRNA in human pancreas, heart, kidney, lung, and placenta. No message was detected in brain, liver, or skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8900283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#85" class="mim-tip-reference" title="Yang, W.-P., Levesque, P. C., Little, W. A., Conder, M. L., Shalaby, F. Y., Blanar, M. A. <strong>KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias.</strong> Proc. Nat. Acad. Sci. 94: 4017-4021, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9108097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9108097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9108097[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.8.4017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9108097">Yang et al. (1997)</a> described the cloning of a full-length KVLQT1 cDNA encoding a 676-amino acid polypeptide with structural characteristics similar to voltage-gated potassium channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9108097" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Barhanin, J., Lesage, F., Guillemare, E., Fink, M., Lazdunski, M., Romey, G. <strong>K(v)LQT1 and IsK (minK) proteins associate to form the I(Ks) cardiac potassium current.</strong> Nature 384: 78-80, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900282</a>] [<a href="https://doi.org/10.1038/384078a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8900282">Barhanin et al. (1996)</a> cloned a full-length KVLQT1 cDNA from a mouse heart library. Its sequence revealed an open reading frame encoding a 604-amino acid polypeptide sharing 90.5% identity with a human KVLQT1 partial sequence. Hydrophobicity analysis predicted a classic voltage-dependent potassium channel topology with 6 transmembrane segments (of the Shaker type) and a long unique C-terminal cytoplasmic domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8900282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="geneStructure" class="mim-anchor"></a>
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<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<div id="mimGeneStructureFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>By genomic sequence analysis, <a href="#72" class="mim-tip-reference" title="Splawski, I., Shen, J., Timothy, K. W., Vincent, G. M., Lehmann, M. H., Keating, M. T. <strong>Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1.</strong> Genomics 51: 86-97, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9693036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9693036</a>] [<a href="https://doi.org/10.1006/geno.1998.5361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9693036">Splawski et al. (1998)</a> found that the KCNQ1 gene contains 16 exons and spans 400 kb. The exon sizes range from 47 to 1,122 bp. <a href="#52" class="mim-tip-reference" title="Neyroud, N., Richard, P., Vignier, N., Donger, C., Denjoy, I., Demay, L., Shkolnikova, M., Pesce, R., Chevalier, P., Hainque, B., Coumel, P., Schwartz, K., Guicheney, P. <strong>Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome.</strong> Circ. Res. 84: 290-297, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10024302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10024302</a>] [<a href="https://doi.org/10.1161/01.res.84.3.290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10024302">Neyroud et al. (1999)</a> comprehensively detailed the genomic structure of KCNQ1. They determined that the gene contains 19 exons and spans more than 400 kb. The authors presented the sequences of exon-intron boundaries and of oligonucleotide primers designed to allow PCR amplification of all exons from genomic DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9693036+10024302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
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<br />
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<div>
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<a id="mapping" class="mim-anchor"></a>
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<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Mapping</strong>
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<p>By positional cloning methods, <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> identified the KVLQT1 gene within the critical region for long QT syndrome on chromosome 11p15. <a href="#65" class="mim-tip-reference" title="Sanguinetti, M. C., Curran, M. E., Zou, A., Shen, J., Spector, P. S., Atkinson, D. L., Keating, M. T. <strong>Coassembly of K(v)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel.</strong> Nature 384: 80-83, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900283</a>] [<a href="https://doi.org/10.1038/384080a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8900283">Sanguinetti et al. (1996)</a> showed that a fragment of the KVLQT1 cDNA mapped to the short arm of chromosome 11. <a href="#52" class="mim-tip-reference" title="Neyroud, N., Richard, P., Vignier, N., Donger, C., Denjoy, I., Demay, L., Shkolnikova, M., Pesce, R., Chevalier, P., Hainque, B., Coumel, P., Schwartz, K., Guicheney, P. <strong>Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome.</strong> Circ. Res. 84: 290-297, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10024302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10024302</a>] [<a href="https://doi.org/10.1161/01.res.84.3.290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10024302">Neyroud et al. (1999)</a> mapped the KCNQ1 gene to 11p15.5. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8528244+8900283+10024302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>To define the function of the KVLQT1 gene, <a href="#65" class="mim-tip-reference" title="Sanguinetti, M. C., Curran, M. E., Zou, A., Shen, J., Spector, P. S., Atkinson, D. L., Keating, M. T. <strong>Coassembly of K(v)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel.</strong> Nature 384: 80-83, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900283</a>] [<a href="https://doi.org/10.1038/384080a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8900283">Sanguinetti et al. (1996)</a> transfected KVLQT1 cDNA into Chinese hamster ovary (CHO) cells. The biophysical properties of the transfected KVLQT1 cDNA clone were unlike those of other known cardiac potassium channels. Through cotransfection studies, they demonstrated that KVLQT1 and ISK (KCNE1; <a href="/entry/176261">176261</a>) coassemble to form the cardiac I(Ks) channel. They noted that 2 delayed-rectifier potassium channels, I(Kr) and I(Ks), modulate action potential duration in cardiac myocytes and that dysfunction of both of the channels contributes to the risk of sudden death from cardiac arrhythmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8900283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Barhanin, J., Lesage, F., Guillemare, E., Fink, M., Lazdunski, M., Romey, G. <strong>K(v)LQT1 and IsK (minK) proteins associate to form the I(Ks) cardiac potassium current.</strong> Nature 384: 78-80, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900282</a>] [<a href="https://doi.org/10.1038/384078a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8900282">Barhanin et al. (1996)</a> expressed KVLQT1 in COS cells and carried out electrophysiologic studies. They demonstrated that KVLQT1 encodes a subunit forming the cardiac ion channel underlying the I(Ks) cardiac current. They observed, however, that an additional subunit, ISK, was required to form the I(Ks) channel. <a href="#7" class="mim-tip-reference" title="Barhanin, J., Lesage, F., Guillemare, E., Fink, M., Lazdunski, M., Romey, G. <strong>K(v)LQT1 and IsK (minK) proteins associate to form the I(Ks) cardiac potassium current.</strong> Nature 384: 78-80, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900282</a>] [<a href="https://doi.org/10.1038/384078a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8900282">Barhanin et al. (1996)</a> noted that the I(Kr) and the I(Ks) currents are the targets of antiarrhythmic drugs and have an important impact in controlling the ventricular repolarization process. They postulated that the molecular identification of the I(Ks) channel should help with the design of new antiarrhythmic drugs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8900282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Expression of KVLQT1 in Xenopus oocytes and human embryonic kidney cells by <a href="#85" class="mim-tip-reference" title="Yang, W.-P., Levesque, P. C., Little, W. A., Conder, M. L., Shalaby, F. Y., Blanar, M. A. <strong>KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias.</strong> Proc. Nat. Acad. Sci. 94: 4017-4021, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9108097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9108097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9108097[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.8.4017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9108097">Yang et al. (1997)</a> elicited a rapidly activating, K(+)-selective outward current. They found that clofilium, a class III antiarrhythmic agent with the propensity to induce torsade de pointes, substantially inhibited the current. Elevation of cAMP levels in oocytes nearly doubled the amplitude of KVLQT1 currents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9108097" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Marx, S. O., Kurokawa, J., Reiken, S., Motoike, H., D'Armiento, J., Marks, A. R., Kass, R. S. <strong>Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel.</strong> Science 295: 496-499, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11799244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11799244</a>] [<a href="https://doi.org/10.1126/science.1066843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11799244">Marx et al. (2002)</a> demonstrated that beta-adrenergic receptor modulation of the slow outward potassium ion current (I-KS) requires targeting of cAMP-dependent protein kinase A (<a href="/entry/188830">188830</a>) and protein phosphatase 1 (PP1; e.g., <a href="/entry/176875">176875</a>) to KCNQ1 through the targeting protein yotiao (<a href="/entry/604001">604001</a>). Yotiao binds to KCNQ1 by a leucine zipper motif, which is disrupted by an LQTS mutation (KCNQ1-G589D; <a href="#0029">607542.0029</a>). Identification of the KCNQ1 macromolecular complex provides a mechanism for sympathetic nervous system modulation of cardiac action potential duration through I-KS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11799244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Melman, Y. F., Um, S. Y., Krumerman, A., Kagan, A., McDonald, T. V. <strong>KCNE1 binds to the KCNQ1 pore to regulate potassium channel activity.</strong> Neuron 42: 927-937, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15207237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15207237</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.06.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15207237">Melman et al. (2004)</a> showed that multiple segments of KCNQ1, including the pore and C terminus, bind the accessory proteins KCNE1 and KCNE3 (<a href="/entry/604433">604433</a>). They demonstrated that all KCNE-binding sites of KCNQ1 are required for proper regulation by the accessory subunit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15207237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To resolve the controversy about messengers regulating KCNQ ion channels during phospholipase C (see <a href="/entry/600810">600810</a>)-mediated suppression of current, <a href="#74" class="mim-tip-reference" title="Suh, B.-C., Inoue, T., Meyer, T., Hille, B. <strong>Rapid chemically induced changes of PtdIns(4,5)P(2) gate KCNQ ion channels.</strong> Science 314: 1454-1457, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16990515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16990515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16990515[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1131163" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16990515">Suh et al. (2006)</a> designed translocatable enzymes that quickly altered the phosphoinositide composition of the plasma membrane after application of a chemical cue. The KCNQ current fell rapidly to zero when phosphatidylinositol 4,5-bisphosphate was depleted without changing calcium ion, diacylglycerol, or inositol 1,4,5-trisphosphate. Current rose by 30% when phosphatidylinositol 4,5-bisphosphate was overproduced and did not change when phosphatidylinositol 3,4,5-trisphosphate was raised. Hence <a href="#74" class="mim-tip-reference" title="Suh, B.-C., Inoue, T., Meyer, T., Hille, B. <strong>Rapid chemically induced changes of PtdIns(4,5)P(2) gate KCNQ ion channels.</strong> Science 314: 1454-1457, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16990515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16990515</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16990515[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1131163" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16990515">Suh et al. (2006)</a> concluded that the depletion of phosphatidylinositol 4,5-bisphosphate suffices to suppress current fully, and other second messengers are not needed. Furthermore, their development of these new compounds allowed additional study of biologic signaling networks involving membrane phosphoinositides. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16990515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#63" class="mim-tip-reference" title="Roepke, T. K., King, E. C., Reyna-Neyra, A., Paroder, M., Purtell, K., Koba, W., Fine, E., Lerner, D. J., Carrasco, N., Abbott, G. W. <strong>Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis.</strong> Nature Med. 15: 1186-1194, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19767733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19767733</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19767733[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19767733">Roepke et al. (2009)</a> demonstrated that both KCNQ1 and KCNE2 (<a href="/entry/603796">603796</a>) were expressed and partially colocalized in human and mouse thyroid glands with the basolaterally located Na(+)/I(-) symporter (NIS) that mediates active I(-) transport, the first step in thyroid hormone biosynthesis. Using the rat thyroid-derived FRTL5 cell line, the authors detected endogenous expression of KCNQ1 and KCNE2 proteins that was upregulated by thyroid-stimulating hormone (TSH; see <a href="/entry/188540">188540</a>) or its major downstream effector cAMP in the cell membrane fraction. The authors identified a TSH-stimulated K(+) current in FRTL5 cells that bore the signature linear current-voltage relationship of KCNQ1-KCNE2 channels and was inhibited by a KCNQ1-specific antagonist. Kcne2 -/- pups nursing from Kcne2 -/- dams had an 87% reduction in thyroid I(-) accumulation compared to wildtype pups. <a href="#63" class="mim-tip-reference" title="Roepke, T. K., King, E. C., Reyna-Neyra, A., Paroder, M., Purtell, K., Koba, W., Fine, E., Lerner, D. J., Carrasco, N., Abbott, G. W. <strong>Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis.</strong> Nature Med. 15: 1186-1194, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19767733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19767733</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19767733[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19767733">Roepke et al. (2009)</a> concluded that the potassium channel subunits KCNQ1 and KCNE2 form a TSH-stimulated constitutively active thyrocyte K(+) channel that is required for normal thyroid hormone biosynthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19767733" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#55" class="mim-tip-reference" title="Osteen, J. D., Gonzalez, C., Sampson, K. J., Iyer, V., Rebolledo, S., Larsson, H. P., Kass, R. S. <strong>KCNE1 alters the voltage sensor movements necessary to open the KCNQ1 channel gate.</strong> Proc. Nat. Acad. Sci. 107: 22710-22715, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21149716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21149716</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21149716[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1016300108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21149716">Osteen et al. (2010)</a> found that coexpression of KCNE1 with KCNQ1 in Xenopus oocytes separated voltage dependence of KCNQ1/KCNE1 potassium channel opening and movement, suggesting an imposed requirement for movement of multiple voltage sensors before channel opening. Multiple separate voltage sensor movements were not needed to activate KCNQ1 alone. The results indicated that KCNE1 modulates KCNQ1 to slow down activation of the KCNQ1/KCNE1 channel by altering the voltage sensor movements necessary to open the channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21149716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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Discrepancies in the codon numbers of the allelic variants exist because of changes in information about the sequence of KCNQ1. <a href="#85" class="mim-tip-reference" title="Yang, W.-P., Levesque, P. C., Little, W. A., Conder, M. L., Shalaby, F. Y., Blanar, M. A. <strong>KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias.</strong> Proc. Nat. Acad. Sci. 94: 4017-4021, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9108097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9108097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9108097[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.8.4017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9108097">Yang et al. (1997)</a> demonstrated that the full-length KCNQ1 cDNA codes for 676 amino acids. Thus, for example, the A341V mutation (<a href="#0010">607542.0010</a>), one of the most frequent causes of type 1 long QT syndrome (<a href="/entry/192500">192500</a>), was denoted A212V by <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> and A246V by <a href="#39" class="mim-tip-reference" title="Li, H., Chen, Q., Moss, A. J., Robinson, J., Goytia, V., Perry, J. C., Vincent, G. M., Priori, S. G., Lehmann, M. H., Denfield, S. W., Duff, D., Kaine, S., Shimizu, W., Schwartz, P. J., Wang, Q., Towbin, J. A. <strong>New mutations in the KVLQT1 potassium channel that cause long QT syndrome.</strong> Circulation 97: 1264-1269, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9570196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9570196</a>] [<a href="https://doi.org/10.1161/01.cir.97.13.1264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9570196">Li et al. (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9108097+9570196+8528244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> found KVLQT1 mutations in affected members of 16 families with long QT syndrome-1, including 1 intragenic deletion (<a href="#0001">607542.0001</a>) and 10 different missense mutations (<a href="#0002">607542.0002</a>-<a href="#0011">607542.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#68" class="mim-tip-reference" title="Shalaby, F. Y., Levesque, P. C., Yang, W.-P., Little, W. A., Conder, M. L., Jenkins-West, T., Blanar, M. A. <strong>Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome.</strong> Circulation 96: 1733-1736, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9323054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9323054</a>] [<a href="https://doi.org/10.1161/01.cir.96.6.1733" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9323054">Shalaby et al. (1997)</a> used site-directed mutagenesis to generate 3 mutant human KVLQT1 cDNAs, equivalent to mutations previously described by <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a>. The corresponding mutant KVLQT1 proteins were coexpressed in Xenopus oocytes with wildtype KVLQT1 and minK (<a href="/entry/176261">176261</a>) proteins. Channel currents were studied using a voltage clamp technique. <a href="#68" class="mim-tip-reference" title="Shalaby, F. Y., Levesque, P. C., Yang, W.-P., Little, W. A., Conder, M. L., Jenkins-West, T., Blanar, M. A. <strong>Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome.</strong> Circulation 96: 1733-1736, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9323054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9323054</a>] [<a href="https://doi.org/10.1161/01.cir.96.6.1733" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9323054">Shalaby et al. (1997)</a> showed that mutations in the putative cytoplasmic loop (e.g., <a href="#0002">607542.0002</a>) and pore signature sequence (e.g., <a href="#0008">607542.0008</a>) abolished KVLQT1 activity when expressed individually. A mutation in the transmembrane region (e.g., <a href="#0006">607542.0006</a>) significantly reduced KVLQT1 activity. When coexpressed with wildtype KVLQT1 protein with or without minK protein, each mutant exerted a dominant-negative effect on the wildtype KVLQT1 current. <a href="#68" class="mim-tip-reference" title="Shalaby, F. Y., Levesque, P. C., Yang, W.-P., Little, W. A., Conder, M. L., Jenkins-West, T., Blanar, M. A. <strong>Dominant-negative KvLQT1 mutations underlie the LQT1 form of long QT syndrome.</strong> Circulation 96: 1733-1736, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9323054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9323054</a>] [<a href="https://doi.org/10.1161/01.cir.96.6.1733" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9323054">Shalaby et al. (1997)</a> concluded that in patients carrying such mutant alleles, diminution in the repolarizing I(ks) current would result in prolongation of the cardiac action potential and predispose to cardiac arrhythmias. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8528244+9323054" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#64" class="mim-tip-reference" title="Russell, M. W., Dick, M., II, Collins, F. S., Brody, L. C. <strong>KVLQT1 mutations in three families with familial or sporadic long QT syndrome.</strong> Hum. Molec. Genet. 5: 1319-1324, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8872472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8872472</a>] [<a href="https://doi.org/10.1093/hmg/5.9.1319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8872472">Russell et al. (1996)</a> used SSCP analysis to screen 2 large and 9 small LQT families for mutations of the KVLQT1 potassium channel gene. They identified a novel missense mutation in 2 unrelated families: a gly314-to-ser substitution (<a href="#0012">607542.0012</a>) in the KVLQT1 gene. In a third family, an ala341-to-val substitution (<a href="#0010">607542.0010</a>) resulted in the spontaneous occurrence of LQT in monozygotic twin offspring of unaffected parents. <a href="#64" class="mim-tip-reference" title="Russell, M. W., Dick, M., II, Collins, F. S., Brody, L. C. <strong>KVLQT1 mutations in three families with familial or sporadic long QT syndrome.</strong> Hum. Molec. Genet. 5: 1319-1324, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8872472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8872472</a>] [<a href="https://doi.org/10.1093/hmg/5.9.1319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8872472">Russell et al. (1996)</a> noted that mutations at this same nucleotide had been observed in 8 of 19 LQT families determined to have KVLQT1 mutations to that time, suggesting a mutation hotspot. Both of the mutations reported in this study occurred at CpG dinucleotides. <a href="#64" class="mim-tip-reference" title="Russell, M. W., Dick, M., II, Collins, F. S., Brody, L. C. <strong>KVLQT1 mutations in three families with familial or sporadic long QT syndrome.</strong> Hum. Molec. Genet. 5: 1319-1324, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8872472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8872472</a>] [<a href="https://doi.org/10.1093/hmg/5.9.1319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8872472">Russell et al. (1996)</a> observed that both of the mutations alter the amino acid sequence in, or adjacent to, the pore of the channel and may diminish the channel's ability to conduct a repolarizing potassium current. <a href="#64" class="mim-tip-reference" title="Russell, M. W., Dick, M., II, Collins, F. S., Brody, L. C. <strong>KVLQT1 mutations in three families with familial or sporadic long QT syndrome.</strong> Hum. Molec. Genet. 5: 1319-1324, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8872472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8872472</a>] [<a href="https://doi.org/10.1093/hmg/5.9.1319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8872472">Russell et al. (1996)</a> reported that their data confirm the role of KVLQT1 in LQT. They noted that all the KVLQT1 mutations reported to that time were missense mutations and suggested that mutant KVLQT1 proteins may exert a dominant-negative effect on repolarizing potassium currents by forming multimers with normal potassium channel protein subunits, dramatically reducing the number of fully functional KVLQT1 channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8872472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 32 Japanese families with LQT, <a href="#75" class="mim-tip-reference" title="Tanaka, T., Nagai, R., Tomoike, H., Takata, S., Yano, K., Yabuta, K., Haneda, N., Nakano, O., Shibata, A., Sawayama, T., Kasai, H., Yazaki, Y., Nakamura, Y. <strong>Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome.</strong> Circulation 95: 565-567, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9024139/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9024139</a>] [<a href="https://doi.org/10.1161/01.cir.95.3.565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9024139">Tanaka et al. (1997)</a> identified mutations in KCNQ1 in 4 families comprising 16 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9024139" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Jongbloed, R. J. E., Wilde, A. A. M., Geelen, J. L. M. C., Doevendans, P., Schaap, C., Van Langen, I., van Tintelen, J. P., Cobben, J. M., Beaufort-Krol, G. C. M., Geraedts, J. P. M., Smeets, H. J. M. <strong>Novel KCNQ1 and HERG missense mutations in Dutch long-QT families.</strong> Hum. Mutat. 13: 301-310, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220144</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:4<301::AID-HUMU7>3.0.CO;2-V" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220144">Jongbloed et al. (1999)</a> screened 24 Dutch LQTS families for mutations in the KCNQ1 and HERG genes. Fourteen missense mutations were identified. Eight of these missense mutations were novel: 3 in the KCNQ1 gene and 5 in the HERG gene. The KCNQ1 mutation G189R (<a href="#0003">607542.0003</a>) and the novel HERG mutation R582C (<a href="#0009">607542.0009</a>) were detected in 2 families each. Genotype-phenotype studies indicated that auditory stimuli trigger cardiac events differentiating LQTS2 from LQTS1. In LQTS1, exercise was the predominant trigger. In addition, a number of asymptomatic gene defect carriers were identified. <a href="#32" class="mim-tip-reference" title="Jongbloed, R. J. E., Wilde, A. A. M., Geelen, J. L. M. C., Doevendans, P., Schaap, C., Van Langen, I., van Tintelen, J. P., Cobben, J. M., Beaufort-Krol, G. C. M., Geraedts, J. P. M., Smeets, H. J. M. <strong>Novel KCNQ1 and HERG missense mutations in Dutch long-QT families.</strong> Hum. Mutat. 13: 301-310, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220144</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:4<301::AID-HUMU7>3.0.CO;2-V" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220144">Jongbloed et al. (1999)</a> concluded that asymptomatic carriers are still at risk of the development of life-threatening arrhythmias, underlining the importance of DNA analysis for unequivocal diagnosis of patients with LQTS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10220144" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#52" class="mim-tip-reference" title="Neyroud, N., Richard, P., Vignier, N., Donger, C., Denjoy, I., Demay, L., Shkolnikova, M., Pesce, R., Chevalier, P., Hainque, B., Coumel, P., Schwartz, K., Guicheney, P. <strong>Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome.</strong> Circ. Res. 84: 290-297, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10024302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10024302</a>] [<a href="https://doi.org/10.1161/01.res.84.3.290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10024302">Neyroud et al. (1999)</a> identified 5 novel mutations in LQTS patients within the C-terminal part of KCNQ1 (see <a href="#0025">607542.0025</a>, <a href="#0026">607542.0026</a>, and <a href="#0027">607542.0027</a>). <a href="#52" class="mim-tip-reference" title="Neyroud, N., Richard, P., Vignier, N., Donger, C., Denjoy, I., Demay, L., Shkolnikova, M., Pesce, R., Chevalier, P., Hainque, B., Coumel, P., Schwartz, K., Guicheney, P. <strong>Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome.</strong> Circ. Res. 84: 290-297, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10024302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10024302</a>] [<a href="https://doi.org/10.1161/01.res.84.3.290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10024302">Neyroud et al. (1999)</a> commented that the low mutation detection rate in large cohorts of LQTS patients may reflect the fact that the C-terminal region had not been analyzed to that time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10024302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>A comprehensive review of the genetic and molecular basis of long QT syndromes was given by Priori et al. (<a href="#59" class="mim-tip-reference" title="Priori, S. G., Barhanin, J., Hauer, R. N. W., Haverkamp, W., Jongsma, H. J., Kleber, A. G., McKenna, W. J., Roden, D. M., Rudy, Y., Schwartz, K., Schwartz, P. J., Towbin, J. A., Wilde, A. M. <strong>Genetic and molecular basis of cardiac arrhythmias: impact on clinical management. Parts I and II.</strong> Circulation 99: 518-528, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9927398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9927398</a>] [<a href="https://doi.org/10.1161/01.cir.99.4.518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9927398">1999</a>, <a href="#58" class="mim-tip-reference" title="Priori, S. G., Barhanin, J., Hauer, R. N. W., Haverkamp, W., Jongsma, H. J., Kleber, A. G., McKenna, W. J., Roden, D. M., Rudy, Y., Schwartz, K., Schwartz, P. J., Towbin, J. A., Wilde, A. M. <strong>Genetic and molecular basis of cardiac arrhythmias: impact on clinical management. Part III.</strong> Circulation 99: 674-681, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9950666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9950666</a>] [<a href="https://doi.org/10.1161/01.cir.99.5.674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9950666">1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9950666+9927398" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 severely affected sisters from a large Belgian family with LQTS, <a href="#11" class="mim-tip-reference" title="Berthet, M., Denjoy, I., Donger, C., Demay, L., Hammoude, H., Klug, D., Schulze-Bahr, E., Richard, P., Funke, H., Schwartz, K., Coumel, P., Hainque, B., Guicheney, P. <strong>C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.</strong> Circulation 99: 1464-1470, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10086971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10086971</a>] [<a href="https://doi.org/10.1161/01.cir.99.11.1464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10086971">Berthet et al. (1999)</a> identified biallelic digenic mutations: a missense mutation in the KCNQ1 gene (A341E; <a href="#0009">607542.0009</a>) and a splice site mutation in the KCNH2 gene (2592+1G-A; <a href="/entry/152427#0019">152427.0019</a>). <a href="#11" class="mim-tip-reference" title="Berthet, M., Denjoy, I., Donger, C., Demay, L., Hammoude, H., Klug, D., Schulze-Bahr, E., Richard, P., Funke, H., Schwartz, K., Coumel, P., Hainque, B., Guicheney, P. <strong>C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.</strong> Circulation 99: 1464-1470, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10086971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10086971</a>] [<a href="https://doi.org/10.1161/01.cir.99.11.1464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10086971">Berthet et al. (1999)</a> stated that this was the first description of double heterozygosity in long QT syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10086971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#71" class="mim-tip-reference" title="Splawski, I., Shen, J., Timothy, K. W., Lehmann, M. H., Priori, S., Robinson, J. L., Moss, A. J., Schwartz, P. J., Towbin, J. A., Vincent, G. M., Keating, M. T. <strong>Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.</strong> Circulation 102: 1178-1185, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973849</a>] [<a href="https://doi.org/10.1161/01.cir.102.10.1178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973849">Splawski et al. (2000)</a> screened 262 unrelated individuals with LQT syndrome for mutations in the 5 defined genes (KCNQ1; KCNH2, <a href="/entry/152427">152427</a>; SCN5A, <a href="/entry/600163">600163</a>; KCNE1; and KCNE2) and identified mutations in 177 individuals (68%). KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%, respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%, 3%, and 2%, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10973849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#84" class="mim-tip-reference" title="Yang, P., Kanki, H., Drolet, B., Yang, T., Wei, J., Viswanathan, P. C., Hohnloser, S. H., Shimizu, W., Schwartz, P. J., Stanton, M., Murray, K. T., Norris, K., George, A. L., Jr., Roden, D. M. <strong>Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.</strong> Circulation 105: 1943-1948, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11997281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11997281</a>] [<a href="https://doi.org/10.1161/01.cir.0000014448.19052.4c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11997281">Yang et al. (2002)</a> analyzed the KCNQ1, KCNH2, and SCN5A genes in 92 patients with drug-induced long QT syndrome and identified 2 missense mutations, 1 in KCNQ1 (<a href="#0031">607542.0031</a>) and 1 in KCNH2 (<a href="/entry/152427#0014">152427.0014</a>), not found in 228 controls, that were shown to reduce K+ currents in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11997281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 13-year-old girl with long QT syndrome, <a href="#5" class="mim-tip-reference" title="Aizawa, Y., Ueda, K., Wu, L., Inagaki, N., Hayashi, T., Takahashi, M., Ohta, M., Kawano, S., Hirano, Y., Yasunami, M., Aizawa, Y., Kimura, A., Hiraoka, M. <strong>Truncated KCNQ1 mutant, A178fs/105, forms hetero-multimer channel with wild-type causing a dominant-negative suppression due to trafficking defect.</strong> FEBS Lett. 574: 145-150, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15358555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15358555</a>] [<a href="https://doi.org/10.1016/j.febslet.2004.08.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15358555">Aizawa et al. (2004)</a> identified a frameshift mutation in the KCNQ1 gene (<a href="#0036">607542.0036</a>) that eliminates the S3 to S6 domains and the C terminus of the KCNQ1 channel. Coexpression experiments in COS-7 cells showed that mutant and wildtype KCNQ1 remained within the cytoplasm rather than being distributed to the plasma membrane. <a href="#5" class="mim-tip-reference" title="Aizawa, Y., Ueda, K., Wu, L., Inagaki, N., Hayashi, T., Takahashi, M., Ohta, M., Kawano, S., Hirano, Y., Yasunami, M., Aizawa, Y., Kimura, A., Hiraoka, M. <strong>Truncated KCNQ1 mutant, A178fs/105, forms hetero-multimer channel with wild-type causing a dominant-negative suppression due to trafficking defect.</strong> FEBS Lett. 574: 145-150, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15358555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15358555</a>] [<a href="https://doi.org/10.1016/j.febslet.2004.08.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15358555">Aizawa et al. (2004)</a> suggested that the truncated mutant forms a heteromultimer with wildtype KCNQ1 and causes a dominant-negative effect due to a trafficking defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15358555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#76" class="mim-tip-reference" title="Tester, D. J., Will, M. L., Haglund, C. M., Ackerman, M. J. <strong>Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.</strong> Heart Rhythm 2: 507-517, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15840476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15840476</a>] [<a href="https://doi.org/10.1016/j.hrthm.2005.01.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15840476">Tester et al. (2005)</a> analyzed 5 LQTS-associated cardiac channel genes in 541 consecutive unrelated patients with LQT syndrome (average QTc, 482 ms). In 272 (50%) patients, they identified 211 different pathogenic mutations, including 88 in KCNQ1, 89 in KCNH2, 32 in SCN5A, and 1 each in KCNE1 and KCNE2. Mutations considered pathogenic were absent in more than 1,400 reference alleles. Among the mutation-positive patients, 29 (11%) had 2 LQTS-causing mutations, of which 16 (8%) were in 2 different LQTS genes (biallelic digenic). <a href="#76" class="mim-tip-reference" title="Tester, D. J., Will, M. L., Haglund, C. M., Ackerman, M. J. <strong>Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.</strong> Heart Rhythm 2: 507-517, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15840476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15840476</a>] [<a href="https://doi.org/10.1016/j.hrthm.2005.01.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15840476">Tester et al. (2005)</a> noted that patients with multiple mutations were younger at diagnosis, but they did not discern any genotype/phenotype correlations associated with location or type of mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15840476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#50" class="mim-tip-reference" title="Napolitano, C., Priori, S. G., Schwartz, P. J., Bloise, R., Ronchetti, E., Nastoli, J., Bottelli, G., Cerrone, M., Leonardi, S. <strong>Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice.</strong> JAMA 294: 2975-2980, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16414944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16414944</a>] [<a href="https://doi.org/10.1001/jama.294.23.2975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16414944">Napolitano et al. (2005)</a> screened the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 430 consecutive patients with LQT syndrome and identified 235 different mutations in 310 (72%) of the patients, 49% of whom had mutations in KCNQ1, 39% in KCNH2, 10% in SCN5A, 1.7% in KCNE1, and 0.7% in KCNE2. Fourteen (4.5%) of the patients carried more than 1 mutation in a gene. Fifty-eight percent of probands carried nonprivate mutations in 64 codons of the KCNQ1, KCNH2, and SCN5A genes; screening in a prospective cohort of 75 probands confirmed the occurrence of mutations at these codons (52%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16414944" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 44 unrelated patients with LQT syndrome, <a href="#45" class="mim-tip-reference" title="Millat, G., Chevalier, P., Restier-Miron, L., Da Costa, A., Bouvagnet, P., Kugener, B., Fayol, L., Gonzalez Armengod, C., Oddou, B., Chanavat, V., Froidefond, E., Perraudin, R., Rousson, R., Rodriguez-Lafrasse, C. <strong>Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.</strong> Clin. Genet. 70: 214-227, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16922724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16922724</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00671.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16922724">Millat et al. (2006)</a> used DHLP chromatography to analyze the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes for mutations and SNPs. Most of the patients (84%) showed a complex molecular pattern, with an identified mutation associated with 1 or more SNPs located in several LQTS genes; 4 of the patients also had a second mutation in a different LQTS gene (biallelic digenic inheritance; see, e.g., <a href="#0038">607542.0038</a> and <a href="#0039">607542.0039</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Arbour, L., Rezazadeh, S., Eldstrom, J., Weget-Simms, G., Rupps, R., Dyer, Z., Tibbits, G., Accili, E., Casey, B., Kmetic, A., Sanatani, S., Fedida, D. <strong>A KCNQ1 V205M missense mutation causes a high rate of long QT syndrome in a First Nations community of northern British Columbia: a community-based approach to understanding the impact.</strong> Genet. Med. 10: 545-550, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18580685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18580685</a>] [<a href="https://doi.org/10.1097/gim.0b013e31817c6b19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18580685">Arbour et al. (2008)</a> identified a missense mutation (<a href="#0040">607542.0040</a>) causing long QT syndrome-1 among a First Nations community of northern British Columbia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18580685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Jervell and Lange-Nielsen Syndrome 1</em></strong></p><p>
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<a href="#53" class="mim-tip-reference" title="Neyroud, N., Tesson, F., Denjoy, I., Leibovici, M., Donger, C., Barhanin, J., Faure, S., Gary, F., Coumel, P., Petit, C., Schwartz, K., Guicheney, P. <strong>A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome.</strong> Nature Genet. 15: 186-189, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020846</a>] [<a href="https://doi.org/10.1038/ng0297-186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020846">Neyroud et al. (1997)</a> used homozygosity mapping to locate the gene for the Jervell and Lange-Nielsen cardioauditory syndrome (JLNS1; <a href="/entry/220400">220400</a>) to the same region of 11p15.5 where the KVLQT1 gene maps. In 3 affected children of 2 families with the disorder, they demonstrated homozygosity for a deletion-insertion mutation in the C-terminal domain of the KVLQT1 gene (<a href="#0013">607542.0013</a>). They noted that this is another instance of dominant or recessive inheritance of disorders due to different mutations in the same gene. <a href="#66" class="mim-tip-reference" title="Schmitt, N., Schwarz, M., Peretz, A., Abitbol, I., Attali, B., Pongs, O. <strong>A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly.</strong> EMBO J. 19: 332-340, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10654932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10654932</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10654932[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/emboj/19.3.332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10654932">Schmitt et al. (2000)</a> identified a small domain between residues 589 and 620 in the KCNQ1 C terminus that may function as an assembly domain for KCNQ1 subunits. KCNQ1 C termini do not assemble and KCNQ1 subunits do not express functional potassium channels without this domain. The authors showed that the deletion-insertion mutation at KCNQ1 residue 540 identified by <a href="#53" class="mim-tip-reference" title="Neyroud, N., Tesson, F., Denjoy, I., Leibovici, M., Donger, C., Barhanin, J., Faure, S., Gary, F., Coumel, P., Petit, C., Schwartz, K., Guicheney, P. <strong>A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome.</strong> Nature Genet. 15: 186-189, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020846</a>] [<a href="https://doi.org/10.1038/ng0297-186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020846">Neyroud et al. (1997)</a> eliminated important parts of the C-terminal assembly domain. Therefore, JLNS mutants may be defective in KCNQ1 subunit assembly. The results provided a molecular basis for the clinical observation that heterozygous JLNS carriers show slight cardiac dysfunction and that the severe JLNS phenotype is characterized by the absence of the KCNQ1 channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10654932+9020846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#77" class="mim-tip-reference" title="Tyson, J., Tranebjaerg, L., McEntagart, M., Larsen, L. A., Christiansen, M., Whiteford, M. L., Bathen, J., Aslaksen, B., Sorland, S. J., Lund, O., Pembrey, M. E., Malcolm, S., Bitner-Glindzicz, M. <strong>Mutational spectrum in the cardioauditory syndrome of Jervell and Lange-Nielsen.</strong> Hum. Genet. 107: 499-503, 2000. Note: Erratum: Hum. Genet. 108: 75 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11140949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11140949</a>] [<a href="https://doi.org/10.1007/s004390000402" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11140949">Tyson et al. (2000)</a> studied 10 JLNS families from Great Britain and Norway and identified 9 different mutations in the KCNQ1 gene, 2 of which were novel. Truncation of the protein proximal to the C-terminal assembly domain was expected to preclude assembly of KCNQ1 monomers into tetramers, explaining the recessive inheritance of JLNS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11140949" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Atrial Fibrillation 3</em></strong></p><p>
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<a href="#18" class="mim-tip-reference" title="Chen, Y.-H., Xu, S.-J., Bendahhou, S., Wang, X.-L., Wang, Y., Xu, W.-Y., Jin, H.-W., Sun, H., Su, X.-Y., Zhuang, Q.-N., Yang, Y.-Q., Li, Y.-B., Liu, Y., Xu, H.-J., Li, X.-F., Ma, N., Mou, C.-P., Chen, Z., Barhanin, J., Huang, W. <strong>KCNQ1 gain-of-function mutation in familial atrial fibrillation.</strong> Science 299: 251-254, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522251</a>] [<a href="https://doi.org/10.1126/science.1077771" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522251">Chen et al. (2003)</a> identified a ser140-to-gly missense mutation (<a href="#0032">607542.0032</a>) in the KCNQ1 gene in affected members of a Chinese family with autosomal dominant atrial fibrillation (ATFB3; <a href="/entry/607554">607554</a>). Functional analysis of this mutant revealed a gain-of-function effect on the KCNQ1/KCNE1 and KCNQ1/KCNE2 currents, which contrasts with the dominant-negative or loss-of-function effects of the KCNQ1 mutations previously identified in patients with long QT syndrome. <a href="#18" class="mim-tip-reference" title="Chen, Y.-H., Xu, S.-J., Bendahhou, S., Wang, X.-L., Wang, Y., Xu, W.-Y., Jin, H.-W., Sun, H., Su, X.-Y., Zhuang, Q.-N., Yang, Y.-Q., Li, Y.-B., Liu, Y., Xu, H.-J., Li, X.-F., Ma, N., Mou, C.-P., Chen, Z., Barhanin, J., Huang, W. <strong>KCNQ1 gain-of-function mutation in familial atrial fibrillation.</strong> Science 299: 251-254, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522251</a>] [<a href="https://doi.org/10.1126/science.1077771" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522251">Chen et al. (2003)</a> concluded that the ser140-to-gly mutation is likely to initiate and maintain atrial fibrillation by reducing action potential duration and effective refractory period in atrial myocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12522251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Johnson, J. N., Tester, D. J., Perry, J., Salisbury, B. A., Reed, C. R., Ackerman, M. J. <strong>Prevalence of early-onset atrial fibrillation in congenital long QT syndrome.</strong> Heart Rhythm 5: 704-709, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18452873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18452873</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18452873[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.hrthm.2008.02.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18452873">Johnson et al. (2008)</a> reported a female patient with onset of atrial fibrillation in the first year of life who was heterozygous for a missense mutation in the KCNQ1 gene (R231H; <a href="#0043">607542.0043</a>). The patient was also found to have a long QT interval at 1 year of age, with a QTc of 479 ms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18452873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a 3-generation family with lone atrial fibrillation, <a href="#20" class="mim-tip-reference" title="Das, S., Makino, S., Melman, Y. F., Shea, M. A., Goyal, S. B., Rosenzweig, A., MacRae, C. A., Ellinor, P. T. <strong>Mutation in the S3 segment of KCNQ1 results in familial lone atrial fibrillation.</strong> Heart Rhythm 6: 1146-1153, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19632626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19632626</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19632626[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.hrthm.2009.04.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19632626">Das et al. (2009)</a> identified heterozygosity for a missense mutation in the KCNQ1 gene (S209P; <a href="#0042">607542.0042</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19632626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a cohort of 231 patients with atrial fibrillation, <a href="#1" class="mim-tip-reference" title="Abraham, R. L., Yang, T., Blair, M., Roden, D. M., Darbar, D. <strong>Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation.</strong> J. Molec. Cell. Cardiol. 48: 181-190, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19646991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19646991</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19646991[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.yjmcc.2009.07.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19646991">Abraham et al. (2010)</a> analyzed the KCNQ1 and NPPA (<a href="/entry/108780">108780</a>) genes and identified heterozygosity for a 9-bp duplication in KCNQ1 (<a href="#0041">607542.0041</a>) in the proband of a Caucasian kindred with early-onset lone atrial fibrillation; the duplication segregated with disease in the family. <a href="#1" class="mim-tip-reference" title="Abraham, R. L., Yang, T., Blair, M., Roden, D. M., Darbar, D. <strong>Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation.</strong> J. Molec. Cell. Cardiol. 48: 181-190, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19646991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19646991</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19646991[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.yjmcc.2009.07.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19646991">Abraham et al. (2010)</a> also identified a missense mutation in the NPPA gene (<a href="/entry/108780#0002">108780.0002</a>) in another family with atrial fibrillation (ATFB6; <a href="/entry/602201">602201</a>) in the cohort; functional analysis revealed strikingly similar gain-of-function defects associated with the mutants, with atrial action potential shortening and altered calcium current as a common mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19646991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 4 families with early-onset atrial fibrillation, <a href="#9" class="mim-tip-reference" title="Bartos, D. C., Anderson, J. B., Bastiaenen, R., Johnson, J. N., Gollob, M. H., Tester, D. J., Burgess, D. E., Homfray, T., Behr, E. R., Ackerman, M. J., Guicheney, P., Delisle, B. P. <strong>A KCNQ1 mutation causes a high penetrance for familial atrial fibrillation.</strong> J. Cardiovasc. Electrophysiol. 24: 562-569, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23350853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23350853</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23350853[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/jce.12068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23350853">Bartos et al. (2013)</a> identified heterozygosity for the R231H mutation in KCNQ1. Twelve of 13 mutation-positive individuals had a normal QTc, and 1 had a prolonged QT interval. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23350853" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a family with atrial fibrillation, <a href="#27" class="mim-tip-reference" title="Guerrier, K., Czosek, R. J., Spar, D. S., Anderson, J. <strong>Long QT genetics manifesting as atrial fibrillation.</strong> Heart Rhythm 10: 1351-1353, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23851063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23851063</a>] [<a href="https://doi.org/10.1016/j.hrthm.2013.07.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23851063">Guerrier et al. (2013)</a> identified heterozygosity for the R231H missense mutation in KCNQ1. <a href="#27" class="mim-tip-reference" title="Guerrier, K., Czosek, R. J., Spar, D. S., Anderson, J. <strong>Long QT genetics manifesting as atrial fibrillation.</strong> Heart Rhythm 10: 1351-1353, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23851063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23851063</a>] [<a href="https://doi.org/10.1016/j.hrthm.2013.07.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23851063">Guerrier et al. (2013)</a> noted that the R231H mutation had previously been identified by <a href="#50" class="mim-tip-reference" title="Napolitano, C., Priori, S. G., Schwartz, P. J., Bloise, R., Ronchetti, E., Nastoli, J., Bottelli, G., Cerrone, M., Leonardi, S. <strong>Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice.</strong> JAMA 294: 2975-2980, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16414944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16414944</a>] [<a href="https://doi.org/10.1001/jama.294.23.2975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16414944">Napolitano et al. (2005)</a> in a study of patients with long QT syndrome, but stated that none of the family members with atrial fibrillation had documented prolonged QT intervals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23851063+16414944" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Hasegawa, K., Ohno, S., Ashihara, T., Itoh, H., Ding, W.-G., Toyoda, F., Makiyama, T., Aoki, H., Nakamura, Y., Delisle, B. P., Matsuura, H., Horie, M. <strong>A novel KCNQ1 missense mutation identified in a patient with juvenile-onset atrial fibrillation causes constitutively open I(Ks) channels.</strong> Heart Rhythm 11: 67-75, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24096004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24096004</a>] [<a href="https://doi.org/10.1016/j.hrthm.2013.09.073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24096004">Hasegawa et al. (2014)</a> screened 30 patients with juvenile-onset atrial fibrillation for mutations in the KCNQ1, KCNH2 (<a href="/entry/152427">152427</a>), KCNE1 (<a href="/entry/176261">176261</a>), KCNE2 (<a href="/entry/603796">603796</a>), KCNE3 (<a href="/entry/604433">604433</a>), KCNE5 (<a href="/entry/300328">300328</a>), KCNJ2 (<a href="/entry/600681">600681</a>), and SCN5A (<a href="/entry/600163">600163</a>) genes, and identified heterozygosity for a missense mutation in KCNQ1 (G229D; <a href="#0044">607542.0044</a>) in a Japanese boy who was diagnosed at 16 years of age with atrial fibrillation. At that time, ECG showed a normal QT interval, but he was later found to have borderline QT prolongation (QTc 452 ms to 480 ms). The mutation was also present in his asymptomatic mother, who also had borderline QT prolongation (QTc 468 ms). Functional analysis indicated that G229D causes constitutively open I(Ks) channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24096004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Short QT Syndrome 2</em></strong></p><p>
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In a 70-year-old man with short QT syndrome-2 (SQT2; <a href="/entry/609621">609621</a>) who survived an episode of ventricular fibrillation, <a href="#10" class="mim-tip-reference" title="Bellocq, C., van Ginneken, A. C. G., Bezzina, C. R., Alders, M., Escande, D., Mannens, M. M. A. M., Baro, I., Wilde, A. A. M. <strong>Mutation in the KCNQ1 gene leading to the short QT-interval syndrome.</strong> Circulation 109: 2394-2397, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15159330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15159330</a>] [<a href="https://doi.org/10.1161/01.CIR.0000130409.72142.FE" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15159330">Bellocq et al. (2004)</a> identified a missense mutation in the KCNQ1 gene (<a href="#0037">607542.0037</a>). Functional studies of the mutant channel revealed that both a pronounced shift of the half-activation potential and an acceleration of the activation kinetics led to a gain of function in I(Ks). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15159330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a female infant with short QT syndrome, atrial fibrillation (AF), and bradycardia <a href="#29" class="mim-tip-reference" title="Hong, K., Piper, D. R., Diaz-Valdecantos, A., Brugada, J., Oliva, A., Burashnikov, E., Santos-de-Soto, J., Grueso-Montero, J., Diaz-Enfante, E., Brugada, P., Sachse, F., Sanguinetti, M. C., Brugada, R. <strong>De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero.</strong> Cardiovasc. Res. 68: 433-440, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16109388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16109388</a>] [<a href="https://doi.org/10.1016/j.cardiores.2005.06.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16109388">Hong et al. (2005)</a> identified heterozygosity for a de novo missense mutation in the KCNQ1 gene (V141M; <a href="#0045">607542.0045</a>). Functional analysis in Xenopus oocytes demonstrated that in contrast to wildtype channels, which exhibited a slowly activating and deactivating voltage-dependent and K(+)-selective current, the V141M mutant channel current developed instantly at all voltages tested, consistent with a constitutively open channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16109388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated girls with short QT syndrome, AF, and bradycardia, <a href="#80" class="mim-tip-reference" title="Villafane, J., Fischbach, P., Gebauer, R. <strong>Short QT syndrome manifesting with neonatal atrial fibrillation and bradycardia.</strong> Cardiology 128: 236-240, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24818999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24818999</a>] [<a href="https://doi.org/10.1159/000360758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24818999">Villafane et al. (2014)</a> identified heterozygosity for the V141M mutation in the KCNQ1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24818999" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 23-year-old man with a slightly shortened QT interval, whose father had died unexpectedly at age 37 years, <a href="#46" class="mim-tip-reference" title="Moreno, C., Oliveras, A., de la Cruz, A., Bartolucci, C., Munoz, C., Salar, E., Gimeno, J. R., Severi, S., Comes, N., Felipe, A., Gonzalez, T., Lambiase, P., Valenzuela, C. <strong>A new KCNQ1 mutation at the S5 segment that impairs its association with KCNE1 is responsible for short QT syndrome.</strong> Cardiovasc. Res. 107: 613-623, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26168993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26168993</a>] [<a href="https://doi.org/10.1093/cvr/cvv196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26168993">Moreno et al. (2015)</a> identified heterozygosity for a missense mutation in the KCNQ1 gene (F279I; <a href="#0046">607542.0046</a>) that was not found in his unaffected sister or mother. Functional analysis showed a negative shift in the activation curve of mutant channels, with acceleration of the activation kinetics resulting in a gain of function in I(Ks). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26168993" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Imprinting</em></strong></p><p>
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Genomic imprinting is the process by which a subset of mammalian genes is 'marked' during gametogenesis such that they are expressed differentially in somatic cells depending on their parental origin. This mark may be differential methylation, because DNA methylation is necessary for the proper regulation of imprinted genes. Furthermore, some differentially methylated regions (DMRs) are thought to represent gametic imprints, because they are differentially methylated in male and female germ cells and remain so throughout development. The DMRs of most imprinted genes are associated with short, G-rich, direct repeat sequences, which may facilitate heterochromatization and gene silencing at imprinted loci. Another characteristic of imprinted genes is their association, in some cases, with imprinted antisense RNA transcripts. At the paternally expressed mouse and human IGF2 (<a href="/entry/147470">147470</a>) and ZPF127 loci, antisense transcripts that are also expressed paternally have been identified and overlap with the protein coding gene. For the maternally expressed IGF2R (<a href="/entry/147280">147280</a>) and UBE3A (<a href="/entry/601623">601623</a>) genes, overlapping antisense transcripts (see SNHG14, <a href="/entry/616259">616259</a>) have been found and are oppositely imprinted with respect to the protein coding gene. Antisense transcripts may serve to regulate overlapping genes by promoter or transcript occlusion or by competing with these loci for regulatory elements such as transcription factors or enhancers (<a href="#70" class="mim-tip-reference" title="Smilinich, N. J., Day, C. D., Fitzpatrick, G. V., Caldwell, G. M., Lossie, A. C., Cooper, P. R., Smallwood, A. C., Joyce, J. A., Schofield, P. N., Reik, W., Nicholls, R. D., Weksberg, R., Driscoll, D. J., Maher, E. R., Shows, T. B., Higgins, M. J. <strong>A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome.</strong> Proc. Nat. Acad. Sci. 96: 8064-8069, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10393948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10393948</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10393948[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.14.8064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10393948">Smilinich et al., 1999</a>). Imprinting control elements are proposed to exist within the KVLQT1 locus, because multiple chromosome rearrangements associated with Beckwith-Wiedemann syndrome (BWS; <a href="/entry/130650">130650</a>) disrupt this gene. The imprinting control regions on chromosome 11p15 associated with H19 (<a href="/entry/103280">103280</a>)/IGF2 and KCNQ1 are referred to as ICR1 (<a href="/entry/616186">616186</a>) and ICR2, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10393948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Lee, M. P., Hu, R.-J., Johnson, L. A., Feinberg, A. P. <strong>Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements.</strong> Nature Genet. 15: 181-185, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020845</a>] [<a href="https://doi.org/10.1038/ng0297-181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020845">Lee et al. (1997)</a> demonstrated that the KVLQT1 gene spans much of the interval between p57(KIP2) (CDKN1C; <a href="/entry/600856">600856</a>) and IGF2 and that, like those 2 genes, it is imprinted. They demonstrated, furthermore, that the KVLQT1 gene is disrupted by chromosomal rearrangements in patients with Beckwith-Wiedemann syndrome, as well as by a balanced chromosomal translocation in an embryonal rhabdoid tumor. They concluded that the lack of parent-of-origin effect in the long QT syndrome (<a href="/entry/192500">192500</a>) must reflect a relative lack of imprinting in the affected tissue, cardiac muscle, thereby representing a novel mechanism for incomplete penetrance of a human disease gene. <a href="#41" class="mim-tip-reference" title="Mannens, M., Wilde, A. <strong>KVLQT1, the rhythm of imprinting.</strong> Nature Genet. 15: 113-115, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020829</a>] [<a href="https://doi.org/10.1038/ng0297-113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020829">Mannens and Wilde (1997)</a> and <a href="#8" class="mim-tip-reference" title="Barlow, D. P. <strong>Box: KVLQT1 complexities in Beckwith-Wiedeman (sic) syndrome.</strong> Nature Genet. 15: 114 only, 1997."None>Barlow (1997)</a> discussed the findings of <a href="#36" class="mim-tip-reference" title="Lee, M. P., Hu, R.-J., Johnson, L. A., Feinberg, A. P. <strong>Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements.</strong> Nature Genet. 15: 181-185, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020845/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020845</a>] [<a href="https://doi.org/10.1038/ng0297-181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020845">Lee et al. (1997)</a> and <a href="#53" class="mim-tip-reference" title="Neyroud, N., Tesson, F., Denjoy, I., Leibovici, M., Donger, C., Barhanin, J., Faure, S., Gary, F., Coumel, P., Petit, C., Schwartz, K., Guicheney, P. <strong>A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome.</strong> Nature Genet. 15: 186-189, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020846</a>] [<a href="https://doi.org/10.1038/ng0297-186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020846">Neyroud et al. (1997)</a> and hypothesized that aberrant expression of the KVLQT1 gene may be responsible for the profound growth abnormalities seen in BWS. Four isoforms of KVLQT1 exist, 2 of which (isoforms 3 and 4) seem to be untranslated. KVLQT1 imprinting may be associated with specific isoforms, as has been shown for IGF2. KVLQT1 isoform 2 seems to be most abundant in heart and is probably biallelically expressed. Isoform 1 is expressed in multiple tissues and is most likely paternally imprinted. The tissue-specific imprinting of KVLQT1 and the presence of multiple isoforms might explain the various modes of inheritance seen in LQT, JLNS, and BWS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9020829+9020846+9020845" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#70" class="mim-tip-reference" title="Smilinich, N. J., Day, C. D., Fitzpatrick, G. V., Caldwell, G. M., Lossie, A. C., Cooper, P. R., Smallwood, A. C., Joyce, J. A., Schofield, P. N., Reik, W., Nicholls, R. D., Weksberg, R., Driscoll, D. J., Maher, E. R., Shows, T. B., Higgins, M. J. <strong>A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome.</strong> Proc. Nat. Acad. Sci. 96: 8064-8069, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10393948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10393948</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10393948[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.14.8064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10393948">Smilinich et al. (1999)</a> identified an evolutionarily conserved, maternally methylated CpG island, which they called KVDMR1, in an intron of the KVLQT1 gene. Among 12 cases of BWS with normal H19 methylation, 5 showed demethylation of KVDMR1 in fibroblast or lymphocyte DNA; on the other hand, in 4 cases of BWS with H19 hypermethylation, methylation at KVDMR1 was normal. Thus, inactivation of H19 and hypomethylation of KVDMR1 (or an associated phenomenon) represented distinct epigenetic anomalies associated with biallelic expression of IGF2. Reverse transcription-PCR analysis of the human and syntenic mouse loci identified a KVDMR1-associated RNA transcribed exclusively from the paternal allele and in the opposite orientation with respect to the maternally expressed KVLQT1 gene. <a href="#70" class="mim-tip-reference" title="Smilinich, N. J., Day, C. D., Fitzpatrick, G. V., Caldwell, G. M., Lossie, A. C., Cooper, P. R., Smallwood, A. C., Joyce, J. A., Schofield, P. N., Reik, W., Nicholls, R. D., Weksberg, R., Driscoll, D. J., Maher, E. R., Shows, T. B., Higgins, M. J. <strong>A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome.</strong> Proc. Nat. Acad. Sci. 96: 8064-8069, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10393948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10393948</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10393948[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.14.8064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10393948">Smilinich et al. (1999)</a> proposed that KVDMR1 and/or its associated antisense RNA represents an additional imprinting control element or center in human 11p15.5 and mouse distal 7 imprinted domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10393948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To explore the importance of imprinted gene clustering, <a href="#19" class="mim-tip-reference" title="Cleary, M. A., van Raamsdonk, C. D., Levorse, J., Zheng, B., Bradley, A., Tilghman, S. M. <strong>Disruption of an imprinted gene cluster by a targeted chromosomal translocation in mice.</strong> Nature Genet. 29: 78-82, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528397</a>] [<a href="https://doi.org/10.1038/ng715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528397">Cleary et al. (2001)</a> used the Cre/loxP recombination system to disrupt a cluster of imprinted genes on mouse distal chromosome 7. In mice carrying a site-specific translocation, t(7;11), separating Cdkn1c and Kcnq1, imprinting of the genes retained on chromosome 7, including Kcnq1, Kcnq1ot1 (<a href="/entry/604115">604115</a>), Ascl2 (<a href="/entry/601886">601886</a>), H19 (<a href="/entry/103280">103280</a>), and Igf2 (<a href="/entry/147470">147470</a>), was unaffected, demonstrating that these genes are not regulated by elements near or telomeric to Cdkn1c. In contrast, expression and imprinting of the translocated Cdkn1c, Slc22a1l (<a href="/entry/602631">602631</a>), and Tssc3 (<a href="/entry/602131">602131</a>) genes on chromosome 11 were affected, consistent with the hypothesis that elements regulating both expression and imprinting of these genes lie within or proximal to Kcnq1. The findings supported the proposal that chromosomal abnormalities, including translocations, within KCNQ1 that are associated with Beckwith-Wiedemann syndrome may disrupt CDKN1C expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11528397" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>One-third of individuals with Beckwith-Wiedemann syndrome lose maternal-specific methylation at KvDMR1, a putative imprinting control region within intron 10 of the KCNQ1 gene (<a href="#35" class="mim-tip-reference" title="Lee, M. P., DeBaun, M. R., Mitsuya, K., Galonek, H. L., Brandenburg, S., Oshimura, M., Feinberg, A. P. <strong>Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor II imprinting.</strong> Proc. Nat. Acad. Sci. 96: 5203-5208, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220444</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10220444[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.9.5203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220444">Lee et al., 1999</a>; <a href="#70" class="mim-tip-reference" title="Smilinich, N. J., Day, C. D., Fitzpatrick, G. V., Caldwell, G. M., Lossie, A. C., Cooper, P. R., Smallwood, A. C., Joyce, J. A., Schofield, P. N., Reik, W., Nicholls, R. D., Weksberg, R., Driscoll, D. J., Maher, E. R., Shows, T. B., Higgins, M. J. <strong>A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome.</strong> Proc. Nat. Acad. Sci. 96: 8064-8069, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10393948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10393948</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10393948[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.14.8064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10393948">Smilinich et al., 1999</a>; <a href="#25" class="mim-tip-reference" title="Engel, J. R., Smallwood, A., Harper, A., Higgins, M. J., Oshimura, M., Reik, W., Schofield, P. N., Maher, E. R. <strong>Epigenotype-phenotype correlations in Beckwith-Wiedemann syndrome.</strong> J. Med. Genet. 37: 921-926, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11106355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11106355</a>] [<a href="https://doi.org/10.1136/jmg.37.12.921" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11106355">Engel et al., 2000</a>). It has been proposed that this epimutation results in aberrant imprinting and, consequently, BWS. <a href="#26" class="mim-tip-reference" title="Fitzpatrick, G. V., Soloway, P. D., Higgins, M. J. <strong>Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1.</strong> Nature Genet. 32: 426-431, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12410230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12410230</a>] [<a href="https://doi.org/10.1038/ng988" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12410230">Fitzpatrick et al. (2002)</a> showed that paternal inheritance of this mutation in mice results in the derepression in cis of 6 genes, including Cdkn1c, which encodes cyclin-dependent kinase inhibitor 1C. Furthermore, fetuses and adult mice that inherited the deletion from their fathers were 20 to 25% smaller than their wildtype littermates. By contrast, maternal inheritance of this deletion had no effect on imprinted gene expression or growth. Thus, the unmethylated paternal KvDMR1 allele regulates imprinted expression by silencing genes on the paternal chromosome. These findings supported the hypothesis that loss of methylation in BWS patients activates the repressive function of KvDMR1 on the maternal chromosome, resulting in abnormal silencing of CDKN1C and the development of BWS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11106355+10220444+12410230+10393948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Mancini-DiNardo, D., Steele, S. J. S., Ingram, R. S., Tilghman, S. M. <strong>A differentially methylated region within the gene Kcnq1 functions as an imprinted promoter and silencer.</strong> Hum. Molec. Genet. 12: 283-294, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12554682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12554682</a>] [<a href="https://doi.org/10.1093/hmg/ddg024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12554682">Mancini-DiNardo et al. (2003)</a> showed that the imprinting control region (ICR) on mouse distal chromosome 7 contains a promoter for a paternally expressed antisense transcript, Kcnq1ot1. Three paternal-specific nuclease-hypersensitive sites, which are required for full promoter activity, lie immediately upstream from the start site. The expression of Kcnq1ot1 during pre- and postnatal development was compared to that of other imprinted genes in its vicinity, Cdkn1c (<a href="/entry/600856">600856</a>) and Kcnq1; a lack of coordination in their expression did not support an enhancer competition model for the action of the ICR in imprinting control. Using a stable transfection assay, the authors showed that the region contains a position-independent and orientation-independent silencer. The authors proposed that the Kcnq1 ICR may function as a silencer on the paternal chromosome to effect the repression of neighboring genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12554682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#30" class="mim-tip-reference" title="Imboden, M., Swan, H., Denjoy, I., Van Langen, I. M., Latinen-Forsblom, P. J., Napolitano, C., Fressart, V., Breithardt, G., Berthet, M., Priori, S., Hainque, B., Wilde, A. A. M., Schulze-Bahr, E., Feingold, J., Guicheney, P. <strong>Female predominance and transmission distortion in the long-QT syndrome.</strong> New Eng. J. Med. 355: 2744-2751, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17192539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17192539</a>] [<a href="https://doi.org/10.1056/NEJMoa042786" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17192539">Imboden et al. (2006)</a> investigated the distribution of mutant alleles for the long-QT syndrome in 484 nuclear families with type I disease (LQT1 due to mutation in the KCNQ1 gene) and 269 nuclear families with type II disease (LQT2 (<a href="/entry/613688">613688</a>) due to mutation in the KCNH2 gene; <a href="/entry/152427">152427</a>). In offspring of the female carriers of LQT1 or male and female carriers of LQT2, classic mendelian inheritance ratios were not observed. Among the 1,534 descendants, the proportion of genetically affected offspring was significantly greater than that expected according to mendelian inheritance: 870 were carriers of a mutation (57%), and 664 were noncarriers (43%) (P less than 0.001). Among the 870 carriers, the allele for the long-QT syndrome was transmitted more often to female offspring (476; 55%) than to male offspring (394; 45%) (P = 0.005). Increased maternal transmission of the long QT syndrome to daughters was also observed, possibly contributing to the excess of female patients with autosomal dominant long QT syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17192539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The relation of ion channels to disease was comprehensively reviewed by <a href="#2" class="mim-tip-reference" title="Ackerman, M. J., Clapham, D. E. <strong>Ion channels--basic science and clinical disease.</strong> New Eng. J. Med. 336: 1575-1586, 1997. Note: Erratum: New Eng. J. Med. 337: 579 only, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9164815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9164815</a>] [<a href="https://doi.org/10.1056/NEJM199705293362207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9164815">Ackerman and Clapham (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9164815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a large collaborative study, <a href="#86" class="mim-tip-reference" title="Zareba, W., Moss, A. J., Schwartz, P. J., Vincent, G. M., Robinson, J. L., Priori, S. G., Benhorin, J., Locati, E. H., Towbin, J. A., Keating, M. T., Lehmann, M. H., Hall, W. J., International Long-QT Syndrome Registry Research Group. <strong>Influence of the genotype on the clinical course of the long-QT syndrome.</strong> New Eng. J. Med. 339: 960-965, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9753711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9753711</a>] [<a href="https://doi.org/10.1056/NEJM199810013391404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9753711">Zareba et al. (1998)</a> demonstrated that the genotype of the long QT syndrome influences the clinical course. The risk of cardiac events (syncope, aborted cardiac arrest, or sudden death) was significantly higher among subjects with mutations at the LQT1 or LQT2 locus than among those with mutations at the LQT3 locus. Although the cumulative mortality was similar regardless of the genotype, the percentage of cardiac events that were lethal was significantly higher in families with mutations at the LQT3 locus. In this large study, 112 patients had mutations at the LQT1 locus, 72 at the LQT2 locus, and 62 at the LQT3 locus. Thus, paradoxically, cardiac events were less frequent in LQT3 but more likely to be lethal; the likelihood of dying during a cardiac event was 20% in families with an LQT3 mutation and 4% with either an LQT1 or an LQT2 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9753711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using SSCP and DNA sequence analyses, <a href="#17" class="mim-tip-reference" title="Chen, S., Zhang, L., Bryant, R. M., Vincent, G. M., Flippin, M., Lee, J. C., Brown, E., Zimmerman, F., Rozich, R., Szafranski, P., Oberti, C., Sterba, R., Marangi, D., Tchou, P. J., Chung, M. K., Wang, Q. <strong>KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death.</strong> Clin. Genet. 63: 273-282, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12702160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12702160</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12702160[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00048.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12702160">Chen et al. (2003)</a> studied the KCNQ1 gene in 102 families with a history of lethal cardiac events: 55 LQTS, 9 Brugada syndrome (<a href="/entry/601144">601144</a>), 18 idiopathic ventricular fibrillation (IVF; <a href="/entry/603829">603829</a>), and 20 acquired LQTS. Families found to have KCNQ1 mutations were phenotyped using ECG parameters and cardiac event history, and genotype-phenotype correlation was performed. No mutations were found in Brugada syndrome, IVF, or acquired LQTS families. Of the 55 LQTS families, 10 had KCNQ1 mutations and 62 carriers were identified. Five novel mutations were identified. There were 6 instances of sudden death and in 2 of these, death was the first symptom. The findings of this study emphasized the reduced penetrance of both the long QT and symptoms, resulting in diagnostic challenges, and the importance of genetic testing for identification of gene carriers with reduced penetrance in order to provide treatment and prevent lethal cardiac arrhythmias and sudden death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12702160" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#83" class="mim-tip-reference" title="Westenskow, P., Splawski, I., Timothy, K. W., Keating, M. T., Sanguinetti, M. C. <strong>Compound mutations: a common cause of severe long-QT syndrome.</strong> Circulation 109: 1834-1841, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15051636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15051636</a>] [<a href="https://doi.org/10.1161/01.CIR.0000125524.34234.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15051636">Westenskow et al. (2004)</a> analyzed the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 252 probands with long QT syndrome and identified 19 with biallelic mutations in LQTS genes, of whom 18 were either compound (monogenic) or double (digenic) heterozygotes and 1 was a homozygote. They also identified 1 patient who had triallelic digenic mutations (see <a href="/entry/152427#0021">152427.0021</a>). Compared with probands who had 1 or no identified mutation, probands with 2 mutations had longer QTc intervals (p less than 0.001) and were 3.5-fold more likely to undergo cardiac arrest (p less than 0.01). Voltage clamp studies in Xenopus oocytes coexpressing wildtype and variant subunits demonstrated a reduction in I(Ks) density that was equivalent to the additive effects of the single mutations. <a href="#83" class="mim-tip-reference" title="Westenskow, P., Splawski, I., Timothy, K. W., Keating, M. T., Sanguinetti, M. C. <strong>Compound mutations: a common cause of severe long-QT syndrome.</strong> Circulation 109: 1834-1841, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15051636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15051636</a>] [<a href="https://doi.org/10.1161/01.CIR.0000125524.34234.13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15051636">Westenskow et al. (2004)</a> concluded that biallelic mono- or digenic mutations (which the authors termed 'compound mutations') cause a severe phenotype and are relatively common in long QT syndrome. The authors noted that these findings support the concept of arrhythmia risk as a multi-hit process and suggested that genotype can be used to predict risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15051636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Brink, P. A., Crotti, L., Corfield, V., Goosen, A., Durrheim, G., Hedley, P., Heradien, M., Geldenhuys, G., Vanoli, E., Bacchini, S., Spazzolini, C., Lundquist, A. L., Roden, D. M., George, A. L., Jr., Schwartz, P. J. <strong>Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.</strong> Circulation 112: 2602-2610, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16246960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16246960</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.105.572453" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16246960">Brink et al. (2005)</a> studied an LQTS founder population (SA-A341V) consisting of 22 apparently unrelated South African kindreds of Afrikaner origin (<a href="#21" class="mim-tip-reference" title="de Jager, T., Corbett, C. H., Badenhorst, J. C. W., Brink, P. A., Corfield, V. A. <strong>Evidence of a long QT founder gene with varying phenotypic expression in South African families.</strong> J. Med. Genet. 33: 567-573, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8818942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8818942</a>] [<a href="https://doi.org/10.1136/jmg.33.7.567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8818942">de Jager et al., 1996</a>), all of which could be traced to a single founding couple of mixed Dutch and French Huguenot origin who married in approximately 1730. <a href="#12" class="mim-tip-reference" title="Brink, P. A., Crotti, L., Corfield, V., Goosen, A., Durrheim, G., Hedley, P., Heradien, M., Geldenhuys, G., Vanoli, E., Bacchini, S., Spazzolini, C., Lundquist, A. L., Roden, D. M., George, A. L., Jr., Schwartz, P. J. <strong>Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.</strong> Circulation 112: 2602-2610, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16246960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16246960</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.105.572453" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16246960">Brink et al. (2005)</a> compared the 166 Afrikaner patients carrying the KCNQ1 A341V mutation (<a href="#0010">607542.0010</a>) to the general LQT1 population (<a href="#61" class="mim-tip-reference" title="Priori, S. G., Schwartz, P. J, Napolitano, C., Bloise, R., Ronchetti, E., Grillo, M., Vicentini, A., Spazzolini, C., Nastoli, J., Bottelli, G., Folli, R., Cappelletti, D. <strong>Risk stratification in the long-QT syndrome.</strong> New Eng. J. Med. 348: 1866-1874, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12736279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12736279</a>] [<a href="https://doi.org/10.1056/NEJMoa022147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12736279">Priori et al., 2003</a>) and found that the SA-A341V group exhibited a significantly more severe form of the disease, with an earlier age of onset, longer QTc intervals, and an increased incidence of a first cardiac event by age 20 years. Functional analysis in CHO cells demonstrated that coexpression of the A341V mutant reduced the magnitude of the wildtype channel repolarizing current I(Ks) by approximately 50%, indicating that the mutation exerts a dominant-negative effect. <a href="#12" class="mim-tip-reference" title="Brink, P. A., Crotti, L., Corfield, V., Goosen, A., Durrheim, G., Hedley, P., Heradien, M., Geldenhuys, G., Vanoli, E., Bacchini, S., Spazzolini, C., Lundquist, A. L., Roden, D. M., George, A. L., Jr., Schwartz, P. J. <strong>Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.</strong> Circulation 112: 2602-2610, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16246960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16246960</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.105.572453" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16246960">Brink et al. (2005)</a> noted that this effect on I(Ks), which activates during increased heart rate and is essential for QT interval adaptation during tachycardia, might explain why 79% of lethal arrhythmic episodes in LQT1 patients with mutations impairing I(Ks) occur during exercise. In contrast, most lethal episodes in LQT2 and LQT3 patients occur during startle reaction and at rest or during sleep, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12736279+16246960+8818942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#37" class="mim-tip-reference" title="Lee, M. P., Ravenel, J. D., Hu, R.-J., Lustig, L. R., Tomaselli, G., Berger, R. D., Brandenburg, S. A., Litzi, T. J., Bunton, T. E., Limb, C., Francis, H., Gorelikow, M., Gu, H., Washington, K., Argani, P., Goldenring, J. R., Coffey, R. J., Feinberg, A. P. <strong>Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice.</strong> J. Clin. Invest. 106: 1447-1455, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11120752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11120752</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11120752[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI10897" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11120752">Lee et al. (2000)</a> found that Kvlqt1 -/- mice were born at the expected mendelian ratio, were viable, and developed normally. However, by 4 weeks of age, Kvlqt1 -/- mice exhibited hyperactivity, with repetitive running, circling, nodding, and wobbling behaviors. Kvlqt1 -/- mice were completely deaf due to defects in inner ear development, and they displayed gastric hyperplasia, likely resulting from an altered cellular repertoire of lineage maturation in gastric mucosa. However, cardiac electrophysiology was normal, and Kvlqt1 -/- mice did not display features of BWS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11120752" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To produce a mouse model for Jervell and Lange-Nielsen syndrome, <a href="#13" class="mim-tip-reference" title="Casimiro, M. C., Knollmann, B. C., Ebert, S. N., Vary, J. C., Jr., Greene, A. E., Franz, M. R., Grinberg, A., Huang, S. P., Pfeifer, K. <strong>Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen syndrome.</strong> Proc. Nat. Acad. Sci. 98: 2526-2531, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11226272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11226272</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11226272[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.041398998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11226272">Casimiro et al. (2001)</a> generated a line of transgenic mice that had a targeted disruption in the Kcnq1 gene. Behavioral analysis demonstrated that the homozygous-null mice were deaf and exhibited a shaker-waltzer phenotype. Histologic analysis of the inner ear structures of these mice showed gross morphologic anomalies because of drastic reduction in the volume of endolymph. ECGs recorded from the null mice demonstrated abnormal T- and P-wave morphologies and prolongation of the QT and JT intervals when measured in vivo, but not in isolated hearts. These changes were indicative of cardiac repolarization defects that appear to be induced by extracardiac signals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11226272" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Casimiro, M. C., Knollmann, B. C., Yamoah, E. N., Nie, L., Vary, J. C., Jr., Sirenko, S. G., Greene, A. E., Grinberg, A., Huang, S. P., Ebert, S. N., Pfeifer, K. <strong>Targeted point mutagenesis of mouse Kcnq1: phenotypic analysis of mice with point mutations that cause Romano-Ward syndrome in humans.</strong> Genomics 84: 555-564, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15498462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15498462</a>] [<a href="https://doi.org/10.1016/j.ygeno.2004.06.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15498462">Casimiro et al. (2004)</a> noted that Kcnq1 knockout results in mice with more severe defects than those in human LQT1 or JLNS1. They developed mouse lines with point mutations in the Kcnq1 gene that cause LQT1 in humans. Mice with an ala340-to-glu mutation had normal hearing but a long QT and therefore modeled patients with LQT1. Mice with a thr311-to-ile mutation phenocopied JLNS1, but they also displayed the shaker/waltzer defect, which is specific to mouse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15498462" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Imprinted genes are clustered in domains, and their allelic repression is mediated by imprinting control regions. These imprinting control regions are marked by DNA methylation, which is essential to maintain imprinting in the embryo. To explore how imprinting is regulated in placenta, <a href="#78" class="mim-tip-reference" title="Umlauf, D., Goto, Y., Cao, R., Cerqueira, F., Wagschal, A., Zhang, Y., Feil, R. <strong>Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes.</strong> Nature Genet. 36: 1296-1300, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15516932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15516932</a>] [<a href="https://doi.org/10.1038/ng1467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15516932">Umlauf et al. (2004)</a> studied the Kcnq1 domain on mouse distal chromosome 7. This large domain is controlled by an intronic imprinting control region (<a href="#26" class="mim-tip-reference" title="Fitzpatrick, G. V., Soloway, P. D., Higgins, M. J. <strong>Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1.</strong> Nature Genet. 32: 426-431, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12410230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12410230</a>] [<a href="https://doi.org/10.1038/ng988" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12410230">Fitzpatrick et al., 2002</a>; <a href="#40" class="mim-tip-reference" title="Mancini-DiNardo, D., Steele, S. J. S., Ingram, R. S., Tilghman, S. M. <strong>A differentially methylated region within the gene Kcnq1 functions as an imprinted promoter and silencer.</strong> Hum. Molec. Genet. 12: 283-294, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12554682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12554682</a>] [<a href="https://doi.org/10.1093/hmg/ddg024" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12554682">Mancini-DiNardo et al., 2003</a>) and comprises multiple genes that are imprinted in placenta, without the involvement of promoter DNA methylation. <a href="#78" class="mim-tip-reference" title="Umlauf, D., Goto, Y., Cao, R., Cerqueira, F., Wagschal, A., Zhang, Y., Feil, R. <strong>Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes.</strong> Nature Genet. 36: 1296-1300, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15516932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15516932</a>] [<a href="https://doi.org/10.1038/ng1467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15516932">Umlauf et al. (2004)</a> found that the paternal repression along the domain involves acquisition of trimethylation at lys27 and dimethylation at lys9 of histone H3 (see <a href="/entry/602810">602810</a>). Eed (<a href="/entry/605984">605984</a>)-Ezh2 (<a href="/entry/601573">601573</a>) Polycomb complexes are recruited to the paternal chromosome and potentially regulate its repressive histone methylation. Studies on embryonic stem cells and early embryos supported the proposal of <a href="#78" class="mim-tip-reference" title="Umlauf, D., Goto, Y., Cao, R., Cerqueira, F., Wagschal, A., Zhang, Y., Feil, R. <strong>Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes.</strong> Nature Genet. 36: 1296-1300, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15516932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15516932</a>] [<a href="https://doi.org/10.1038/ng1467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15516932">Umlauf et al. (2004)</a> that chromatin repression is established early in development and is maintained in the placenta. In the embryo, on the other hand, imprinting is stably maintained only at genes that have promoter DNA methylation. Random X inactivation in the embryo proper also involves repressive histone methylation and recruitment of Eed-Ezh2 complexes (<a href="#69" class="mim-tip-reference" title="Silva, J., Mak, W., Zvetkova, I., Appanah, R., Nesterova, T. B., Webster, Z., Peters, A. H. F. M., Jenuwein, T., Otte, A. P., Brockdorff, N. <strong>Establishment of histone H3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 Polycomb group complexes.</strong> Dev. Cell 4: 481-495, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12689588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12689588</a>] [<a href="https://doi.org/10.1016/s1534-5807(03)00068-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12689588">Silva et al., 2003</a>). <a href="#78" class="mim-tip-reference" title="Umlauf, D., Goto, Y., Cao, R., Cerqueira, F., Wagschal, A., Zhang, Y., Feil, R. <strong>Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes.</strong> Nature Genet. 36: 1296-1300, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15516932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15516932</a>] [<a href="https://doi.org/10.1038/ng1467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15516932">Umlauf et al. (2004)</a> concluded that their data underscored the importance of histone methylation in placental imprinting and identified mechanistic similarities with X chromosome inactivation in extraembryonic tissues, suggesting that the 2 epigenetic mechanisms are evolutionarily linked. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15516932+12410230+12689588+12554682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Studying imprinting in the placenta in the region of distal mouse chromosome 7, <a href="#38" class="mim-tip-reference" title="Lewis, A., Mitsuya, K., Umlauf, D., Smith, P., Dean, W., Walter, J., Higgins, M., Feil, R., Reik, W. <strong>Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation.</strong> Nature Genet. 36: 1291-1295, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15516931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15516931</a>] [<a href="https://doi.org/10.1038/ng1468" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15516931">Lewis et al. (2004)</a> found that the silent paternal alleles of imprinted genes are marked in the trophoblast by repressive histone modifications (dimethylation at lys9 of histone H3 and trimethylation at lys27 of histone H3), which were disrupted when imprinting center-2 (IC2) on mouse distal chromosome 7 was deleted. The deletion led to reactivation of the paternal alleles. <a href="#38" class="mim-tip-reference" title="Lewis, A., Mitsuya, K., Umlauf, D., Smith, P., Dean, W., Walter, J., Higgins, M., Feil, R., Reik, W. <strong>Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation.</strong> Nature Genet. 36: 1291-1295, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15516931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15516931</a>] [<a href="https://doi.org/10.1038/ng1468" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15516931">Lewis et al. (2004)</a> proposed that an evolutionarily older imprinting mechanism limited to extraembryonic tissues was based on histone modifications. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15516931" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Elso, C. M., Lu, X., Culiat, C. T., Rutledge, J. C., Cacheiro, N. L. A., Generoso, W. M., Stubbs, L. J. <strong>Heightened susceptibility to chronic gastritis, hyperplasia and metaplasia in Kcnq1 mutant mice.</strong> Hum. Molec. Genet. 13: 2813-2821, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15385447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15385447</a>] [<a href="https://doi.org/10.1093/hmg/ddh307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15385447">Elso et al. (2004)</a> characterized 2 mouse lines carrying mutant alleles of Kcnq1, which very rapidly established chronic gastritis in a bacterial pathogen-exposed environment. Independent of infection, mutant mice developed gastric hyperplasia, hypochlorhydria, and mucin dysregulation, as well as metaplasia, dysplasia, and premalignant adenomatous hyperplasia of the stomach. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15385447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using pharmacologic inhibition and gene knockout in mice, <a href="#79" class="mim-tip-reference" title="Vallon, V., Grahammer, F., Volkl, H., Sandu, C. D., Richter, K., Rexhepaj, R., Gerlach, U., Rong, Q., Pfeifer, K., Lang, F. <strong>KCNQ1-dependent transport in renal and gastrointestinal epithelia.</strong> Proc. Nat. Acad. Sci. 102: 17864-17869, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16314573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16314573</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16314573[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0505860102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16314573">Vallon et al. (2005)</a> demonstrated the importance of Kcnq1 channel complexes in maintenance of the driving force for proximal tubular and intestinal Na+ absorption, gastric acid secretion, and cAMP-induced jejunal Cl- secretion. In the kidney, Kcnq1 was dispensable under basal conditions; however, luminal Kcnq1 repolarized the proximal tubule and stabilized the driving force for Na+ reabsorption under conditions of increased glucose or amino acid resorption. In mice lacking functional Kcnq1, impaired intestinal absorption was associated with reduced serum vitamin B12 concentrations, mild macrocytic anemia, and fecal loss of Na+ and K+, the latter affecting K+ homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16314573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In studies of Drosophila, <a href="#54" class="mim-tip-reference" title="Ocorr, K., Reeves, N. L., Wessells, R. J., Fink, M., Chen, H.-S. V., Akasaka, T., Yasuda, S., Metzger, J. M., Giles, W., Posakony, J. W., Bodmer, R. <strong>KCNQ potassium channel mutations cause cardiac arrhythmias in Drosophila that mimic the effects of aging.</strong> Proc. Nat. Acad. Sci. 104: 3943-3948, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360457</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360457[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0609278104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17360457">Ocorr et al. (2007)</a> observed a markedly elevated incidence of cardiac dysfunction and arrhythmias in aging fruit fly hearts and a concomitant decrease in expression of Kcnq, which is the Drosophila homolog of human KCNQ1. Hearts from young Kcnq-mutant fruit flies exhibited arrhythmias reminiscent of torsade de pointes and had severely increased susceptibility to pacing-induced cardiac dysfunction at young ages, characteristics that are observed only at advanced ages in wildtype flies. Alterations in rhythmicity of the mutant flies was rescued by transgenic wildtype Kcnq, and heart-specific Kcnq overexpression in old wildtype flies reversed the age-dependent increase in arrhythmias. <a href="#54" class="mim-tip-reference" title="Ocorr, K., Reeves, N. L., Wessells, R. J., Fink, M., Chen, H.-S. V., Akasaka, T., Yasuda, S., Metzger, J. M., Giles, W., Posakony, J. W., Bodmer, R. <strong>KCNQ potassium channel mutations cause cardiac arrhythmias in Drosophila that mimic the effects of aging.</strong> Proc. Nat. Acad. Sci. 104: 3943-3948, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17360457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17360457</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17360457[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0609278104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17360457">Ocorr et al. (2007)</a> suggested that an age-dependent decrease in KCNQ1 expression within the heart may contribute to the increased incidence of arrhythmia observed with age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17360457" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>46 Selected Examples</a>):</strong>
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<a href="/allelicVariants/607542" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607542[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397508113 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397508113;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397508113" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397508113" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>Using SSCP analysis, <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> demonstrated a deletion in the KVLQT1 gene in a sporadic case of long QT syndrome-1 (LQT1; <a href="/entry/192500">192500</a>). Deletion of 3 nucleotides, TCG, changed codon 72 from TTC (phe) to TGG (trp) and deleted the first G of codon 73. (Codon 72 used to be known as codon 38 and codon 73 as codon 39.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs120074177 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074177;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs120074177?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074177" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074177" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003260 OR RCV000057693" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003260, RCV000057693" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003260...</a>
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<p>Using SSCP analysis, <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> found a GCC (ala) to CCC (pro) transversion in codon 83 of the KVLQT1 gene in a sporadic case of LQT1 (<a href="/entry/192500">192500</a>). (This variant used to be known as ALA49PRO and ALA83PRO.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894252 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894252;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104894252" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs104894252" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894255 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894255;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104894255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs104894255" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003261 OR RCV000057702 OR RCV000223880 OR RCV001383882" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003261, RCV000057702, RCV000223880, RCV001383882" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003261...</a>
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<p>In a family in which 3 members had LQT1 (<a href="/entry/192500">192500</a>), <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> demonstrated a GGG (gly) to AGG (arg) transition in codon 189 of the KVLQT1 gene. <a href="#32" class="mim-tip-reference" title="Jongbloed, R. J. E., Wilde, A. A. M., Geelen, J. L. M. C., Doevendans, P., Schaap, C., Van Langen, I., van Tintelen, J. P., Cobben, J. M., Beaufort-Krol, G. C. M., Geraedts, J. P. M., Smeets, H. J. M. <strong>Novel KCNQ1 and HERG missense mutations in Dutch long-QT families.</strong> Hum. Mutat. 13: 301-310, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10220144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10220144</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:4<301::AID-HUMU7>3.0.CO;2-V" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10220144">Jongbloed et al. (1999)</a> identified this mutation in 2 families with LQT1. (This variant used to be known as GLY60ARG and GLY94ARG.) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8528244+10220144" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 LONG QT SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs120074178 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074178;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs120074178?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074178" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074178" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003264 OR RCV000046088 OR RCV000057706 OR RCV000182086 OR RCV000588393 OR RCV001841223" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003264, RCV000046088, RCV000057706, RCV000182086, RCV000588393, RCV001841223" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003264...</a>
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<p>In a family with 2 members affected by LQT1 (<a href="/entry/192500">192500</a>), <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> used SSCP analysis to demonstrate a CGG (arg) to CAG (gln) transition in codon 95 of the KVLQT1 gene. (This variant used to be known as ARG61GLN and ARG95GLN.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Moretti, A., Bellin, M., Welling, A., Jung, C. B., Lam, J. T., Bott-Flugel, L., Dorn, T., Goedel, A., Hohnke, C., Hofmann, F., Seyfarth, M., Sinnecker, D., Schomig, A., Laugwitz, K.-L. <strong>Patient-specific induced pluripotent stem-cell models for long-QT syndrome.</strong> New Eng. J. Med. 363: 1397-1409, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20660394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20660394</a>] [<a href="https://doi.org/10.1056/NEJMoa0908679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20660394">Moretti et al. (2010)</a> reported the creation of patient-specific induced pluripotent stem (IPS) cells containing the R190Q mutation in KCNQ1. They compared IPS cells derived from dermal fibroblasts from 2 patients with this mutation with those from 2 control individuals. The cells were able to generate functional myocytes that showed a ventricular, atrial, or nodal phenotype, as evidenced by expression of cell type-specific markers and as seen in recordings of the action potentials in single cells. The duration of the action potential was markedly prolonged in ventricular and atrial cells derived from patients with LQTS1, as compared with cells from control subjects. Further characterization of the role of the R190Q KCNQ1 mutation in the pathogenesis of LQTS1 revealed a dominant-negative trafficking defect associated with a 70 to 80% reduction in I(Ks) current and altered channel activation and deactivation properties. Moreover, <a href="#47" class="mim-tip-reference" title="Moretti, A., Bellin, M., Welling, A., Jung, C. B., Lam, J. T., Bott-Flugel, L., Dorn, T., Goedel, A., Hohnke, C., Hofmann, F., Seyfarth, M., Sinnecker, D., Schomig, A., Laugwitz, K.-L. <strong>Patient-specific induced pluripotent stem-cell models for long-QT syndrome.</strong> New Eng. J. Med. 363: 1397-1409, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20660394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20660394</a>] [<a href="https://doi.org/10.1056/NEJMoa0908679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20660394">Moretti et al. (2010)</a> showed that myocytes derived from patients with LQTS1 had an increased susceptibility to catecholamine-induced tachyarrhythmia and that beta-blockade attenuated this phenotype, as was demonstrated in the patients themselves. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20660394" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs120074179 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074179;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074179" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074179" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003265 OR RCV000003296 OR RCV000057749 OR RCV000182109 OR RCV000190212 OR RCV000619506" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003265, RCV000003296, RCV000057749, RCV000182109, RCV000190212, RCV000619506" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003265...</a>
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<p>In a kindred in which 70 members were affected by LQT1 (<a href="/entry/192500">192500</a>), <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> used SSCP analysis to demonstrate a GTG (val) to ATG (met) transition in codon 159 of the KVLQT1 gene. (This variant used to be known as VAL125MET and VAL159MET.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 LONG QT SYNDROME 1</strong>
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KCNQ1, LEU273PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs120074180 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074180;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs120074180?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074180" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003266 OR RCV000057769 OR RCV000182120 OR RCV000620696 OR RCV001192509" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003266, RCV000057769, RCV000182120, RCV000620696, RCV001192509" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003266...</a>
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<p>In a kindred in which 2 members were affected by LQT1 (<a href="/entry/192500">192500</a>), <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> demonstrated a CTC (leu) to TTC (phe) transition in codon 273 of the KVLQT1 gene. (This variant used to be known as LEU144PHE and LEU178PHE.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 LONG QT SYNDROME 1</strong>
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KCNQ1, GLY306ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs120074181 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074181;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003262 OR RCV000057797 OR RCV000182132" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003262, RCV000057797, RCV000182132" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003262...</a>
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<p>In a sporadic case of LQT1 (<a href="/entry/192500">192500</a>), <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> demonstrated a GGG (gly) to AGG (arg) transition in codon 211 of the KVLQT1 gene. (This mutation used to be known as GLY177ARG and GLY211ARG.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0008 LONG QT SYNDROME 1</strong>
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KCNQ1, THR312ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs120074182 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074182;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074182" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074182" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003263 OR RCV000057808 OR RCV000182136 OR RCV001386969 OR RCV001841222 OR RCV002444417" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003263, RCV000057808, RCV000182136, RCV001386969, RCV001841222, RCV002444417" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003263...</a>
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<p>In a sporadic case of LQT1 (<a href="/entry/192500">192500</a>), <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> demonstrated a ACC (thr) to ATC (ile) transition in codon 217 of the KVLQT1 gene. (This mutation used to be known as THR183ILE and THR217ILE.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs12720459 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12720459;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs12720459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs12720459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003267 OR RCV000003268 OR RCV000045932 OR RCV000057526 OR RCV000182154 OR RCV000621485 OR RCV003591617" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003267, RCV000003268, RCV000045932, RCV000057526, RCV000182154, RCV000621485, RCV003591617" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003267...</a>
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<p>In 2 kindreds with 8 members affected by LQT1 (<a href="/entry/192500">192500</a>), <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> demonstrated a GCG (ala) to GAG (glu) transversion in codon 341 (A341E) of the KCNQ1 gene. (This variant used to be known as ALA212GLU and ALA246GLU.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 severely affected sisters from a large Belgian family with long QT syndrome (see <a href="/entry/192500">192500</a>), <a href="#11" class="mim-tip-reference" title="Berthet, M., Denjoy, I., Donger, C., Demay, L., Hammoude, H., Klug, D., Schulze-Bahr, E., Richard, P., Funke, H., Schwartz, K., Coumel, P., Hainque, B., Guicheney, P. <strong>C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.</strong> Circulation 99: 1464-1470, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10086971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10086971</a>] [<a href="https://doi.org/10.1161/01.cir.99.11.1464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10086971">Berthet et al. (1999)</a> identified biallelic digenic mutations: the A341E substitution in exon 6, within the S6 transmembrane domain of KCNQ1; and a splice site mutation in the KCNH2 gene (2592+1G-A; <a href="/entry/152427#0019">152427.0019</a>). The father and his affected relatives were heterozygous for the A341E mutation in KCNQ1; the mother, a more mildly affected sister, and a grandson were heterozygous for the splice site mutation in KCNH2. Neither mutation was found in 2 unaffected sibs or in other unaffected family members. <a href="#11" class="mim-tip-reference" title="Berthet, M., Denjoy, I., Donger, C., Demay, L., Hammoude, H., Klug, D., Schulze-Bahr, E., Richard, P., Funke, H., Schwartz, K., Coumel, P., Hainque, B., Guicheney, P. <strong>C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.</strong> Circulation 99: 1464-1470, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10086971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10086971</a>] [<a href="https://doi.org/10.1161/01.cir.99.11.1464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10086971">Berthet et al. (1999)</a> stated that this was the first description of double heterozygosity in long QT syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10086971" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs12720459 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12720459;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs12720459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs12720459" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003269 OR RCV000057528 OR RCV000171124 OR RCV000619686" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003269, RCV000057528, RCV000171124, RCV000619686" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003269...</a>
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<p>In 5 kindreds (K1807, K161, K162, K163, and K164) with 47 members affected by LQT1 (<a href="/entry/192500">192500</a>), <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> demonstrated a GCG (ala) to GTG (val) transversion in codon 341 of the KVLQT1 gene. The mutation segregated with disease in the families and was not found in DNA samples from 200 unrelated controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a South African family of Afrikaner origin with LQT (pedigree 166), <a href="#21" class="mim-tip-reference" title="de Jager, T., Corbett, C. H., Badenhorst, J. C. W., Brink, P. A., Corfield, V. A. <strong>Evidence of a long QT founder gene with varying phenotypic expression in South African families.</strong> J. Med. Genet. 33: 567-573, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8818942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8818942</a>] [<a href="https://doi.org/10.1136/jmg.33.7.567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8818942">de Jager et al. (1996)</a> identified heterozygosity for the A341V mutation in the KVLQT1 gene. Haplotype analysis of this family and 4 Afrikaner families previously studied by <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> (pedigrees 161, 162, 163, and 164) revealed that all 5 families shared a common haplotype, indicating a founder effect. Noting differences in severity of disease between the 2 largest families, 161 and 162, <a href="#21" class="mim-tip-reference" title="de Jager, T., Corbett, C. H., Badenhorst, J. C. W., Brink, P. A., Corfield, V. A. <strong>Evidence of a long QT founder gene with varying phenotypic expression in South African families.</strong> J. Med. Genet. 33: 567-573, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8818942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8818942</a>] [<a href="https://doi.org/10.1136/jmg.33.7.567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8818942">de Jager et al. (1996)</a> suggested that the spectrum of clinical symptoms might reflect the influence of different modulating environmental or genetic backgrounds on expression of the same mutant allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8528244+8818942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#64" class="mim-tip-reference" title="Russell, M. W., Dick, M., II, Collins, F. S., Brody, L. C. <strong>KVLQT1 mutations in three families with familial or sporadic long QT syndrome.</strong> Hum. Molec. Genet. 5: 1319-1324, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8872472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8872472</a>] [<a href="https://doi.org/10.1093/hmg/5.9.1319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8872472">Russell et al. (1996)</a> detected this mutation in the spontaneous occurrence of LQT in monozygotic twin offspring of normal parents. This mutation would be expected to encode a potassium channel with altered conductance properties. They noted that mutations at this same nucleotide have been observed in 8 of 19 LQT families determined to have KVLQT1 mutations to that time, suggesting a mutation hotspot. (This variant used to be known as ALA212VAL and ALA246VAL.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8872472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Brink, P. A., Crotti, L., Corfield, V., Goosen, A., Durrheim, G., Hedley, P., Heradien, M., Geldenhuys, G., Vanoli, E., Bacchini, S., Spazzolini, C., Lundquist, A. L., Roden, D. M., George, A. L., Jr., Schwartz, P. J. <strong>Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.</strong> Circulation 112: 2602-2610, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16246960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16246960</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.105.572453" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16246960">Brink et al. (2005)</a> studied an LQTS founder population (SA-A341V) consisting of 22 apparently unrelated South African kindreds of Afrikaner origin (including pedigrees 161, 162, 163, 164, and 166), all of which could be traced to a single founding couple of mixed Dutch and French Huguenot origin who married in approximately 1730. Comparing the Afrikaner patients to the general LQT1 population, <a href="#12" class="mim-tip-reference" title="Brink, P. A., Crotti, L., Corfield, V., Goosen, A., Durrheim, G., Hedley, P., Heradien, M., Geldenhuys, G., Vanoli, E., Bacchini, S., Spazzolini, C., Lundquist, A. L., Roden, D. M., George, A. L., Jr., Schwartz, P. J. <strong>Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.</strong> Circulation 112: 2602-2610, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16246960/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16246960</a>] [<a href="https://doi.org/10.1161/CIRCULATIONAHA.105.572453" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16246960">Brink et al. (2005)</a> found that the SA-A341V group exhibited a significantly more severe form of the disease, with an earlier age of onset, longer QTc intervals, and an increased incidence of first cardiac event by age 20 years. Functional analysis in CHO cells demonstrated that coexpression of the A341V mutant reduced the magnitude of wildtype channel repolarizing current by approximately 50%, indicating that the mutation exerts a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16246960" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Modifier Effects of Variation in the AKAP9 Gene</em></strong></p><p>
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In 349 members of a South African founder population of Afrikaner origin with LQT1, 168 of whom carried an identical-by-descent A341V mutation, <a href="#22" class="mim-tip-reference" title="de Villiers, C. P., van der Merwe, L., Crotti, L., Goosen, A., George, A. L., Schwartz, P. J., Brink, P. A., Moolman-Smook, J. C., Corfield, V. A. <strong>AKAP9 is a genetic modifier of congenital long-QT syndrome type 1.</strong> Circ. Cardiovasc. Genet. 7: 599-606, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25087618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25087618</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25087618[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.113.000580" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25087618">de Villiers et al. (2014)</a> genotyped 4 SNPs in the AKAP9 gene (<a href="/entry/604001">604001</a>) and found statistically significant associations between certain alleles, genotypes, and haplotypes and phenotypic traits such as QTc interval length, risk of cardiac events, and/or disease severity. <a href="#22" class="mim-tip-reference" title="de Villiers, C. P., van der Merwe, L., Crotti, L., Goosen, A., George, A. L., Schwartz, P. J., Brink, P. A., Moolman-Smook, J. C., Corfield, V. A. <strong>AKAP9 is a genetic modifier of congenital long-QT syndrome type 1.</strong> Circ. Cardiovasc. Genet. 7: 599-606, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25087618/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25087618</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25087618[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.113.000580" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25087618">De Villiers et al. (2014)</a> stated that these results clearly demonstrated that AKAP9 contributes to LQTS phenotypic variability; however, the authors noted that because these SNPs are located in intronic regions of the gene, functional or regulatory variants in linkage disequilibrium with the SNPs were likely to be responsible for the modifying effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25087618" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs120074183 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074183;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003270 OR RCV000057536 OR RCV002512696" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003270, RCV000057536, RCV002512696" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003270...</a>
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<p>In a family with 11 members affected by LQT1 (<a href="/entry/192500">192500</a>), <a href="#81" class="mim-tip-reference" title="Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T. <strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong> Nature Genet. 12: 17-23, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>] [<a href="https://doi.org/10.1038/ng0196-17" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528244">Wang et al. (1996)</a> demonstrated a GGG (gly) to GAG (glu) transversion in codon 250 of the KVLQT1 gene. (This variant used to be known as GLY216GLU and GLY250GLU.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 LONG QT SYNDROME 1</strong>
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KCNQ1, GLY314SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs120074184 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074184;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003271 OR RCV000057810 OR RCV000182137 OR RCV000852434 OR RCV002371756" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003271, RCV000057810, RCV000182137, RCV000852434, RCV002371756" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003271...</a>
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<p><a href="#64" class="mim-tip-reference" title="Russell, M. W., Dick, M., II, Collins, F. S., Brody, L. C. <strong>KVLQT1 mutations in three families with familial or sporadic long QT syndrome.</strong> Hum. Molec. Genet. 5: 1319-1324, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8872472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8872472</a>] [<a href="https://doi.org/10.1093/hmg/5.9.1319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8872472">Russell et al. (1996)</a> reported a mutation resulting in a gly219-to-ser substitution in 2 LQT1 (<a href="/entry/192500">192500</a>) families. (This variant used to be known as GLY185SER and GLY219SER.) This mutation would be expected to encode a potassium channel with altered conductance properties. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8872472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 JERVELL AND LANGE-NIELSEN SYNDROME 1</strong>
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KCNQ1, 7-BP DEL/8-BP INS, NT1244
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397515637 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515637;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397515637" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397515637" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003272" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003272" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003272</a>
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<p>In 3 children with Jervell and Lange-Nielsen cardioauditory syndrome (JLNS1; <a href="/entry/220400">220400</a>) from 2 consanguineous families, <a href="#53" class="mim-tip-reference" title="Neyroud, N., Tesson, F., Denjoy, I., Leibovici, M., Donger, C., Barhanin, J., Faure, S., Gary, F., Coumel, P., Petit, C., Schwartz, K., Guicheney, P. <strong>A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome.</strong> Nature Genet. 15: 186-189, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9020846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9020846</a>] [<a href="https://doi.org/10.1038/ng0297-186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9020846">Neyroud et al. (1997)</a> found homozygosity for a deletion-insertion mutation in the C-terminal domain of the KVLQT1 gene. At nucleotide 1244, a deletion of 7 bp and an insertion of 8 bp was found in affected individuals. The mutation resulted in a frameshift from codon 415, leading to a premature stop signal at codon 522 close to the end of the coding sequence, which is at codon 547. Several other members of the 2 families were heterozygous for the mutation. Both families originated from Kabylia, which suggested founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9020846" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0014" class="mim-anchor"></a>
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<strong>.0014 JERVELL AND LANGE-NIELSEN SYNDROME 1</strong>
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KCNQ1, 1-BP INS, 282G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397508117 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397508117;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397508117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397508117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003273 OR RCV000046086 OR RCV000182266 OR RCV000617403 OR RCV003319311 OR RCV004724785" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003273, RCV000046086, RCV000182266, RCV000617403, RCV003319311, RCV004724785" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003273...</a>
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<p>In a patient with Jervell and Lange-Nielson syndrome (JLNS1; <a href="/entry/220400">220400</a>), <a href="#73" class="mim-tip-reference" title="Splawski, I., Timothy, K. W., Vincent, G. M., Atkinson, D. L., Keating, M. T. <strong>Molecular basis of the long-QT syndrome associated with deafness.</strong> New Eng. J. Med. 336: 1562-1567, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9164812/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9164812</a>] [<a href="https://doi.org/10.1056/NEJM199705293362204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9164812">Splawski et al. (1997)</a> found homozygosity for a 1-bp insertion (G) after nucleotide 282 of the KVLQT1 gene. The insertion caused a frameshift, disrupting the coding sequence after the second putative membrane-spanning domain of the KVLQT1 protein and leading to a premature stop codon at nucleotide 564. The proband was born to second-cousin parents. At 35 weeks' gestation, the obstetrician informed the mother that the fetal heart rate had dropped to 70 to 80 beats per minute. At 38 weeks, the heart rate continued to be slow, and slow heart rate persisted after birth. One hour after delivery, at the time of the first bottle feeding, the infant had cyanosis and hypotonia. A diagnosis of LQT was made and treatment with propranolol was started. On the eighth day, audiograms indicated bilateral sensory deafness. The family members were not evaluated at that time. Seven months after the delivery of the proband, the mother had a cardiac arrest and died when her alarm clock sounded. She was exhausted and very anxious at the time. Investigation of the family demonstrated an extensive involvement of many members with typical heterozygous LQT. Linkage analysis showed that the disorder mapped to the KVLQT1 region on 11p15.5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9164812" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0015" class="mim-anchor"></a>
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<strong>.0015 LONG QT SYNDROME 1</strong>
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KCNQ1, ARG555CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs120074185 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074185;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs120074185?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003274 OR RCV000046011 OR RCV000057613 OR RCV000182211 OR RCV000618290 OR RCV001841224" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003274, RCV000046011, RCV000057613, RCV000182211, RCV000618290, RCV001841224" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003274...</a>
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<p>In a study of 20 families originating from France with Romano-Ward syndrome (LQT1; <a href="/entry/192500">192500</a>), <a href="#23" class="mim-tip-reference" title="Donger, C., Denjoy, I., Berthet, M., Neyroud, N., Cruaud, C., Bennaceur, M., Chivoret, G., Schwartz, K., Coumel, P., Guicheney, P. <strong>KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome.</strong> Circulation 96: 2778-2781, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9386136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9386136</a>] [<a href="https://doi.org/10.1161/01.cir.96.9.2778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9386136">Donger et al. (1997)</a> identified a C-to-T transition at nucleotide 1663 of the KVLQT1 gene causing a missense arg555-to-cys substitution in the C-terminal domain. In 3 large kindreds, there was a total of 44 carriers of this mutation. Only 5 living subjects experienced syncope and there were 2 sudden deaths. Syncope or death occurred only in the presence of drugs known to modify ventricular repolarization (terfenadine, disopyramide, meflaquine, and diuretics). Carriers of the arg555-to-cys mutation had only minor or no prolongation of the QT interval. <a href="#23" class="mim-tip-reference" title="Donger, C., Denjoy, I., Berthet, M., Neyroud, N., Cruaud, C., Bennaceur, M., Chivoret, G., Schwartz, K., Coumel, P., Guicheney, P. <strong>KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome.</strong> Circulation 96: 2778-2781, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9386136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9386136</a>] [<a href="https://doi.org/10.1161/01.cir.96.9.2778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9386136">Donger et al. (1997)</a> proposed that this allelic variant causes a forme fruste LQT1 phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9386136" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 JERVELL AND LANGE-NIELSEN SYNDROME 1</strong>
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KCNQ1, TRP305SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs120074186 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074186;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs120074186?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003275 OR RCV000057796 OR RCV000182130 OR RCV000622153 OR RCV001385529" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003275, RCV000057796, RCV000182130, RCV000622153, RCV001385529" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003275...</a>
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<p>In 2 consanguineous Jervell and Lange-Nielsen syndrome (JLNS1; <a href="/entry/220400">220400</a>) families, <a href="#51" class="mim-tip-reference" title="Neyroud, N., Denjoy, I., Donger, C., Gary, F., Villain, E., Leenhardt, A., Benali, K., Schwartz, K., Coumel, P., Guicheney, P. <strong>Heterozygous mutation in the pore of potassium channel gene KvLQT1 causes an apparently normal phenotype in long QT syndrome.</strong> Europ. J. Hum. Genet. 6: 129-133, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9781056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9781056</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9781056">Neyroud et al. (1998)</a> identified a trp305-to-ser mutation in the pore region of KCNQ1 by PCR-SSCP analysis. In contrast to several missense mutations found in the same region of the KCNQ1 gene in heterozygous state in Ward-Romano syndrome patients, which are associated with severe cardiac phenotypes, the heterozygous state of the W305S mutation yielded an apparently normal phenotype. This is the same phenomenon as that observed in a number of other situations: different mutations in the same gene produce a phenotype that may be recessive or dominant and the phenotype may be the same or different in the case of the 2 modes of inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9781056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs120074187 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074187;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs120074187?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074187" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003276 OR RCV000057789 OR RCV000182128 OR RCV000541920 OR RCV000621158 OR RCV001102803 OR RCV001104722 OR RCV001841225" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003276, RCV000057789, RCV000182128, RCV000541920, RCV000621158, RCV001102803, RCV001104722, RCV001841225" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003276...</a>
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<p><a href="#60" class="mim-tip-reference" title="Priori, S. G., Schwartz, P. J., Napolitano, C., Bianchi, L., Dennis, A., De Fusco, M., Brown, A. M., Casari, G. <strong>A recessive variant of the Romano-Ward Long-QT syndrome?</strong> Circulation 97: 2420-2425, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9641694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9641694</a>] [<a href="https://doi.org/10.1161/01.cir.97.24.2420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9641694">Priori et al. (1998)</a> described a 9-year-old boy with classic Romano-Ward syndrome (LQT1; <a href="/entry/192500">192500</a>) (syncope, prolonged QT interval, normal audiogram) born to second cousins. Two brothers of the proband had died suddenly, one at rest and the other while swimming. Sequence analysis in the proband demonstrated a novel homozygous missense mutation, a G-to-A transition resulting in an alanine-to-threonine amino acid substitution at position 300 of the KVLQT1 protein. Both parents were heterozygous for this mutation and had normal QT intervals. None of 100 control chromosomes exhibited this mutation. Coexpression of the mutant KVLQT1 protein with minK (<a href="/entry/176261">176261</a>) in Xenopus oocytes demonstrated a mild electrophysiologic effect on ion flux. The authors commented that this mutation in the homozygous state caused Romano-Ward syndrome and not Jervell and Lange-Nielson syndrome (<a href="/entry/220400">220400</a>), citing it as evidence for a recessive variant of Romano-Ward syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9641694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0018 LONG QT SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397508069 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397508069;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397508069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397508069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003277" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003277" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003277</a>
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<p>After identifying a 10-year-old boy with long QT syndrome (<a href="/entry/192500">192500</a>) after a near-drowning that required defibrillation from torsade de pointes, <a href="#3" class="mim-tip-reference" title="Ackerman, M. J., Schroeder, J. J., Berry, R., Schaid, D. J., Porter, C.-B. J., Michels, V. V., Thibodeau, S. N. <strong>A novel mutation in KVLQT1 is the molecular basis of inherited long QT syndrome in a near-drowning patient's family.</strong> Pediat. Res. 44: 148-153, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9702906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9702906</a>] [<a href="https://doi.org/10.1203/00006450-199808000-00002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9702906">Ackerman et al. (1998)</a> evaluated first-degree relatives and found a 4-generation family comprising 26 individuals with 4 additional symptomatic and 8 asymptomatic members harboring an abnormally prolonged QT interval. Linkage to the 11p15.5 region was found with a maximum lod score of 3.36. A mutation search revealed a 3-bp deletion resulting in an in-frame deletion of codon 339 for phenylalanine. <a href="#3" class="mim-tip-reference" title="Ackerman, M. J., Schroeder, J. J., Berry, R., Schaid, D. J., Porter, C.-B. J., Michels, V. V., Thibodeau, S. N. <strong>A novel mutation in KVLQT1 is the molecular basis of inherited long QT syndrome in a near-drowning patient's family.</strong> Pediat. Res. 44: 148-153, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9702906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9702906</a>] [<a href="https://doi.org/10.1203/00006450-199808000-00002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9702906">Ackerman et al. (1998)</a> pointed out that the delF339 mutation is closely situated to codon 341, which is the site of 2 common mutations, A341V (<a href="#0010">607542.0010</a>) and A341E (<a href="#0009">607542.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9702906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397508107 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397508107;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397508107" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397508107" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003278 OR RCV000692974 OR RCV001567589 OR RCV002415390 OR RCV002476915" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003278, RCV000692974, RCV001567589, RCV002415390, RCV002476915" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003278...</a>
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<p>In a 19-year-old woman with LQT1 (<a href="/entry/192500">192500</a>) who had been asymptomatic but who died after a near-drowning, <a href="#4" class="mim-tip-reference" title="Ackerman, M. J., Tester, D. J., Porter, C. J., Edwards, W. D. <strong>Molecular diagnosis of the inherited long-QT syndrome in a woman who died after near-drowning.</strong> New Eng. J. Med. 341: 1121-1125, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10511610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10511610</a>] [<a href="https://doi.org/10.1056/NEJM199910073411504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10511610">Ackerman et al. (1999)</a> demonstrated by molecular tests at autopsy a 9-bp deletion involving nucleotides 373 through 381 of the KCNQ1 gene. The 9-bp deletion (GCCGCGCCC) resulted in an in-frame deletion of 3 amino acids (alanine, alanine, and proline) from position 71 through 73 in the cytoplasmic N-terminal region of the KCNQ1 ion channel subunit. The woman's maternal grandfather, mother, and 18-year-old sister also had the 9-bp deletion. It appears that a substantial number of unexplained drownings may have a basis in the long QT syndrome. Although the mother had electrocardiographic changes of long QT syndrome, the 18-year-old sister who was a carrier had equivocal or normal electrocardiogram in the view of half a panel of expert electrocardiographers. The resuscitation of the proband, although ultimately unsuccessful because of the extended period of anoxia, did allow electrocardiographic documentation of QT prolongation, which was a notable finding, given the entirely asymptomatic personal and family history. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10511610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs17215500 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs17215500;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs17215500?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs17215500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs17215500" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003279 OR RCV000148548 OR RCV000182196 OR RCV000251958 OR RCV000515748 OR RCV000614524 OR RCV000779058 OR RCV000999897 OR RCV001256915 OR RCV001841226 OR RCV001847566" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003279, RCV000148548, RCV000182196, RCV000251958, RCV000515748, RCV000614524, RCV000779058, RCV000999897, RCV001256915, RCV001841226, RCV001847566" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003279...</a>
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<p><a href="#34" class="mim-tip-reference" title="Larsen, L. A., Fosdal, I., Andersen, P. S., Kanters, J. K., Vuust, J., Wettrell, G., Christiansen, M. <strong>Recessive Romano-Ward syndrome associated with compound heterozygosity for two mutations in the KVLQT1 gene.</strong> Europ. J. Hum. Genet. 7: 724-728, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10482963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10482963</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10482963">Larsen et al. (1999)</a> described a Swedish family in which the proband and his brother suffered from severe Romano-Ward syndrome (LQT1; <a href="/entry/192500">192500</a>) associated with compound heterozygosity for 2 mutations in the KCNQ1 gene: R518X and A525T. The mutations were found to segregate in heterozygosity in the maternal and paternal lineage, respectively. None of the those heterozygous for a mutation exhibited clinical long QT syndrome. No hearing defects were found in the proband. The data strongly indicated that compound heterozygosity for these 2 mutations is the cause of the autosomal recessive form of RWS in this family. A recessive variant of the Ward-Romano long QT syndrome (<a href="#0017">607542.0017</a>) was suggested by <a href="#60" class="mim-tip-reference" title="Priori, S. G., Schwartz, P. J., Napolitano, C., Bianchi, L., Dennis, A., De Fusco, M., Brown, A. M., Casari, G. <strong>A recessive variant of the Romano-Ward Long-QT syndrome?</strong> Circulation 97: 2420-2425, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9641694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9641694</a>] [<a href="https://doi.org/10.1161/01.cir.97.24.2420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9641694">Priori et al. (1998)</a> on the basis of a finding of homozygosity in a consanguineous family. <a href="#34" class="mim-tip-reference" title="Larsen, L. A., Fosdal, I., Andersen, P. S., Kanters, J. K., Vuust, J., Wettrell, G., Christiansen, M. <strong>Recessive Romano-Ward syndrome associated with compound heterozygosity for two mutations in the KVLQT1 gene.</strong> Europ. J. Hum. Genet. 7: 724-728, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10482963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10482963</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10482963">Larsen et al. (1999)</a> suggested that 'sporadic RWS' should be considered as potentially recessive RWS, and efforts made to determine the molecular defects and identify carriers in the family, since they may be at risk of dying suddenly from drug-induced LQTS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10482963+9641694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs120074188 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074188;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs120074188?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003280 OR RCV000057600 OR RCV000182202 OR RCV000622131 OR RCV001851605" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003280, RCV000057600, RCV000182202, RCV000622131, RCV001851605" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003280...</a>
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<p>For discussion of the ala525-to-thr (A525T) mutation in the KCNQ1 gene that was found in compound heterozygous state in 2 brothers with severe Romano-Ward syndrome (LQT1; <a href="/entry/192500">192500</a>) by <a href="#34" class="mim-tip-reference" title="Larsen, L. A., Fosdal, I., Andersen, P. S., Kanters, J. K., Vuust, J., Wettrell, G., Christiansen, M. <strong>Recessive Romano-Ward syndrome associated with compound heterozygosity for two mutations in the KVLQT1 gene.</strong> Europ. J. Hum. Genet. 7: 724-728, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10482963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10482963</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10482963">Larsen et al. (1999)</a>, see <a href="#0020">607542.0020</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10482963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397508110 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397508110;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397508110" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397508110" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003281 OR RCV000182294 OR RCV001061673 OR RCV004991998" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003281, RCV000182294, RCV001061673, RCV004991998" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003281...</a>
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<p><a href="#16" class="mim-tip-reference" title="Chen, Q., Zhang, D., Gingell, R. L., Moss, A. J., Napolitano, C., Priori, S. G., Schwartz, P. J., Kehoe, E., Robinson, J. L., Schulze-Bahr, E., Wang, Q., Towbin, J. A. <strong>Homozygous deletion in KVLQT1 associated with Jervell and Lange-Nielsen syndrome.</strong> Circulation 99: 1344-1347, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077519</a>] [<a href="https://doi.org/10.1161/01.cir.99.10.1344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10077519">Chen et al. (1999)</a> reported a small Amish family in which 2 sibs fulfilled the diagnostic criteria for Jervell and Lange-Nielsen syndrome (JLNS1; <a href="/entry/220400">220400</a>). Both were homozygous for a novel 2-bp deletion in the S2 transmembrane domain of KVLQT1. This mutation predicts a frameshift leading to protein truncation. The protein product was predicted to be functionless due to most transmembrane domains and the pore region of the KVLQT1 protein having been deleted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10077519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906290 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906290;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387906290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387906290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003282 OR RCV002512697" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003282, RCV002512697" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003282...</a>
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<p><a href="#48" class="mim-tip-reference" title="Murray, A., Donger, C., Fenske, C., Spillman, I., Richard, P., Dong, Y. B., Neyroud, N., Chevalier, P., Denjoy, I., Carter, N., Syrris, P., Afzal, A. P., Patton, M. A., Guicheney, P., Jeffery, S. <strong>Splicing mutations in KCNQ1: a mutation hot spot at codon 344 that produces in frame transcripts.</strong> Circulation 100: 1077-1084, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10477533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10477533</a>] [<a href="https://doi.org/10.1161/01.cir.100.10.1077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10477533">Murray et al. (1999)</a> examined a French LQTS (<a href="/entry/192500">192500</a>) family and found a novel G-to-C transversion at position 922 -1 in the splice acceptor site of intron 5 of the KCNQ1 gene. The effect on splicing efficiency was not determined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10477533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1800171 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800171;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1800171?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1800171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1800171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003283 OR RCV000045941 OR RCV000182159 OR RCV000498423 OR RCV000621184 OR RCV002247243 OR RCV004017223" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003283, RCV000045941, RCV000182159, RCV000498423, RCV000621184, RCV002247243, RCV004017223" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003283...</a>
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<p><a href="#48" class="mim-tip-reference" title="Murray, A., Donger, C., Fenske, C., Spillman, I., Richard, P., Dong, Y. B., Neyroud, N., Chevalier, P., Denjoy, I., Carter, N., Syrris, P., Afzal, A. P., Patton, M. A., Guicheney, P., Jeffery, S. <strong>Splicing mutations in KCNQ1: a mutation hot spot at codon 344 that produces in frame transcripts.</strong> Circulation 100: 1077-1084, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10477533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10477533</a>] [<a href="https://doi.org/10.1161/01.cir.100.10.1077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10477533">Murray et al. (1999)</a> found linkage to KCNQ1 in a families with LQTS (<a href="/entry/192500">192500</a>) and detected a G-to-C transversion at position 1032 within the last codon of exon 6. The coded alanine was conserved. RT-PCR from fresh blood samples from the proband and his affected mother demonstrated transcripts lacking exons 6 and 7. Transcripts lacking exon 7 were also found in lymphocyte DNA from a patient with this mutation and in normal cardiac tissue from a patient without LQTS. The reading frame remained intact, resulting in the deletion of the pore, or S6, domain. These observations suggested that the G-to-C transversion in the exon 6/intron 7 consensus splice donor sequence affects splicing efficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10477533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The authors also found a G-to-A transition at position 1032 in 2 unrelated French families. This had been independently reported in 5 other families by <a href="#39" class="mim-tip-reference" title="Li, H., Chen, Q., Moss, A. J., Robinson, J., Goytia, V., Perry, J. C., Vincent, G. M., Priori, S. G., Lehmann, M. H., Denfield, S. W., Duff, D., Kaine, S., Shimizu, W., Schwartz, P. J., Wang, Q., Towbin, J. A. <strong>New mutations in the KVLQT1 potassium channel that cause long QT syndrome.</strong> Circulation 97: 1264-1269, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9570196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9570196</a>] [<a href="https://doi.org/10.1161/01.cir.97.13.1264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9570196">Li et al. (1998)</a> and <a href="#33" class="mim-tip-reference" title="Kanters, J. K., Larsen, L. A., Orholm, M., Agner, E., Anderson, P. S., Vuust, J., Christiansen, M. <strong>Novel donor splice site mutation in the KVLQT1 gene is associated with the long QT syndrome.</strong> J. Cardiovasc. Electrophysiol. 9: 620-624, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9654228/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9654228</a>] [<a href="https://doi.org/10.1111/j.1540-8167.1998.tb00944.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9654228">Kanters et al. (1998)</a>. <a href="#48" class="mim-tip-reference" title="Murray, A., Donger, C., Fenske, C., Spillman, I., Richard, P., Dong, Y. B., Neyroud, N., Chevalier, P., Denjoy, I., Carter, N., Syrris, P., Afzal, A. P., Patton, M. A., Guicheney, P., Jeffery, S. <strong>Splicing mutations in KCNQ1: a mutation hot spot at codon 344 that produces in frame transcripts.</strong> Circulation 100: 1077-1084, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10477533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10477533</a>] [<a href="https://doi.org/10.1161/01.cir.100.10.1077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10477533">Murray et al. (1999)</a> suggested that base position 1032 represented a mutation hotspot within KCNQ1. The commonest site for mutation is codon 341, in association with a methylated CpG dinucleotide. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9654228+9570196+10477533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397508104 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397508104;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397508104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397508104" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003284 OR RCV000046040 OR RCV000182288 OR RCV000622116 OR RCV001195549 OR RCV001841642" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003284, RCV000046040, RCV000182288, RCV000622116, RCV001195549, RCV001841642" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003284...</a>
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<p>In affected individuals in a family with Romano-Ward syndrome (LQT1; <a href="/entry/192500">192500</a>), <a href="#52" class="mim-tip-reference" title="Neyroud, N., Richard, P., Vignier, N., Donger, C., Denjoy, I., Demay, L., Shkolnikova, M., Pesce, R., Chevalier, P., Hainque, B., Coumel, P., Schwartz, K., Guicheney, P. <strong>Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome.</strong> Circ. Res. 84: 290-297, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10024302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10024302</a>] [<a href="https://doi.org/10.1161/01.res.84.3.290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10024302">Neyroud et al. (1999)</a>, detected insertion of a C at nucleotide position 1893 in exon 15. This created a frameshift with a premature stop codon 19 amino acids later, resulting in a largely intact protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10024302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0026 JERVELL AND LANGE-NIELSEN SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397508103 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397508103;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397508103" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397508103" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003285 OR RCV000182287 OR RCV001386478 OR RCV002408547 OR RCV002490606 OR RCV003591641 OR RCV004537220" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003285, RCV000182287, RCV001386478, RCV002408547, RCV002490606, RCV003591641, RCV004537220" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003285...</a>
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<p><a href="#52" class="mim-tip-reference" title="Neyroud, N., Richard, P., Vignier, N., Donger, C., Denjoy, I., Demay, L., Shkolnikova, M., Pesce, R., Chevalier, P., Hainque, B., Coumel, P., Schwartz, K., Guicheney, P. <strong>Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome.</strong> Circ. Res. 84: 290-297, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10024302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10024302</a>] [<a href="https://doi.org/10.1161/01.res.84.3.290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10024302">Neyroud et al. (1999)</a> found that a male with Jervell and Lange-Nielsen syndrome (JLNS1; <a href="/entry/220400">220400</a>) was compound heterozygous for a frameshift mutation in exon 15 of the KCNQ1 gene and another mutation that was not identified. The frameshift, caused by a 20-bp deletion at nucleotide position 1892, created a premature stop codon 13 amino acids later. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10024302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0027 JERVELL AND LANGE-NIELSEN SYNDROME 1</strong>
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KCNQ1, THR587MET
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs120074189 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074189;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003286 OR RCV000046026 OR RCV000057632 OR RCV000182221 OR RCV000619349 OR RCV003319300 OR RCV004732528" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003286, RCV000046026, RCV000057632, RCV000182221, RCV000619349, RCV003319300, RCV004732528" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003286...</a>
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<p><a href="#52" class="mim-tip-reference" title="Neyroud, N., Richard, P., Vignier, N., Donger, C., Denjoy, I., Demay, L., Shkolnikova, M., Pesce, R., Chevalier, P., Hainque, B., Coumel, P., Schwartz, K., Guicheney, P. <strong>Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome.</strong> Circ. Res. 84: 290-297, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10024302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10024302</a>] [<a href="https://doi.org/10.1161/01.res.84.3.290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10024302">Neyroud et al. (1999)</a> reported that a male patient (family JLN12664) with Jervell Lange-Nielsen syndrome (JLNS1; <a href="/entry/220400">220400</a>) was compound heterozygous for 2 mutations in the KCNQ1 gene: a de novo 1760C-T transition in exon 14, resulting in a thr587-to-met substitution, on the paternal allele, and a maternally derived splice site mutation in intron 1 (<a href="#0028">607542.0028</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10024302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0028 JERVELL AND LANGE-NIELSEN SYNDROME 1</strong>
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KCNQ1, IVS1
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003287" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003287" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003287</a>
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<p><a href="#52" class="mim-tip-reference" title="Neyroud, N., Richard, P., Vignier, N., Donger, C., Denjoy, I., Demay, L., Shkolnikova, M., Pesce, R., Chevalier, P., Hainque, B., Coumel, P., Schwartz, K., Guicheney, P. <strong>Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome.</strong> Circ. Res. 84: 290-297, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10024302/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10024302</a>] [<a href="https://doi.org/10.1161/01.res.84.3.290" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10024302">Neyroud et al. (1999)</a> reported that a male patient with Jervell Lange-Nielsen syndrome (JLNS1; <a href="/entry/220400">220400</a>) was compound heterozygous for 2 mutations in the KCNQ1 gene: a de novo 1760C-T transition in exon 14, resulting in a thr587-to-met substitution (<a href="#0027">607542.0027</a>), on the paternal allele, and a maternally derived splice mutation in intron 1. No additional information was provided for the intron 1 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10024302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0029 LONG QT SYNDROME 1</strong>
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JERVELL AND LANGE-NIELSEN SYNDROME 1, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs120074190 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074190;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs120074190?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003288 OR RCV000003289 OR RCV000057633 OR RCV000182223 OR RCV000622145 OR RCV000699476 OR RCV001258106 OR RCV001841227" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003288, RCV000003289, RCV000057633, RCV000182223, RCV000622145, RCV000699476, RCV001258106, RCV001841227" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003288...</a>
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<p><a href="#57" class="mim-tip-reference" title="Piippo, K., Swan, H., Pasternack, M., Chapman, H., Paavonen, K., Viitasalo, M., Toivonen, L., Kontula, K. <strong>A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics.</strong> J. Am. Coll. Cardiol. 37: 562-568, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11216980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11216980</a>] [<a href="https://doi.org/10.1016/s0735-1097(00)01124-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11216980">Piippo et al. (2001)</a> identified a novel missense mutation in the KCNQ1 gene in Finns with Jervell and Lange-Nielsen syndrome (JLNS1; <a href="/entry/220400">220400</a>) or long QT syndrome (<a href="/entry/192500">192500</a>). The mutation, a glycine-to-aspartic acid substitution at codon 589 (G589D) in the C terminus, was identified in homozygous state in 2 sibs with Jervell and Lange-Nielsen syndrome and in heterozygous state in 34 of 114 probands with Romano-Ward syndrome and 282 family members. The mean rate-corrected QT intervals of the 316 heterozygous subjects and 423 noncarriers were 460 +/- 40 ms and 410 +/- 20 ms (p less than 0.001), respectively. <a href="#57" class="mim-tip-reference" title="Piippo, K., Swan, H., Pasternack, M., Chapman, H., Paavonen, K., Viitasalo, M., Toivonen, L., Kontula, K. <strong>A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics.</strong> J. Am. Coll. Cardiol. 37: 562-568, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11216980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11216980</a>] [<a href="https://doi.org/10.1016/s0735-1097(00)01124-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11216980">Piippo et al. (2001)</a> concluded that the G589D mutation accounts for 30% of Finnish cases with long QT syndrome and may be associated with both Romano-Ward and Jervell and Lange-Nielsen phenotypes of the syndrome. They suggested that the relative enrichment of this mutation most likely represents a founder gene effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11216980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs120074191 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074191;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003290 OR RCV000057662 OR RCV001349040" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003290, RCV000057662, RCV001349040" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003290...</a>
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<p><a href="#67" class="mim-tip-reference" title="Schwartz, P. J., Priori, S. G., Bloise, R., Napolitano, C., Ronchetti, E., Piccinini, A., Goj, C., Breithardt, G., Schulze-Bahr, E., Wedekind, H., Nastoli, J. <strong>Molecular diagnosis in a child with sudden infant death syndrome. (Letter)</strong> Lancet 358: 1342-1343, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11684219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11684219</a>] [<a href="https://doi.org/10.1016/S0140-6736(01)06450-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11684219">Schwartz et al. (2001)</a> identified 2 Italian families with LQT1 (<a href="/entry/192500">192500</a>) with the same heterozygous 350C-T transition in the KCNQ1 gene, resulting in a pro117-to-leu (P117L) substitution. In 1 family, an infant had died of SIDS and was found postmortem to have a de novo mutation. In the other family, several members had long QT syndrome. The mutation was not found in 800 reference alleles of Italian origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11684219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs17221854 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs17221854;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs17221854?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs17221854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs17221854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003291 OR RCV000003292 OR RCV000057628 OR RCV000182219 OR RCV000762837 OR RCV001824559 OR RCV001851606 OR RCV003591618 OR RCV004018545" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003291, RCV000003292, RCV000057628, RCV000182219, RCV000762837, RCV001824559, RCV001851606, RCV003591618, RCV004018545" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003291...</a>
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<p>In a patient with long QT syndrome (<a href="/entry/192500">192500</a>), <a href="#71" class="mim-tip-reference" title="Splawski, I., Shen, J., Timothy, K. W., Lehmann, M. H., Priori, S., Robinson, J. L., Moss, A. J., Schwartz, P. J., Towbin, J. A., Vincent, G. M., Keating, M. T. <strong>Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2.</strong> Circulation 102: 1178-1185, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10973849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10973849</a>] [<a href="https://doi.org/10.1161/01.cir.102.10.1178" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10973849">Splawski et al. (2000)</a> identified heterozygosity for a 1747C-T transition in exon 15 of the KCNQ1 gene, resulting in an arg583-to-cys (R583C) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10973849" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient who developed QT prolongation and torsade de pointes while taking the drug dofetilide (see <a href="/entry/192500">192500</a>), <a href="#84" class="mim-tip-reference" title="Yang, P., Kanki, H., Drolet, B., Yang, T., Wei, J., Viswanathan, P. C., Hohnloser, S. H., Shimizu, W., Schwartz, P. J., Stanton, M., Murray, K. T., Norris, K., George, A. L., Jr., Roden, D. M. <strong>Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.</strong> Circulation 105: 1943-1948, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11997281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11997281</a>] [<a href="https://doi.org/10.1161/01.cir.0000014448.19052.4c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11997281">Yang et al. (2002)</a> identified heterozygosity for an R583C mutation in the KCNQ1 gene. The mutation was not found in 228 controls. In vitro expression studies of the mutant protein confirmed a significant reduction in potassium currents, suggesting that the R583C mutation was responsible for the patient's response to dofetilide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11997281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs120074192 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074192;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 4-generation family with autosomal dominant atrial fibrillation (ATFB3; <a href="/entry/607554">607554</a>) from Shandong Province, China, <a href="#18" class="mim-tip-reference" title="Chen, Y.-H., Xu, S.-J., Bendahhou, S., Wang, X.-L., Wang, Y., Xu, W.-Y., Jin, H.-W., Sun, H., Su, X.-Y., Zhuang, Q.-N., Yang, Y.-Q., Li, Y.-B., Liu, Y., Xu, H.-J., Li, X.-F., Ma, N., Mou, C.-P., Chen, Z., Barhanin, J., Huang, W. <strong>KCNQ1 gain-of-function mutation in familial atrial fibrillation.</strong> Science 299: 251-254, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522251</a>] [<a href="https://doi.org/10.1126/science.1077771" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522251">Chen et al. (2003)</a> identified an A-to-G substitution at nucleotide 418 of the KCNQ1 gene leading to a ser-to-gly substitution at codon 140 in all affected family members. This mutation was not observed in normal individuals in the family with 1 exception, which <a href="#18" class="mim-tip-reference" title="Chen, Y.-H., Xu, S.-J., Bendahhou, S., Wang, X.-L., Wang, Y., Xu, W.-Y., Jin, H.-W., Sun, H., Su, X.-Y., Zhuang, Q.-N., Yang, Y.-Q., Li, Y.-B., Liu, Y., Xu, H.-J., Li, X.-F., Ma, N., Mou, C.-P., Chen, Z., Barhanin, J., Huang, W. <strong>KCNQ1 gain-of-function mutation in familial atrial fibrillation.</strong> Science 299: 251-254, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522251</a>] [<a href="https://doi.org/10.1126/science.1077771" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522251">Chen et al. (2003)</a> ascribed to delayed manifestation or incomplete penetrance. A prolonged QTc interval was observed in 9 of the 16 affected family members, ranging from 450 to 530 ms. The mutation was absent in 188 healthy control individuals. The serine at position 140 is well conserved among different species and is located in the S1 transmembrane segment of KCNQ1 in a position close to the extracellular surface of the plasma membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12522251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using Xenopus oocytes expressing human KCNQ1 in the presence or absence of KCNE1 (<a href="/entry/176261">176261</a>), <a href="#56" class="mim-tip-reference" title="Peng, G., Barro-Soria, R., Sampson, K. J., Larsson, H. P., Kass, R. S. <strong>Gating mechanisms underlying deactivation slowing by two KCNQ1 atrial fibrillation mutations.</strong> Sci. Rep. 7: 45911, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28383569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28383569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28383569[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/srep45911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28383569">Peng et al. (2017)</a> characterized 2 KCNQ1 gain-of-function mutations that cause atrial fibrillation, S140G and val141 to met (V141M; <a href="#0045">607542.0045</a>). In the absence of KCNE1, S140G, but not V141M, slowed voltage sensor movement, leading to indirect slowing of current deactivation. Slowing of voltage sensor deactivation by S140G in the absence of KCNE1 was independent of channel opening. When KCNE1 was coexpressed, S140G slowed both current deactivation and voltage sensor movement, whereas V141M slowed current deactivation without slowing voltage sensor movement. Slowing of voltage sensor deactivation by S140G in the presence of KCNE1 was dependent on channel opening. The authors proposed a molecular mechanism underlying the effects of the KCNQ1 mutations on channel gating and suggested that KCNE1 mediates changes in pore movement and voltage sensor-pore coupling to slow channel deactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28383569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs120074193 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074193;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs120074193?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003294 OR RCV000057765 OR RCV000182118 OR RCV000477568 OR RCV000762834 OR RCV001002562 OR RCV002408447" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003294, RCV000057765, RCV000182118, RCV000477568, RCV000762834, RCV001002562, RCV002408447" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003294...</a>
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<p><a href="#62" class="mim-tip-reference" title="Reardon, W., Lewis, N., Hughes, H. E. <strong>Consanguinity, cardiac arrest, hearing impairment and ECG abnormalities: counselling pitfalls in the Romano-Ward syndrome.</strong> J. Med. Genet. 30: 325-327, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8487283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8487283</a>] [<a href="https://doi.org/10.1136/jmg.30.4.325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8487283">Reardon et al. (1993)</a> reported a family in which the proband had a cardiac arrest at 4 years of age; she and her brother were then found to have a QTc of 490 ms. The parents of the proband were first cousins and there were hearing abnormalities reported in several family members. It was uncertain whether the diagnosis should be Romano-Ward syndrome (<a href="/entry/192500">192500</a>), which is dominant, or Jervell and Lange-Nielsen syndrome (<a href="/entry/220400">220400</a>), which is recessive. <a href="#49" class="mim-tip-reference" title="Murray, A., Potet, F., Bellocq, C., Baro, I., Reardon, W., Hughes, H. E., Jeffery, S. <strong>Mutation in KCNQ1 that has both recessive and dominant characteristics.</strong> J. Med. Genet. 39: 681-685, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12205113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12205113</a>] [<a href="https://doi.org/10.1136/jmg.39.9.681" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12205113">Murray et al. (2002)</a> identified a gly269-to-ser (G269S) mutation in the KCNQ1 gene in homozygous state in the proband and her brother. Functional studies indicated that the mutation had both recessive and dominant characteristics. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8487283+12205113" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0034 LONG QT SYNDROME 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs120074194 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074194;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003295 OR RCV000046133 OR RCV000057766 OR RCV000182119 OR RCV002415391 OR RCV004540987" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003295, RCV000046133, RCV000057766, RCV000182119, RCV002415391, RCV004540987" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003295...</a>
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<p>In 8 affected members of a family with a severe form of dominantly inherited Romano-Ward syndrome (<a href="/entry/192500">192500</a>), 5 of whom had sudden deaths, <a href="#23" class="mim-tip-reference" title="Donger, C., Denjoy, I., Berthet, M., Neyroud, N., Cruaud, C., Bennaceur, M., Chivoret, G., Schwartz, K., Coumel, P., Guicheney, P. <strong>KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome.</strong> Circulation 96: 2778-2781, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9386136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9386136</a>] [<a href="https://doi.org/10.1161/01.cir.96.9.2778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9386136">Donger et al. (1997)</a> identified a gly269-to-asp (G269D) mutation in the KCNQ1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9386136" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0035 LONG QT SYNDROME 1</strong>
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KCNQ1, VAL254MET AND VAL417MET
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267607197 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607197;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267607197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267607197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003265 OR RCV000003296 OR RCV000057749 OR RCV000182109 OR RCV000190212 OR RCV000619506 OR RCV001841405" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003265, RCV000003296, RCV000057749, RCV000182109, RCV000190212, RCV000619506, RCV001841405" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003265...</a>
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<p><a href="#82" class="mim-tip-reference" title="Wedekind, H., Schwarz, M., Hauenschild, S., Djonlagic, H., Haverkamp, W., Breithardt, G., Wulfing, T., Pongs, O., Isbrandt, D., Schulze-Bahr, E. <strong>Effective long-term control of cardiac events with beta-blockers in a family with a common LQT1 mutation.</strong> Clin. Genet. 65: 233-241, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14756674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14756674</a>] [<a href="https://doi.org/10.1111/j.0009-9163.2004.00221.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14756674">Wedekind et al. (2004)</a> described a 4-generation family with long QT syndrome (<a href="/entry/192500">192500</a>) in which 7 members were carriers of 2 amino acid alterations in cis in the KCNQ1 gene: val254 to met (V254M) and val417 to met (V417M). Voltage clamp recordings of mutant KCNQ1 protein in Xenopus oocytes showed that only the V254M mutation reduced the I(Ks) current and that the effect of the V417M variant was negligible. The family exhibited the complete clinical spectrum of the disease, from asymptomatic patients to victims of sudden death before beta-blocker therapy. Of 9 family members, 1 female died suddenly before treatment, 3 females of the second generation were asymptomatic, and 4 members of the third and fourth generations were symptomatic. All mutation carriers were treated with beta-blockers and remained asymptomatic for a follow-up of up to 23 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14756674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0036 LONG QT SYNDROME 1</strong>
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KCNQ1, 1-BP DEL/2-BP INS, NT533
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397508115 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397508115;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397508115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397508115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003297" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003297" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003297</a>
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<p>In a 13-year-old girl with long QT syndrome (<a href="/entry/192500">192500</a>), <a href="#5" class="mim-tip-reference" title="Aizawa, Y., Ueda, K., Wu, L., Inagaki, N., Hayashi, T., Takahashi, M., Ohta, M., Kawano, S., Hirano, Y., Yasunami, M., Aizawa, Y., Kimura, A., Hiraoka, M. <strong>Truncated KCNQ1 mutant, A178fs/105, forms hetero-multimer channel with wild-type causing a dominant-negative suppression due to trafficking defect.</strong> FEBS Lett. 574: 145-150, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15358555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15358555</a>] [<a href="https://doi.org/10.1016/j.febslet.2004.08.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15358555">Aizawa et al. (2004)</a> identified a C-to-GG substitution at nucleotide 533 in the KCNQ1 gene, causing a frameshift at alanine-178 and resulting in a truncated protein with elimination of the S3 to S6 domains and the C terminus of the KCNQ1 channel. Coexpression experiments in COS-7 cells showed that mutant and wildtype KCNQ1 remained within the cytoplasm rather than being distributed to the plasma membrane, suggesting that the truncated mutant forms a heteromultimer with wildtype KCNQ1 and causes a dominant-negative effect due to a trafficking defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15358555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0037" class="mim-anchor"></a>
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<strong>.0037 SHORT QT SYNDROME 2</strong>
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KCNQ1, VAL307LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs120074195 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074195;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs120074195?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003298 OR RCV000057800 OR RCV003996077" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003298, RCV000057800, RCV003996077" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003298...</a>
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<p>In a 70-year-old man with short QT syndrome-2 (SQT2; <a href="/entry/609621">609621</a>) who survived an episode of ventricular fibrillation, <a href="#10" class="mim-tip-reference" title="Bellocq, C., van Ginneken, A. C. G., Bezzina, C. R., Alders, M., Escande, D., Mannens, M. M. A. M., Baro, I., Wilde, A. A. M. <strong>Mutation in the KCNQ1 gene leading to the short QT-interval syndrome.</strong> Circulation 109: 2394-2397, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15159330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15159330</a>] [<a href="https://doi.org/10.1161/01.CIR.0000130409.72142.FE" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15159330">Bellocq et al. (2004)</a> identified a 919G-C transversion in the KCNQ1 gene, resulting in a val307-to-leu (V307L) substitution. Functional studies of the mutant channel revealed that both a pronounced shift of the half-activation potential and an acceleration of the activation kinetics led to a gain of function in I(Ks). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15159330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Functional studies of the mutant channel revealed that both a pronounced shift of the half-activation potential and an acceleration of the activation kinetics led to a gain of function in I(Ks).</p>
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<a id="0038" class="mim-anchor"></a>
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<strong>.0038 LONG QT SYNDROME 1/2, DIGENIC</strong>
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KCNQ1, 1-BP DEL, 562T
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397508116 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397508116;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs397508116?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397508116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397508116" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003299" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003299" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003299</a>
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<p>In a female infant with a family history of sudden death, who had severe, continuous bradycardia in utero that was confirmed after birth and a QTc of 485 ms (see <a href="/entry/192500">192500</a>), <a href="#45" class="mim-tip-reference" title="Millat, G., Chevalier, P., Restier-Miron, L., Da Costa, A., Bouvagnet, P., Kugener, B., Fayol, L., Gonzalez Armengod, C., Oddou, B., Chanavat, V., Froidefond, E., Perraudin, R., Rousson, R., Rodriguez-Lafrasse, C. <strong>Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.</strong> Clin. Genet. 70: 214-227, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16922724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16922724</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00671.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16922724">Millat et al. (2006)</a> identified biallelic digenic mutations: a 1-bp deletion (562delT) in exon 2 of the KCNQ1 gene, causing a frameshift at trp188, and an insertion in the KCNH2 gene (2775insG; <a href="/entry/152427#0020">152427.0020</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0039 LONG QT SYNDROME 1/2, DIGENIC</strong>
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KCNQ1, ARG243PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs120074196 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs120074196;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs120074196?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs120074196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs120074196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003300 OR RCV000057743" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003300, RCV000057743" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003300...</a>
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<p>In a female infant with fetal and neonatal bradycardia and a QTc of 570 ms (see <a href="/entry/192500">192500</a>), <a href="#45" class="mim-tip-reference" title="Millat, G., Chevalier, P., Restier-Miron, L., Da Costa, A., Bouvagnet, P., Kugener, B., Fayol, L., Gonzalez Armengod, C., Oddou, B., Chanavat, V., Froidefond, E., Perraudin, R., Rousson, R., Rodriguez-Lafrasse, C. <strong>Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.</strong> Clin. Genet. 70: 214-227, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16922724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16922724</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00671.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16922724">Millat et al. (2006)</a> identified biallelic digenic mutations: a 728G-C transversion in exon 4 of the KCNQ1 gene, resulting in an arg243-to-pro (R243P) substitution, and a missense mutation in the KCNH2 gene (R948C; <a href="/entry/152427#0022">152427.0022</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0040" class="mim-anchor"></a>
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<strong>.0040 LONG QT SYNDROME 1</strong>
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KCNQ1, VAL205MET
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs151344631 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs151344631;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs151344631?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs151344631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs151344631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000030815 OR RCV000057723 OR RCV000119056 OR RCV000148547 OR RCV000252730" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030815, RCV000057723, RCV000119056, RCV000148547, RCV000252730" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030815...</a>
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<p>In 2 severely affected index cases with long QT syndrome (LQT1; <a href="/entry/192500">192500</a>) from a First Nations community in northern British Columbia (Gitxsan), <a href="#6" class="mim-tip-reference" title="Arbour, L., Rezazadeh, S., Eldstrom, J., Weget-Simms, G., Rupps, R., Dyer, Z., Tibbits, G., Accili, E., Casey, B., Kmetic, A., Sanatani, S., Fedida, D. <strong>A KCNQ1 V205M missense mutation causes a high rate of long QT syndrome in a First Nations community of northern British Columbia: a community-based approach to understanding the impact.</strong> Genet. Med. 10: 545-550, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18580685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18580685</a>] [<a href="https://doi.org/10.1097/gim.0b013e31817c6b19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18580685">Arbour et al. (2008)</a> identified a G-to-A transition in exon 4 of the KCNQ1 gene that resulted in a val-to-met substitution at codon 205 (V205M). Identification of the mutation prompted the ascertainment of 122 relatives using community-based participatory research principles. The 22 further mutation carriers identified had a significantly higher mean corrected QT interval than noncarriers (465 +/- 28 milliseconds vs 434 +/- 26 milliseconds, P less than 0.0001); however, 30% of carriers had a corrected QT interval below 440 milliseconds. In transfected mouse Itk cells this mutation suppressed I(Ks) by causing a dramatic depolarizing shift in activation voltage coupled with acceleration of channel deactivation. <a href="#6" class="mim-tip-reference" title="Arbour, L., Rezazadeh, S., Eldstrom, J., Weget-Simms, G., Rupps, R., Dyer, Z., Tibbits, G., Accili, E., Casey, B., Kmetic, A., Sanatani, S., Fedida, D. <strong>A KCNQ1 V205M missense mutation causes a high rate of long QT syndrome in a First Nations community of northern British Columbia: a community-based approach to understanding the impact.</strong> Genet. Med. 10: 545-550, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18580685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18580685</a>] [<a href="https://doi.org/10.1097/gim.0b013e31817c6b19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18580685">Arbour et al. (2008)</a> concluded that this mutation likely conferred increased susceptibility to arrhythmias because of decreased I(Ks) current. Even with a common mutation within a relatively homogeneous population, clinical expression remains variable, supporting the difficulty of definitive diagnosis without genetic testing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18580685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0041" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0041 ATRIAL FIBRILLATION, FAMILIAL, 3</strong>
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KCNQ1, 9-BP DUP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs397515877 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397515877;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs397515877?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397515877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397515877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000035343 OR RCV000114749 OR RCV000250643 OR RCV000852643 OR RCV001080143 OR RCV001719723 OR RCV004534735" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000035343, RCV000114749, RCV000250643, RCV000852643, RCV001080143, RCV001719723, RCV004534735" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000035343...</a>
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<p>In affected members of a Caucasian kindred segregating autosomal dominant early-onset lone atrial fibrillation (ATFB3; <a href="/entry/607554">607554</a>), <a href="#1" class="mim-tip-reference" title="Abraham, R. L., Yang, T., Blair, M., Roden, D. M., Darbar, D. <strong>Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation.</strong> J. Molec. Cell. Cardiol. 48: 181-190, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19646991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19646991</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19646991[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.yjmcc.2009.07.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19646991">Abraham et al. (2010)</a> identified heterozygosity for a 9-bp duplication in the KCNQ1 gene, resulting in insertion of isoleucine, alanine, and proline at positions 54 to 56. The duplication was present in all 4 affected family members and in 2 symptomatic family members in whom atrial fibrillation had not yet been documented. It was not found in 3 unaffected family members or in Caucasian, Han Chinese, and Asian population controls; however, the duplication was detected in 2 (2.1%) of 94 African American control chromosomes that had been obtained from the anonymous Coriell repository, for which no clinical information was available. Functional analysis in CHO cells demonstrated that coexpression of mutant KCNQ1 with its ancillary subunit KCNE1 (<a href="/entry/176261">176261</a>) generated approximately 3-fold larger currents that also activated much earlier than wildtype currents. The mutant accelerated both activation and deactivation over all voltages. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19646991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0042" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0042 ATRIAL FIBRILLATION, FAMILIAL, 3</strong>
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KCNQ1, SER209PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199472705 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199472705;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199472705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199472705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000057725 OR RCV000115006 OR RCV000232681" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000057725, RCV000115006, RCV000232681" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000057725...</a>
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<p>In affected members of a 3-generation family with lone atrial fibrillation (ATFB3; <a href="/entry/607554">607554</a>), <a href="#20" class="mim-tip-reference" title="Das, S., Makino, S., Melman, Y. F., Shea, M. A., Goyal, S. B., Rosenzweig, A., MacRae, C. A., Ellinor, P. T. <strong>Mutation in the S3 segment of KCNQ1 results in familial lone atrial fibrillation.</strong> Heart Rhythm 6: 1146-1153, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19632626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19632626</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19632626[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.hrthm.2009.04.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19632626">Das et al. (2009)</a> identified heterozygosity for a c.625C-T transition in the KCNQ1 gene, resulting in a ser209-to-pro (S209P) substitution at a highly conserved residue in the C-terminal half of the third transmembrane region (S3b) of the channel protein. The mutation was incompletely penetrant, as 1 carrier individual with an affected child was unaffected both by history and by longitudinal ECG monitoring; however, the mutation was not found in more than 1,000 control chromosomes. Mutation carriers had a longer QRS duration and a trend toward larger left atrial dimension than noncarriers, but there was no difference in PR or corrected QT interval. Functional analysis in COS-7 cells demonstrated that S209P mutant channels activate more rapidly, deactivate more slowly, and have a hyperpolarizing shift in the voltage deactivation curve compared to wildtype. In addition, a fraction of mutant channels are constitutively open at all voltages, resulting in a net increase in I(Ks) current. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19632626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs199472709 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199472709;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs199472709?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199472709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199472709" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000046107 OR RCV000057734 OR RCV000115007 OR RCV000115008 OR RCV000182101 OR RCV000762833 OR RCV002371883" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000046107, RCV000057734, RCV000115007, RCV000115008, RCV000182101, RCV000762833, RCV002371883" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000046107...</a>
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<p><a href="#31" class="mim-tip-reference" title="Johnson, J. N., Tester, D. J., Perry, J., Salisbury, B. A., Reed, C. R., Ackerman, M. J. <strong>Prevalence of early-onset atrial fibrillation in congenital long QT syndrome.</strong> Heart Rhythm 5: 704-709, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18452873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18452873</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18452873[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.hrthm.2008.02.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18452873">Johnson et al. (2008)</a> reported a female patient with onset of atrial fibrillation (ATFB3; <a href="/entry/607554">607554</a>) in the first year of life who was heterozygous for a c.692G-A transition in exon 5 of the KCNQ1 gene, resulting in an arg231-to-his (R231H) substitution. The patient was also found to have a long QT interval (see <a href="/entry/192500">192500</a>) at 1 year of age, with a QTc of 479 ms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18452873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 4 families with early-onset atrial fibrillation, <a href="#9" class="mim-tip-reference" title="Bartos, D. C., Anderson, J. B., Bastiaenen, R., Johnson, J. N., Gollob, M. H., Tester, D. J., Burgess, D. E., Homfray, T., Behr, E. R., Ackerman, M. J., Guicheney, P., Delisle, B. P. <strong>A KCNQ1 mutation causes a high penetrance for familial atrial fibrillation.</strong> J. Cardiovasc. Electrophysiol. 24: 562-569, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23350853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23350853</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23350853[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1111/jce.12068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23350853">Bartos et al. (2013)</a> identified heterozygosity for the R231H mutation in KCNQ1. Twelve of 13 mutation-positive individuals had a normal QTc, and 1 had a prolonged QT interval. Functional analysis indicated that the R231H mutation increases the amount of KCNQ1 current during the atrial action potential, thus dramatically shortening its duration. R231H also disrupts PKA (see <a href="/entry/188830">188830</a>) regulation of the KCNQ1 current and is associated with borderline and adrenergic-induced QT interval prolongation in patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23350853" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a family with atrial fibrillation, <a href="#27" class="mim-tip-reference" title="Guerrier, K., Czosek, R. J., Spar, D. S., Anderson, J. <strong>Long QT genetics manifesting as atrial fibrillation.</strong> Heart Rhythm 10: 1351-1353, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23851063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23851063</a>] [<a href="https://doi.org/10.1016/j.hrthm.2013.07.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23851063">Guerrier et al. (2013)</a> identified heterozygosity for the R231H missense mutation in KCNQ1. <a href="#27" class="mim-tip-reference" title="Guerrier, K., Czosek, R. J., Spar, D. S., Anderson, J. <strong>Long QT genetics manifesting as atrial fibrillation.</strong> Heart Rhythm 10: 1351-1353, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23851063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23851063</a>] [<a href="https://doi.org/10.1016/j.hrthm.2013.07.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23851063">Guerrier et al. (2013)</a> noted that the R231H mutation had previously been identified by <a href="#50" class="mim-tip-reference" title="Napolitano, C., Priori, S. G., Schwartz, P. J., Bloise, R., Ronchetti, E., Nastoli, J., Bottelli, G., Cerrone, M., Leonardi, S. <strong>Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice.</strong> JAMA 294: 2975-2980, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16414944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16414944</a>] [<a href="https://doi.org/10.1001/jama.294.23.2975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16414944">Napolitano et al. (2005)</a> in a study of patients with long QT syndrome, but stated that none of the family members with atrial fibrillation had documented prolonged QT intervals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23851063+16414944" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199472708 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199472708;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199472708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199472708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000057732 OR RCV000115009 OR RCV000182099 OR RCV001320480 OR RCV003335080" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000057732, RCV000115009, RCV000182099, RCV001320480, RCV003335080" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000057732...</a>
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<p>In a Japanese boy who was diagnosed at 16 years of age with atrial fibrillation (ATFB3; <a href="/entry/607554">607554</a>), <a href="#28" class="mim-tip-reference" title="Hasegawa, K., Ohno, S., Ashihara, T., Itoh, H., Ding, W.-G., Toyoda, F., Makiyama, T., Aoki, H., Nakamura, Y., Delisle, B. P., Matsuura, H., Horie, M. <strong>A novel KCNQ1 missense mutation identified in a patient with juvenile-onset atrial fibrillation causes constitutively open I(Ks) channels.</strong> Heart Rhythm 11: 67-75, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24096004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24096004</a>] [<a href="https://doi.org/10.1016/j.hrthm.2013.09.073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24096004">Hasegawa et al. (2014)</a> identified heterozygosity for a c.686G-A transition in the KCNQ1 gene, resulting in a gly229-to-asp (G229D) substitution at a highly conserved residue in the fourth transmembrane segment (S4), which is known to be a voltage sensor. Although ECG at the time of diagnosis showed a normal QT interval, the proband was later found to have borderline QT prolongation (QTc 452 ms to 480 ms), and the mutation was detected in his asymptomatic mother, who also had borderline QT prolongation (QTc 468 ms). The mutation was not found in 400 Japanese control alleles or in the NHLBI Exome Sequencing Project Exome Variant Server database. G229D mutant channels in CHO cells displayed unique functional properties, including a large instantaneous activating component without deactivation after repolarization. <a href="#28" class="mim-tip-reference" title="Hasegawa, K., Ohno, S., Ashihara, T., Itoh, H., Ding, W.-G., Toyoda, F., Makiyama, T., Aoki, H., Nakamura, Y., Delisle, B. P., Matsuura, H., Horie, M. <strong>A novel KCNQ1 missense mutation identified in a patient with juvenile-onset atrial fibrillation causes constitutively open I(Ks) channels.</strong> Heart Rhythm 11: 67-75, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24096004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24096004</a>] [<a href="https://doi.org/10.1016/j.hrthm.2013.09.073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24096004">Hasegawa et al. (2014)</a> concluded that G229D alters I(Ks) activity and kinetics, thereby increasing arrhythmogenicity to atrial fibrillation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24096004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs199472687 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199472687;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs199472687" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs199472687" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000057674 OR RCV000417071 OR RCV000468931 OR RCV000494365 OR RCV000621525" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000057674, RCV000417071, RCV000468931, RCV000494365, RCV000621525" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000057674...</a>
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<p>In a female infant with short QT interval, atrial fibrillation, and bradycardia (SQT2; <a href="/entry/609621">609621</a>), <a href="#29" class="mim-tip-reference" title="Hong, K., Piper, D. R., Diaz-Valdecantos, A., Brugada, J., Oliva, A., Burashnikov, E., Santos-de-Soto, J., Grueso-Montero, J., Diaz-Enfante, E., Brugada, P., Sachse, F., Sanguinetti, M. C., Brugada, R. <strong>De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero.</strong> Cardiovasc. Res. 68: 433-440, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16109388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16109388</a>] [<a href="https://doi.org/10.1016/j.cardiores.2005.06.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16109388">Hong et al. (2005)</a> identified heterozygosity for a c.421G-A transition in the KCNQ1 gene, resulting in a val141-to-met (V141M) substitution within transmembrane domain S1. Functional analysis in Xenopus oocytes demonstrated that in contrast to wildtype channels, which exhibited a slowly activating and deactivating voltage-dependent and K(+)-selective current, the V141M mutant channel current developed instantly at all voltages tested, consistent with a constitutively open channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16109388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated girls with short QT syndrome, AF, and bradycardia, <a href="#80" class="mim-tip-reference" title="Villafane, J., Fischbach, P., Gebauer, R. <strong>Short QT syndrome manifesting with neonatal atrial fibrillation and bradycardia.</strong> Cardiology 128: 236-240, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24818999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24818999</a>] [<a href="https://doi.org/10.1159/000360758" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24818999">Villafane et al. (2014)</a> identified heterozygosity for the V141M mutation in the KCNQ1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24818999" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using Xenopus oocytes expressing human KCNQ1 in the presence or absence of KCNE1 (<a href="/entry/176261">176261</a>), <a href="#56" class="mim-tip-reference" title="Peng, G., Barro-Soria, R., Sampson, K. J., Larsson, H. P., Kass, R. S. <strong>Gating mechanisms underlying deactivation slowing by two KCNQ1 atrial fibrillation mutations.</strong> Sci. Rep. 7: 45911, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28383569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28383569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28383569[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/srep45911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28383569">Peng et al. (2017)</a> characterized 2 KCNQ1 gain-of-function mutations that cause atrial fibrillation, ser140 to gly (S140G; <a href="#0032">607542.0032</a>) and V141M. In the absence of KCNE1, S140G, but not V141M, slowed voltage sensor movement, leading to indirect slowing of current deactivation. Slowing of voltage sensor deactivation by S140G in the absence of KCNE1 was independent of channel opening. When KCNE1 was coexpressed, S140G slowed both current deactivation and voltage sensor movement, whereas V141M slowed current deactivation without slowing voltage sensor movement. Slowing of voltage sensor deactivation by S140G in the presence of KCNE1 was dependent on channel opening. The authors proposed a molecular mechanism underlying the effects of the KCNQ1 mutations on channel gating and suggested that KCNE1 mediates changes in pore movement and voltage sensor-pore coupling to slow channel deactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28383569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0046 SHORT QT SYNDROME 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057519584 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519584;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1057519584" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1057519584" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000417068" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000417068" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000417068</a>
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<p>In a 23-year-old man with a slightly shortened QT interval and a family history of sudden cardiac death (SQT2; <a href="/entry/609621">609621</a>), <a href="#46" class="mim-tip-reference" title="Moreno, C., Oliveras, A., de la Cruz, A., Bartolucci, C., Munoz, C., Salar, E., Gimeno, J. R., Severi, S., Comes, N., Felipe, A., Gonzalez, T., Lambiase, P., Valenzuela, C. <strong>A new KCNQ1 mutation at the S5 segment that impairs its association with KCNE1 is responsible for short QT syndrome.</strong> Cardiovasc. Res. 107: 613-623, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26168993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26168993</a>] [<a href="https://doi.org/10.1093/cvr/cvv196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26168993">Moreno et al. (2015)</a> identified heterozygosity for a c.127910T-A transversion in exon 6 of the KCNQ1 gene, resulting in a phe279-to-ile (F279I) substitution at a conserved residue within the S5 transmembrane segment. The mutation was not present in his unaffected sister or mother; no DNA was available from his father, who had died unexpectedly at age 37 years. Functional analysis of the F279I mutant in the presence of KCNE1 (<a href="/entry/176261">176261</a>) showed a negative shift in the activation curve and an acceleration of the activation kinetics resulting in a gain of function in I(Ks). In addition, coimmunoprecipitation studies and Foster resonance energy transfer (FRET) experiments demonstrated that coassembly between F279I channels and KCNE1 was markedly decreased compared to wildtype channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26168993" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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Abraham, R. L., Yang, T., Blair, M., Roden, D. M., Darbar, D.
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<strong>Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation.</strong>
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Ackerman, M. J., Clapham, D. E.
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<strong>Ion channels--basic science and clinical disease.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9164815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9164815</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9164815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM199705293362207" target="_blank">Full Text</a>]
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Ackerman, M. J., Schroeder, J. J., Berry, R., Schaid, D. J., Porter, C.-B. J., Michels, V. V., Thibodeau, S. N.
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<strong>A novel mutation in KVLQT1 is the molecular basis of inherited long QT syndrome in a near-drowning patient's family.</strong>
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Pediat. Res. 44: 148-153, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9702906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9702906</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9702906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1203/00006450-199808000-00002" target="_blank">Full Text</a>]
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Ackerman, M. J., Tester, D. J., Porter, C. J., Edwards, W. D.
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<strong>Molecular diagnosis of the inherited long-QT syndrome in a woman who died after near-drowning.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10511610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10511610</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10511610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM199910073411504" target="_blank">Full Text</a>]
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Aizawa, Y., Ueda, K., Wu, L., Inagaki, N., Hayashi, T., Takahashi, M., Ohta, M., Kawano, S., Hirano, Y., Yasunami, M., Aizawa, Y., Kimura, A., Hiraoka, M.
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<strong>Truncated KCNQ1 mutant, A178fs/105, forms hetero-multimer channel with wild-type causing a dominant-negative suppression due to trafficking defect.</strong>
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FEBS Lett. 574: 145-150, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15358555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15358555</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15358555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.febslet.2004.08.018" target="_blank">Full Text</a>]
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Arbour, L., Rezazadeh, S., Eldstrom, J., Weget-Simms, G., Rupps, R., Dyer, Z., Tibbits, G., Accili, E., Casey, B., Kmetic, A., Sanatani, S., Fedida, D.
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<strong>A KCNQ1 V205M missense mutation causes a high rate of long QT syndrome in a First Nations community of northern British Columbia: a community-based approach to understanding the impact.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18580685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18580685</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18580685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Barhanin, J., Lesage, F., Guillemare, E., Fink, M., Lazdunski, M., Romey, G.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900282</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8900282" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Bartos, D. C., Anderson, J. B., Bastiaenen, R., Johnson, J. N., Gollob, M. H., Tester, D. J., Burgess, D. E., Homfray, T., Behr, E. R., Ackerman, M. J., Guicheney, P., Delisle, B. P.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23350853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23350853</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23350853[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23350853" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/jce.12068" target="_blank">Full Text</a>]
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Bellocq, C., van Ginneken, A. C. G., Bezzina, C. R., Alders, M., Escande, D., Mannens, M. M. A. M., Baro, I., Wilde, A. A. M.
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<strong>Mutation in the KCNQ1 gene leading to the short QT-interval syndrome.</strong>
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Circulation 109: 2394-2397, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15159330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15159330</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15159330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/01.CIR.0000130409.72142.FE" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.cir.99.11.1464" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.hrthm.2013.07.012" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.hrthm.2013.09.073" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.cardiores.2005.06.023" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa042786" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.hrthm.2008.02.007" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:4<301::AID-HUMU7>3.0.CO;2-V" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1540-8167.1998.tb00944.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.96.9.5203" target="_blank">Full Text</a>]
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Tanaka, T., Nagai, R., Tomoike, H., Takata, S., Yano, K., Yabuta, K., Haneda, N., Nakano, O., Shibata, A., Sawayama, T., Kasai, H., Yazaki, Y., Nakamura, Y.
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<strong>Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome.</strong>
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[<a href="https://doi.org/10.1161/01.cir.95.3.565" target="_blank">Full Text</a>]
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<a id="Tester2005" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1016/j.hrthm.2005.01.020" target="_blank">Full Text</a>]
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Tyson, J., Tranebjaerg, L., McEntagart, M., Larsen, L. A., Christiansen, M., Whiteford, M. L., Bathen, J., Aslaksen, B., Sorland, S. J., Lund, O., Pembrey, M. E., Malcolm, S., Bitner-Glindzicz, M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11140949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11140949</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11140949" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390000402" target="_blank">Full Text</a>]
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<strong>Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15516932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15516932</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15516932" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1467" target="_blank">Full Text</a>]
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Vallon, V., Grahammer, F., Volkl, H., Sandu, C. D., Richter, K., Rexhepaj, R., Gerlach, U., Rong, Q., Pfeifer, K., Lang, F.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16314573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16314573</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16314573[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16314573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0505860102" target="_blank">Full Text</a>]
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Villafane, J., Fischbach, P., Gebauer, R.
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<strong>Short QT syndrome manifesting with neonatal atrial fibrillation and bradycardia.</strong>
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Cardiology 128: 236-240, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24818999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24818999</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24818999" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1159/000360758" target="_blank">Full Text</a>]
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Wang, Q., Curran, M. E., Splawski, I., Burn, T. C., Millholland, J. M., VanRaay, T. J., Shen, J., Timothy, K. W., Vincent, G. M., de Jager, T., Schwartz, P. J., Towbin, J. A., Moss, A. J., Atkinson, D. L., Landes, G. M., Connors, T. D., Keating, M. T.
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<strong>Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias.</strong>
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Nature Genet. 12: 17-23, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528244</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng0196-17" target="_blank">Full Text</a>]
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Wedekind, H., Schwarz, M., Hauenschild, S., Djonlagic, H., Haverkamp, W., Breithardt, G., Wulfing, T., Pongs, O., Isbrandt, D., Schulze-Bahr, E.
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<strong>Effective long-term control of cardiac events with beta-blockers in a family with a common LQT1 mutation.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14756674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14756674</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14756674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.0009-9163.2004.00221.x" target="_blank">Full Text</a>]
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Westenskow, P., Splawski, I., Timothy, K. W., Keating, M. T., Sanguinetti, M. C.
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<strong>Compound mutations: a common cause of severe long-QT syndrome.</strong>
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Circulation 109: 1834-1841, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15051636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15051636</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15051636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/01.CIR.0000125524.34234.13" target="_blank">Full Text</a>]
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Yang, P., Kanki, H., Drolet, B., Yang, T., Wei, J., Viswanathan, P. C., Hohnloser, S. H., Shimizu, W., Schwartz, P. J., Stanton, M., Murray, K. T., Norris, K., George, A. L., Jr., Roden, D. M.
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<strong>Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.</strong>
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Circulation 105: 1943-1948, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11997281/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11997281</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11997281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1161/01.cir.0000014448.19052.4c" target="_blank">Full Text</a>]
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Yang, W.-P., Levesque, P. C., Little, W. A., Conder, M. L., Shalaby, F. Y., Blanar, M. A.
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<strong>KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias.</strong>
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Proc. Nat. Acad. Sci. 94: 4017-4021, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9108097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9108097</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9108097[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9108097" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.94.8.4017" target="_blank">Full Text</a>]
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Zareba, W., Moss, A. J., Schwartz, P. J., Vincent, G. M., Robinson, J. L., Priori, S. G., Benhorin, J., Locati, E. H., Towbin, J. A., Keating, M. T., Lehmann, M. H., Hall, W. J., International Long-QT Syndrome Registry Research Group.
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<strong>Influence of the genotype on the clinical course of the long-QT syndrome.</strong>
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New Eng. J. Med. 339: 960-965, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9753711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9753711</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9753711" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM199810013391404" target="_blank">Full Text</a>]
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Bao Lige - updated : 10/12/2022
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Bao Lige - updated : 01/21/2022<br>Marla J. F. O'Neill - updated : 05/02/2017<br>Marla J. F. O'Neill - updated : 02/09/2017<br>Marla J. F. O'Neill - updated : 4/17/2014<br>Ada Hamosh - updated : 9/28/2012<br>Ada Hamosh - updated : 10/12/2010<br>Marla J. F. O'Neill - updated : 11/16/2009<br>Marla J. F. O'Neill - updated : 5/14/2008<br>Marla J. F. O'Neill - updated : 2/12/2008<br>George E. Tiller - updated : 5/22/2007<br>Marla J. F. O'Neill - updated : 4/11/2007<br>Ada Hamosh - updated : 2/6/2007<br>Marla J. F. O'Neill - updated : 11/9/2006<br>Patricia A. Hartz - updated : 1/27/2006<br>Marla J. F. O'Neill - updated : 9/29/2005<br>Patricia A. Hartz - updated : 5/12/2005<br>George E. Tiller - updated : 12/29/2004<br>Marla J. F. O'Neill - updated : 12/6/2004<br>Victor A. McKusick - updated : 11/19/2004<br>Patricia A. Hartz - updated : 8/26/2004<br>Victor A. McKusick - updated : 2/25/2004<br>Victor A. McKusick - updated : 12/22/2003<br>Victor A. McKusick - updated : 5/12/2003<br>Ada Hamosh - updated : 2/6/2003
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Cassandra L. Kniffin : 2/4/2003
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mgross : 10/12/2022<br>alopez : 06/22/2022<br>mgross : 01/21/2022<br>mgross : 10/26/2017<br>alopez : 05/02/2017<br>alopez : 04/27/2017<br>carol : 02/09/2017<br>carol : 02/06/2017<br>carol : 02/03/2017<br>carol : 08/14/2015<br>mcolton : 8/12/2015<br>mgross : 3/20/2015<br>mgross : 1/12/2015<br>carol : 4/30/2014<br>mcolton : 4/21/2014<br>carol : 4/17/2014<br>carol : 4/17/2014<br>carol : 4/3/2013<br>mgross : 2/5/2013<br>alopez : 10/3/2012<br>terry : 9/28/2012<br>terry : 6/7/2012<br>carol : 6/1/2011<br>carol : 1/14/2011<br>carol : 1/13/2011<br>alopez : 10/12/2010<br>terry : 10/12/2010<br>alopez : 7/21/2010<br>terry : 7/7/2010<br>wwang : 11/17/2009<br>terry : 11/16/2009<br>alopez : 10/31/2008<br>terry : 10/22/2008<br>alopez : 10/13/2008<br>carol : 5/14/2008<br>wwang : 2/26/2008<br>terry : 2/12/2008<br>alopez : 10/3/2007<br>carol : 9/7/2007<br>wwang : 5/30/2007<br>terry : 5/22/2007<br>wwang : 4/12/2007<br>terry : 4/11/2007<br>alopez : 2/8/2007<br>terry : 2/6/2007<br>carol : 11/9/2006<br>alopez : 3/16/2006<br>alopez : 2/3/2006<br>mgross : 2/2/2006<br>terry : 1/27/2006<br>wwang : 9/29/2005<br>terry : 9/29/2005<br>terry : 9/29/2005<br>terry : 8/3/2005<br>wwang : 5/20/2005<br>wwang : 5/16/2005<br>terry : 5/12/2005<br>terry : 4/6/2005<br>alopez : 12/29/2004<br>carol : 12/6/2004<br>carol : 12/6/2004<br>carol : 11/30/2004<br>alopez : 11/30/2004<br>tkritzer : 11/22/2004<br>tkritzer : 11/19/2004<br>mgross : 8/30/2004<br>terry : 8/26/2004<br>tkritzer : 3/1/2004<br>terry : 2/25/2004<br>tkritzer : 12/29/2003<br>tkritzer : 12/26/2003<br>terry : 12/22/2003<br>cwells : 11/7/2003<br>tkritzer : 5/14/2003<br>terry : 5/12/2003<br>alopez : 2/10/2003<br>terry : 2/6/2003<br>carol : 2/5/2003<br>ckniffin : 2/5/2003
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<h3>
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<span class="mim-font">
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<strong>*</strong> 607542
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 1; KCNQ1
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</span>
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</h3>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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KVLQT1<br />
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POTASSIUM CHANNEL, VOLTAGE-GATED, SHAKER-RELATED SUBFAMILY, MEMBER 9; KCNA9<br />
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KCNA8
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: KCNQ1</em></strong>
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</span>
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</p>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 20852007;
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 11p15.5-p15.4
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:2,445,008-2,849,105 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="5">
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<span class="mim-font">
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11p15.5-p15.4
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Long QT syndrome 1, acquired, susceptibility to}
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</td>
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<td>
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<span class="mim-font">
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192500
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</span>
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<td>
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Atrial fibrillation, familial, 3
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</span>
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</td>
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<td>
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<span class="mim-font">
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607554
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</span>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Jervell and Lange-Nielsen syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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220400
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Long QT syndrome 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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192500
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Short QT syndrome 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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609621
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Present in all eukaryotic cells, their diverse functions include maintaining membrane potential, regulating cell volume, and modulating electrical excitability in neurons. The delayed rectifier function of potassium channels allows nerve cells to efficiently repolarize following an action potential. In Drosophila, 4 sequence-related K+ channel genes--Shaker, Shaw, Shab, and Shal--have been identified. Each has been shown to have a human homolog (Chandy et al., 1990; McPherson et al., 1991). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using positional cloning methods, Wang et al. (1996) identified a gene, which they called KVLQT1, within the critical region for long QT syndrome-1 locus (LQT1; 192500) on chromosome 11. KVLQT1 is strongly expressed in the heart and encodes a protein with structural features of a voltage-gated potassium channel. The longest open reading frame of the KVLQT1 cDNA spans 1,645 bp. </p><p>Sanguinetti et al. (1996) identified an apparently full-length human cDNA clone for KVLQT1. This clone predicted a 581-amino acid protein. Northern blot analysis detected a single 3.2-kb mRNA in human pancreas, heart, kidney, lung, and placenta. No message was detected in brain, liver, or skeletal muscle. </p><p>Yang et al. (1997) described the cloning of a full-length KVLQT1 cDNA encoding a 676-amino acid polypeptide with structural characteristics similar to voltage-gated potassium channels. </p><p>Barhanin et al. (1996) cloned a full-length KVLQT1 cDNA from a mouse heart library. Its sequence revealed an open reading frame encoding a 604-amino acid polypeptide sharing 90.5% identity with a human KVLQT1 partial sequence. Hydrophobicity analysis predicted a classic voltage-dependent potassium channel topology with 6 transmembrane segments (of the Shaker type) and a long unique C-terminal cytoplasmic domain. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Splawski et al. (1998) found that the KCNQ1 gene contains 16 exons and spans 400 kb. The exon sizes range from 47 to 1,122 bp. Neyroud et al. (1999) comprehensively detailed the genomic structure of KCNQ1. They determined that the gene contains 19 exons and spans more than 400 kb. The authors presented the sequences of exon-intron boundaries and of oligonucleotide primers designed to allow PCR amplification of all exons from genomic DNA. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By positional cloning methods, Wang et al. (1996) identified the KVLQT1 gene within the critical region for long QT syndrome on chromosome 11p15. Sanguinetti et al. (1996) showed that a fragment of the KVLQT1 cDNA mapped to the short arm of chromosome 11. Neyroud et al. (1999) mapped the KCNQ1 gene to 11p15.5. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To define the function of the KVLQT1 gene, Sanguinetti et al. (1996) transfected KVLQT1 cDNA into Chinese hamster ovary (CHO) cells. The biophysical properties of the transfected KVLQT1 cDNA clone were unlike those of other known cardiac potassium channels. Through cotransfection studies, they demonstrated that KVLQT1 and ISK (KCNE1; 176261) coassemble to form the cardiac I(Ks) channel. They noted that 2 delayed-rectifier potassium channels, I(Kr) and I(Ks), modulate action potential duration in cardiac myocytes and that dysfunction of both of the channels contributes to the risk of sudden death from cardiac arrhythmia. </p><p>Barhanin et al. (1996) expressed KVLQT1 in COS cells and carried out electrophysiologic studies. They demonstrated that KVLQT1 encodes a subunit forming the cardiac ion channel underlying the I(Ks) cardiac current. They observed, however, that an additional subunit, ISK, was required to form the I(Ks) channel. Barhanin et al. (1996) noted that the I(Kr) and the I(Ks) currents are the targets of antiarrhythmic drugs and have an important impact in controlling the ventricular repolarization process. They postulated that the molecular identification of the I(Ks) channel should help with the design of new antiarrhythmic drugs. </p><p>Expression of KVLQT1 in Xenopus oocytes and human embryonic kidney cells by Yang et al. (1997) elicited a rapidly activating, K(+)-selective outward current. They found that clofilium, a class III antiarrhythmic agent with the propensity to induce torsade de pointes, substantially inhibited the current. Elevation of cAMP levels in oocytes nearly doubled the amplitude of KVLQT1 currents. </p><p>Marx et al. (2002) demonstrated that beta-adrenergic receptor modulation of the slow outward potassium ion current (I-KS) requires targeting of cAMP-dependent protein kinase A (188830) and protein phosphatase 1 (PP1; e.g., 176875) to KCNQ1 through the targeting protein yotiao (604001). Yotiao binds to KCNQ1 by a leucine zipper motif, which is disrupted by an LQTS mutation (KCNQ1-G589D; 607542.0029). Identification of the KCNQ1 macromolecular complex provides a mechanism for sympathetic nervous system modulation of cardiac action potential duration through I-KS. </p><p>Melman et al. (2004) showed that multiple segments of KCNQ1, including the pore and C terminus, bind the accessory proteins KCNE1 and KCNE3 (604433). They demonstrated that all KCNE-binding sites of KCNQ1 are required for proper regulation by the accessory subunit. </p><p>To resolve the controversy about messengers regulating KCNQ ion channels during phospholipase C (see 600810)-mediated suppression of current, Suh et al. (2006) designed translocatable enzymes that quickly altered the phosphoinositide composition of the plasma membrane after application of a chemical cue. The KCNQ current fell rapidly to zero when phosphatidylinositol 4,5-bisphosphate was depleted without changing calcium ion, diacylglycerol, or inositol 1,4,5-trisphosphate. Current rose by 30% when phosphatidylinositol 4,5-bisphosphate was overproduced and did not change when phosphatidylinositol 3,4,5-trisphosphate was raised. Hence Suh et al. (2006) concluded that the depletion of phosphatidylinositol 4,5-bisphosphate suffices to suppress current fully, and other second messengers are not needed. Furthermore, their development of these new compounds allowed additional study of biologic signaling networks involving membrane phosphoinositides. </p><p>Roepke et al. (2009) demonstrated that both KCNQ1 and KCNE2 (603796) were expressed and partially colocalized in human and mouse thyroid glands with the basolaterally located Na(+)/I(-) symporter (NIS) that mediates active I(-) transport, the first step in thyroid hormone biosynthesis. Using the rat thyroid-derived FRTL5 cell line, the authors detected endogenous expression of KCNQ1 and KCNE2 proteins that was upregulated by thyroid-stimulating hormone (TSH; see 188540) or its major downstream effector cAMP in the cell membrane fraction. The authors identified a TSH-stimulated K(+) current in FRTL5 cells that bore the signature linear current-voltage relationship of KCNQ1-KCNE2 channels and was inhibited by a KCNQ1-specific antagonist. Kcne2 -/- pups nursing from Kcne2 -/- dams had an 87% reduction in thyroid I(-) accumulation compared to wildtype pups. Roepke et al. (2009) concluded that the potassium channel subunits KCNQ1 and KCNE2 form a TSH-stimulated constitutively active thyrocyte K(+) channel that is required for normal thyroid hormone biosynthesis. </p><p>Osteen et al. (2010) found that coexpression of KCNE1 with KCNQ1 in Xenopus oocytes separated voltage dependence of KCNQ1/KCNE1 potassium channel opening and movement, suggesting an imposed requirement for movement of multiple voltage sensors before channel opening. Multiple separate voltage sensor movements were not needed to activate KCNQ1 alone. The results indicated that KCNE1 modulates KCNQ1 to slow down activation of the KCNQ1/KCNE1 channel by altering the voltage sensor movements necessary to open the channel. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Long QT Syndrome 1</em></strong></p><p>
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Discrepancies in the codon numbers of the allelic variants exist because of changes in information about the sequence of KCNQ1. Yang et al. (1997) demonstrated that the full-length KCNQ1 cDNA codes for 676 amino acids. Thus, for example, the A341V mutation (607542.0010), one of the most frequent causes of type 1 long QT syndrome (192500), was denoted A212V by Wang et al. (1996) and A246V by Li et al. (1998). </p><p>Wang et al. (1996) found KVLQT1 mutations in affected members of 16 families with long QT syndrome-1, including 1 intragenic deletion (607542.0001) and 10 different missense mutations (607542.0002-607542.0011). </p><p>Shalaby et al. (1997) used site-directed mutagenesis to generate 3 mutant human KVLQT1 cDNAs, equivalent to mutations previously described by Wang et al. (1996). The corresponding mutant KVLQT1 proteins were coexpressed in Xenopus oocytes with wildtype KVLQT1 and minK (176261) proteins. Channel currents were studied using a voltage clamp technique. Shalaby et al. (1997) showed that mutations in the putative cytoplasmic loop (e.g., 607542.0002) and pore signature sequence (e.g., 607542.0008) abolished KVLQT1 activity when expressed individually. A mutation in the transmembrane region (e.g., 607542.0006) significantly reduced KVLQT1 activity. When coexpressed with wildtype KVLQT1 protein with or without minK protein, each mutant exerted a dominant-negative effect on the wildtype KVLQT1 current. Shalaby et al. (1997) concluded that in patients carrying such mutant alleles, diminution in the repolarizing I(ks) current would result in prolongation of the cardiac action potential and predispose to cardiac arrhythmias. </p><p>Russell et al. (1996) used SSCP analysis to screen 2 large and 9 small LQT families for mutations of the KVLQT1 potassium channel gene. They identified a novel missense mutation in 2 unrelated families: a gly314-to-ser substitution (607542.0012) in the KVLQT1 gene. In a third family, an ala341-to-val substitution (607542.0010) resulted in the spontaneous occurrence of LQT in monozygotic twin offspring of unaffected parents. Russell et al. (1996) noted that mutations at this same nucleotide had been observed in 8 of 19 LQT families determined to have KVLQT1 mutations to that time, suggesting a mutation hotspot. Both of the mutations reported in this study occurred at CpG dinucleotides. Russell et al. (1996) observed that both of the mutations alter the amino acid sequence in, or adjacent to, the pore of the channel and may diminish the channel's ability to conduct a repolarizing potassium current. Russell et al. (1996) reported that their data confirm the role of KVLQT1 in LQT. They noted that all the KVLQT1 mutations reported to that time were missense mutations and suggested that mutant KVLQT1 proteins may exert a dominant-negative effect on repolarizing potassium currents by forming multimers with normal potassium channel protein subunits, dramatically reducing the number of fully functional KVLQT1 channels. </p><p>Among 32 Japanese families with LQT, Tanaka et al. (1997) identified mutations in KCNQ1 in 4 families comprising 16 patients. </p><p>Jongbloed et al. (1999) screened 24 Dutch LQTS families for mutations in the KCNQ1 and HERG genes. Fourteen missense mutations were identified. Eight of these missense mutations were novel: 3 in the KCNQ1 gene and 5 in the HERG gene. The KCNQ1 mutation G189R (607542.0003) and the novel HERG mutation R582C (607542.0009) were detected in 2 families each. Genotype-phenotype studies indicated that auditory stimuli trigger cardiac events differentiating LQTS2 from LQTS1. In LQTS1, exercise was the predominant trigger. In addition, a number of asymptomatic gene defect carriers were identified. Jongbloed et al. (1999) concluded that asymptomatic carriers are still at risk of the development of life-threatening arrhythmias, underlining the importance of DNA analysis for unequivocal diagnosis of patients with LQTS. </p><p>Neyroud et al. (1999) identified 5 novel mutations in LQTS patients within the C-terminal part of KCNQ1 (see 607542.0025, 607542.0026, and 607542.0027). Neyroud et al. (1999) commented that the low mutation detection rate in large cohorts of LQTS patients may reflect the fact that the C-terminal region had not been analyzed to that time. </p><p>A comprehensive review of the genetic and molecular basis of long QT syndromes was given by Priori et al. (1999, 1999). </p><p>In 2 severely affected sisters from a large Belgian family with LQTS, Berthet et al. (1999) identified biallelic digenic mutations: a missense mutation in the KCNQ1 gene (A341E; 607542.0009) and a splice site mutation in the KCNH2 gene (2592+1G-A; 152427.0019). Berthet et al. (1999) stated that this was the first description of double heterozygosity in long QT syndrome. </p><p>Splawski et al. (2000) screened 262 unrelated individuals with LQT syndrome for mutations in the 5 defined genes (KCNQ1; KCNH2, 152427; SCN5A, 600163; KCNE1; and KCNE2) and identified mutations in 177 individuals (68%). KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%, respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%, 3%, and 2%, respectively). </p><p>Yang et al. (2002) analyzed the KCNQ1, KCNH2, and SCN5A genes in 92 patients with drug-induced long QT syndrome and identified 2 missense mutations, 1 in KCNQ1 (607542.0031) and 1 in KCNH2 (152427.0014), not found in 228 controls, that were shown to reduce K+ currents in vitro. </p><p>In a 13-year-old girl with long QT syndrome, Aizawa et al. (2004) identified a frameshift mutation in the KCNQ1 gene (607542.0036) that eliminates the S3 to S6 domains and the C terminus of the KCNQ1 channel. Coexpression experiments in COS-7 cells showed that mutant and wildtype KCNQ1 remained within the cytoplasm rather than being distributed to the plasma membrane. Aizawa et al. (2004) suggested that the truncated mutant forms a heteromultimer with wildtype KCNQ1 and causes a dominant-negative effect due to a trafficking defect. </p><p>Tester et al. (2005) analyzed 5 LQTS-associated cardiac channel genes in 541 consecutive unrelated patients with LQT syndrome (average QTc, 482 ms). In 272 (50%) patients, they identified 211 different pathogenic mutations, including 88 in KCNQ1, 89 in KCNH2, 32 in SCN5A, and 1 each in KCNE1 and KCNE2. Mutations considered pathogenic were absent in more than 1,400 reference alleles. Among the mutation-positive patients, 29 (11%) had 2 LQTS-causing mutations, of which 16 (8%) were in 2 different LQTS genes (biallelic digenic). Tester et al. (2005) noted that patients with multiple mutations were younger at diagnosis, but they did not discern any genotype/phenotype correlations associated with location or type of mutation. </p><p>Napolitano et al. (2005) screened the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 430 consecutive patients with LQT syndrome and identified 235 different mutations in 310 (72%) of the patients, 49% of whom had mutations in KCNQ1, 39% in KCNH2, 10% in SCN5A, 1.7% in KCNE1, and 0.7% in KCNE2. Fourteen (4.5%) of the patients carried more than 1 mutation in a gene. Fifty-eight percent of probands carried nonprivate mutations in 64 codons of the KCNQ1, KCNH2, and SCN5A genes; screening in a prospective cohort of 75 probands confirmed the occurrence of mutations at these codons (52%). </p><p>In 44 unrelated patients with LQT syndrome, Millat et al. (2006) used DHLP chromatography to analyze the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes for mutations and SNPs. Most of the patients (84%) showed a complex molecular pattern, with an identified mutation associated with 1 or more SNPs located in several LQTS genes; 4 of the patients also had a second mutation in a different LQTS gene (biallelic digenic inheritance; see, e.g., 607542.0038 and 607542.0039). </p><p>Arbour et al. (2008) identified a missense mutation (607542.0040) causing long QT syndrome-1 among a First Nations community of northern British Columbia. </p><p><strong><em>Jervell and Lange-Nielsen Syndrome 1</em></strong></p><p>
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Neyroud et al. (1997) used homozygosity mapping to locate the gene for the Jervell and Lange-Nielsen cardioauditory syndrome (JLNS1; 220400) to the same region of 11p15.5 where the KVLQT1 gene maps. In 3 affected children of 2 families with the disorder, they demonstrated homozygosity for a deletion-insertion mutation in the C-terminal domain of the KVLQT1 gene (607542.0013). They noted that this is another instance of dominant or recessive inheritance of disorders due to different mutations in the same gene. Schmitt et al. (2000) identified a small domain between residues 589 and 620 in the KCNQ1 C terminus that may function as an assembly domain for KCNQ1 subunits. KCNQ1 C termini do not assemble and KCNQ1 subunits do not express functional potassium channels without this domain. The authors showed that the deletion-insertion mutation at KCNQ1 residue 540 identified by Neyroud et al. (1997) eliminated important parts of the C-terminal assembly domain. Therefore, JLNS mutants may be defective in KCNQ1 subunit assembly. The results provided a molecular basis for the clinical observation that heterozygous JLNS carriers show slight cardiac dysfunction and that the severe JLNS phenotype is characterized by the absence of the KCNQ1 channel. </p><p>Tyson et al. (2000) studied 10 JLNS families from Great Britain and Norway and identified 9 different mutations in the KCNQ1 gene, 2 of which were novel. Truncation of the protein proximal to the C-terminal assembly domain was expected to preclude assembly of KCNQ1 monomers into tetramers, explaining the recessive inheritance of JLNS. </p><p><strong><em>Atrial Fibrillation 3</em></strong></p><p>
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Chen et al. (2003) identified a ser140-to-gly missense mutation (607542.0032) in the KCNQ1 gene in affected members of a Chinese family with autosomal dominant atrial fibrillation (ATFB3; 607554). Functional analysis of this mutant revealed a gain-of-function effect on the KCNQ1/KCNE1 and KCNQ1/KCNE2 currents, which contrasts with the dominant-negative or loss-of-function effects of the KCNQ1 mutations previously identified in patients with long QT syndrome. Chen et al. (2003) concluded that the ser140-to-gly mutation is likely to initiate and maintain atrial fibrillation by reducing action potential duration and effective refractory period in atrial myocytes. </p><p>Johnson et al. (2008) reported a female patient with onset of atrial fibrillation in the first year of life who was heterozygous for a missense mutation in the KCNQ1 gene (R231H; 607542.0043). The patient was also found to have a long QT interval at 1 year of age, with a QTc of 479 ms. </p><p>In affected members of a 3-generation family with lone atrial fibrillation, Das et al. (2009) identified heterozygosity for a missense mutation in the KCNQ1 gene (S209P; 607542.0042). </p><p>In a cohort of 231 patients with atrial fibrillation, Abraham et al. (2010) analyzed the KCNQ1 and NPPA (108780) genes and identified heterozygosity for a 9-bp duplication in KCNQ1 (607542.0041) in the proband of a Caucasian kindred with early-onset lone atrial fibrillation; the duplication segregated with disease in the family. Abraham et al. (2010) also identified a missense mutation in the NPPA gene (108780.0002) in another family with atrial fibrillation (ATFB6; 602201) in the cohort; functional analysis revealed strikingly similar gain-of-function defects associated with the mutants, with atrial action potential shortening and altered calcium current as a common mechanism. </p><p>In affected members of 4 families with early-onset atrial fibrillation, Bartos et al. (2013) identified heterozygosity for the R231H mutation in KCNQ1. Twelve of 13 mutation-positive individuals had a normal QTc, and 1 had a prolonged QT interval. </p><p>In affected members of a family with atrial fibrillation, Guerrier et al. (2013) identified heterozygosity for the R231H missense mutation in KCNQ1. Guerrier et al. (2013) noted that the R231H mutation had previously been identified by Napolitano et al. (2005) in a study of patients with long QT syndrome, but stated that none of the family members with atrial fibrillation had documented prolonged QT intervals. </p><p>Hasegawa et al. (2014) screened 30 patients with juvenile-onset atrial fibrillation for mutations in the KCNQ1, KCNH2 (152427), KCNE1 (176261), KCNE2 (603796), KCNE3 (604433), KCNE5 (300328), KCNJ2 (600681), and SCN5A (600163) genes, and identified heterozygosity for a missense mutation in KCNQ1 (G229D; 607542.0044) in a Japanese boy who was diagnosed at 16 years of age with atrial fibrillation. At that time, ECG showed a normal QT interval, but he was later found to have borderline QT prolongation (QTc 452 ms to 480 ms). The mutation was also present in his asymptomatic mother, who also had borderline QT prolongation (QTc 468 ms). Functional analysis indicated that G229D causes constitutively open I(Ks) channels. </p><p><strong><em>Short QT Syndrome 2</em></strong></p><p>
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In a 70-year-old man with short QT syndrome-2 (SQT2; 609621) who survived an episode of ventricular fibrillation, Bellocq et al. (2004) identified a missense mutation in the KCNQ1 gene (607542.0037). Functional studies of the mutant channel revealed that both a pronounced shift of the half-activation potential and an acceleration of the activation kinetics led to a gain of function in I(Ks). </p><p>In a female infant with short QT syndrome, atrial fibrillation (AF), and bradycardia Hong et al. (2005) identified heterozygosity for a de novo missense mutation in the KCNQ1 gene (V141M; 607542.0045). Functional analysis in Xenopus oocytes demonstrated that in contrast to wildtype channels, which exhibited a slowly activating and deactivating voltage-dependent and K(+)-selective current, the V141M mutant channel current developed instantly at all voltages tested, consistent with a constitutively open channel. </p><p>In 2 unrelated girls with short QT syndrome, AF, and bradycardia, Villafane et al. (2014) identified heterozygosity for the V141M mutation in the KCNQ1 gene. </p><p>In a 23-year-old man with a slightly shortened QT interval, whose father had died unexpectedly at age 37 years, Moreno et al. (2015) identified heterozygosity for a missense mutation in the KCNQ1 gene (F279I; 607542.0046) that was not found in his unaffected sister or mother. Functional analysis showed a negative shift in the activation curve of mutant channels, with acceleration of the activation kinetics resulting in a gain of function in I(Ks). </p><p><strong><em>Imprinting</em></strong></p><p>
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Genomic imprinting is the process by which a subset of mammalian genes is 'marked' during gametogenesis such that they are expressed differentially in somatic cells depending on their parental origin. This mark may be differential methylation, because DNA methylation is necessary for the proper regulation of imprinted genes. Furthermore, some differentially methylated regions (DMRs) are thought to represent gametic imprints, because they are differentially methylated in male and female germ cells and remain so throughout development. The DMRs of most imprinted genes are associated with short, G-rich, direct repeat sequences, which may facilitate heterochromatization and gene silencing at imprinted loci. Another characteristic of imprinted genes is their association, in some cases, with imprinted antisense RNA transcripts. At the paternally expressed mouse and human IGF2 (147470) and ZPF127 loci, antisense transcripts that are also expressed paternally have been identified and overlap with the protein coding gene. For the maternally expressed IGF2R (147280) and UBE3A (601623) genes, overlapping antisense transcripts (see SNHG14, 616259) have been found and are oppositely imprinted with respect to the protein coding gene. Antisense transcripts may serve to regulate overlapping genes by promoter or transcript occlusion or by competing with these loci for regulatory elements such as transcription factors or enhancers (Smilinich et al., 1999). Imprinting control elements are proposed to exist within the KVLQT1 locus, because multiple chromosome rearrangements associated with Beckwith-Wiedemann syndrome (BWS; 130650) disrupt this gene. The imprinting control regions on chromosome 11p15 associated with H19 (103280)/IGF2 and KCNQ1 are referred to as ICR1 (616186) and ICR2, respectively. </p><p>Lee et al. (1997) demonstrated that the KVLQT1 gene spans much of the interval between p57(KIP2) (CDKN1C; 600856) and IGF2 and that, like those 2 genes, it is imprinted. They demonstrated, furthermore, that the KVLQT1 gene is disrupted by chromosomal rearrangements in patients with Beckwith-Wiedemann syndrome, as well as by a balanced chromosomal translocation in an embryonal rhabdoid tumor. They concluded that the lack of parent-of-origin effect in the long QT syndrome (192500) must reflect a relative lack of imprinting in the affected tissue, cardiac muscle, thereby representing a novel mechanism for incomplete penetrance of a human disease gene. Mannens and Wilde (1997) and Barlow (1997) discussed the findings of Lee et al. (1997) and Neyroud et al. (1997) and hypothesized that aberrant expression of the KVLQT1 gene may be responsible for the profound growth abnormalities seen in BWS. Four isoforms of KVLQT1 exist, 2 of which (isoforms 3 and 4) seem to be untranslated. KVLQT1 imprinting may be associated with specific isoforms, as has been shown for IGF2. KVLQT1 isoform 2 seems to be most abundant in heart and is probably biallelically expressed. Isoform 1 is expressed in multiple tissues and is most likely paternally imprinted. The tissue-specific imprinting of KVLQT1 and the presence of multiple isoforms might explain the various modes of inheritance seen in LQT, JLNS, and BWS. </p><p>Smilinich et al. (1999) identified an evolutionarily conserved, maternally methylated CpG island, which they called KVDMR1, in an intron of the KVLQT1 gene. Among 12 cases of BWS with normal H19 methylation, 5 showed demethylation of KVDMR1 in fibroblast or lymphocyte DNA; on the other hand, in 4 cases of BWS with H19 hypermethylation, methylation at KVDMR1 was normal. Thus, inactivation of H19 and hypomethylation of KVDMR1 (or an associated phenomenon) represented distinct epigenetic anomalies associated with biallelic expression of IGF2. Reverse transcription-PCR analysis of the human and syntenic mouse loci identified a KVDMR1-associated RNA transcribed exclusively from the paternal allele and in the opposite orientation with respect to the maternally expressed KVLQT1 gene. Smilinich et al. (1999) proposed that KVDMR1 and/or its associated antisense RNA represents an additional imprinting control element or center in human 11p15.5 and mouse distal 7 imprinted domains. </p><p>To explore the importance of imprinted gene clustering, Cleary et al. (2001) used the Cre/loxP recombination system to disrupt a cluster of imprinted genes on mouse distal chromosome 7. In mice carrying a site-specific translocation, t(7;11), separating Cdkn1c and Kcnq1, imprinting of the genes retained on chromosome 7, including Kcnq1, Kcnq1ot1 (604115), Ascl2 (601886), H19 (103280), and Igf2 (147470), was unaffected, demonstrating that these genes are not regulated by elements near or telomeric to Cdkn1c. In contrast, expression and imprinting of the translocated Cdkn1c, Slc22a1l (602631), and Tssc3 (602131) genes on chromosome 11 were affected, consistent with the hypothesis that elements regulating both expression and imprinting of these genes lie within or proximal to Kcnq1. The findings supported the proposal that chromosomal abnormalities, including translocations, within KCNQ1 that are associated with Beckwith-Wiedemann syndrome may disrupt CDKN1C expression. </p><p>One-third of individuals with Beckwith-Wiedemann syndrome lose maternal-specific methylation at KvDMR1, a putative imprinting control region within intron 10 of the KCNQ1 gene (Lee et al., 1999; Smilinich et al., 1999; Engel et al., 2000). It has been proposed that this epimutation results in aberrant imprinting and, consequently, BWS. Fitzpatrick et al. (2002) showed that paternal inheritance of this mutation in mice results in the derepression in cis of 6 genes, including Cdkn1c, which encodes cyclin-dependent kinase inhibitor 1C. Furthermore, fetuses and adult mice that inherited the deletion from their fathers were 20 to 25% smaller than their wildtype littermates. By contrast, maternal inheritance of this deletion had no effect on imprinted gene expression or growth. Thus, the unmethylated paternal KvDMR1 allele regulates imprinted expression by silencing genes on the paternal chromosome. These findings supported the hypothesis that loss of methylation in BWS patients activates the repressive function of KvDMR1 on the maternal chromosome, resulting in abnormal silencing of CDKN1C and the development of BWS. </p><p>Mancini-DiNardo et al. (2003) showed that the imprinting control region (ICR) on mouse distal chromosome 7 contains a promoter for a paternally expressed antisense transcript, Kcnq1ot1. Three paternal-specific nuclease-hypersensitive sites, which are required for full promoter activity, lie immediately upstream from the start site. The expression of Kcnq1ot1 during pre- and postnatal development was compared to that of other imprinted genes in its vicinity, Cdkn1c (600856) and Kcnq1; a lack of coordination in their expression did not support an enhancer competition model for the action of the ICR in imprinting control. Using a stable transfection assay, the authors showed that the region contains a position-independent and orientation-independent silencer. The authors proposed that the Kcnq1 ICR may function as a silencer on the paternal chromosome to effect the repression of neighboring genes. </p><p>Imboden et al. (2006) investigated the distribution of mutant alleles for the long-QT syndrome in 484 nuclear families with type I disease (LQT1 due to mutation in the KCNQ1 gene) and 269 nuclear families with type II disease (LQT2 (613688) due to mutation in the KCNH2 gene; 152427). In offspring of the female carriers of LQT1 or male and female carriers of LQT2, classic mendelian inheritance ratios were not observed. Among the 1,534 descendants, the proportion of genetically affected offspring was significantly greater than that expected according to mendelian inheritance: 870 were carriers of a mutation (57%), and 664 were noncarriers (43%) (P less than 0.001). Among the 870 carriers, the allele for the long-QT syndrome was transmitted more often to female offspring (476; 55%) than to male offspring (394; 45%) (P = 0.005). Increased maternal transmission of the long QT syndrome to daughters was also observed, possibly contributing to the excess of female patients with autosomal dominant long QT syndrome. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>The relation of ion channels to disease was comprehensively reviewed by Ackerman and Clapham (1997). </p><p>In a large collaborative study, Zareba et al. (1998) demonstrated that the genotype of the long QT syndrome influences the clinical course. The risk of cardiac events (syncope, aborted cardiac arrest, or sudden death) was significantly higher among subjects with mutations at the LQT1 or LQT2 locus than among those with mutations at the LQT3 locus. Although the cumulative mortality was similar regardless of the genotype, the percentage of cardiac events that were lethal was significantly higher in families with mutations at the LQT3 locus. In this large study, 112 patients had mutations at the LQT1 locus, 72 at the LQT2 locus, and 62 at the LQT3 locus. Thus, paradoxically, cardiac events were less frequent in LQT3 but more likely to be lethal; the likelihood of dying during a cardiac event was 20% in families with an LQT3 mutation and 4% with either an LQT1 or an LQT2 mutation. </p><p>Using SSCP and DNA sequence analyses, Chen et al. (2003) studied the KCNQ1 gene in 102 families with a history of lethal cardiac events: 55 LQTS, 9 Brugada syndrome (601144), 18 idiopathic ventricular fibrillation (IVF; 603829), and 20 acquired LQTS. Families found to have KCNQ1 mutations were phenotyped using ECG parameters and cardiac event history, and genotype-phenotype correlation was performed. No mutations were found in Brugada syndrome, IVF, or acquired LQTS families. Of the 55 LQTS families, 10 had KCNQ1 mutations and 62 carriers were identified. Five novel mutations were identified. There were 6 instances of sudden death and in 2 of these, death was the first symptom. The findings of this study emphasized the reduced penetrance of both the long QT and symptoms, resulting in diagnostic challenges, and the importance of genetic testing for identification of gene carriers with reduced penetrance in order to provide treatment and prevent lethal cardiac arrhythmias and sudden death. </p><p>Westenskow et al. (2004) analyzed the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 252 probands with long QT syndrome and identified 19 with biallelic mutations in LQTS genes, of whom 18 were either compound (monogenic) or double (digenic) heterozygotes and 1 was a homozygote. They also identified 1 patient who had triallelic digenic mutations (see 152427.0021). Compared with probands who had 1 or no identified mutation, probands with 2 mutations had longer QTc intervals (p less than 0.001) and were 3.5-fold more likely to undergo cardiac arrest (p less than 0.01). Voltage clamp studies in Xenopus oocytes coexpressing wildtype and variant subunits demonstrated a reduction in I(Ks) density that was equivalent to the additive effects of the single mutations. Westenskow et al. (2004) concluded that biallelic mono- or digenic mutations (which the authors termed 'compound mutations') cause a severe phenotype and are relatively common in long QT syndrome. The authors noted that these findings support the concept of arrhythmia risk as a multi-hit process and suggested that genotype can be used to predict risk. </p><p>Brink et al. (2005) studied an LQTS founder population (SA-A341V) consisting of 22 apparently unrelated South African kindreds of Afrikaner origin (de Jager et al., 1996), all of which could be traced to a single founding couple of mixed Dutch and French Huguenot origin who married in approximately 1730. Brink et al. (2005) compared the 166 Afrikaner patients carrying the KCNQ1 A341V mutation (607542.0010) to the general LQT1 population (Priori et al., 2003) and found that the SA-A341V group exhibited a significantly more severe form of the disease, with an earlier age of onset, longer QTc intervals, and an increased incidence of a first cardiac event by age 20 years. Functional analysis in CHO cells demonstrated that coexpression of the A341V mutant reduced the magnitude of the wildtype channel repolarizing current I(Ks) by approximately 50%, indicating that the mutation exerts a dominant-negative effect. Brink et al. (2005) noted that this effect on I(Ks), which activates during increased heart rate and is essential for QT interval adaptation during tachycardia, might explain why 79% of lethal arrhythmic episodes in LQT1 patients with mutations impairing I(Ks) occur during exercise. In contrast, most lethal episodes in LQT2 and LQT3 patients occur during startle reaction and at rest or during sleep, respectively. </p>
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<p>Lee et al. (2000) found that Kvlqt1 -/- mice were born at the expected mendelian ratio, were viable, and developed normally. However, by 4 weeks of age, Kvlqt1 -/- mice exhibited hyperactivity, with repetitive running, circling, nodding, and wobbling behaviors. Kvlqt1 -/- mice were completely deaf due to defects in inner ear development, and they displayed gastric hyperplasia, likely resulting from an altered cellular repertoire of lineage maturation in gastric mucosa. However, cardiac electrophysiology was normal, and Kvlqt1 -/- mice did not display features of BWS. </p><p>To produce a mouse model for Jervell and Lange-Nielsen syndrome, Casimiro et al. (2001) generated a line of transgenic mice that had a targeted disruption in the Kcnq1 gene. Behavioral analysis demonstrated that the homozygous-null mice were deaf and exhibited a shaker-waltzer phenotype. Histologic analysis of the inner ear structures of these mice showed gross morphologic anomalies because of drastic reduction in the volume of endolymph. ECGs recorded from the null mice demonstrated abnormal T- and P-wave morphologies and prolongation of the QT and JT intervals when measured in vivo, but not in isolated hearts. These changes were indicative of cardiac repolarization defects that appear to be induced by extracardiac signals. </p><p>Casimiro et al. (2004) noted that Kcnq1 knockout results in mice with more severe defects than those in human LQT1 or JLNS1. They developed mouse lines with point mutations in the Kcnq1 gene that cause LQT1 in humans. Mice with an ala340-to-glu mutation had normal hearing but a long QT and therefore modeled patients with LQT1. Mice with a thr311-to-ile mutation phenocopied JLNS1, but they also displayed the shaker/waltzer defect, which is specific to mouse. </p><p>Imprinted genes are clustered in domains, and their allelic repression is mediated by imprinting control regions. These imprinting control regions are marked by DNA methylation, which is essential to maintain imprinting in the embryo. To explore how imprinting is regulated in placenta, Umlauf et al. (2004) studied the Kcnq1 domain on mouse distal chromosome 7. This large domain is controlled by an intronic imprinting control region (Fitzpatrick et al., 2002; Mancini-DiNardo et al., 2003) and comprises multiple genes that are imprinted in placenta, without the involvement of promoter DNA methylation. Umlauf et al. (2004) found that the paternal repression along the domain involves acquisition of trimethylation at lys27 and dimethylation at lys9 of histone H3 (see 602810). Eed (605984)-Ezh2 (601573) Polycomb complexes are recruited to the paternal chromosome and potentially regulate its repressive histone methylation. Studies on embryonic stem cells and early embryos supported the proposal of Umlauf et al. (2004) that chromatin repression is established early in development and is maintained in the placenta. In the embryo, on the other hand, imprinting is stably maintained only at genes that have promoter DNA methylation. Random X inactivation in the embryo proper also involves repressive histone methylation and recruitment of Eed-Ezh2 complexes (Silva et al., 2003). Umlauf et al. (2004) concluded that their data underscored the importance of histone methylation in placental imprinting and identified mechanistic similarities with X chromosome inactivation in extraembryonic tissues, suggesting that the 2 epigenetic mechanisms are evolutionarily linked. </p><p>Studying imprinting in the placenta in the region of distal mouse chromosome 7, Lewis et al. (2004) found that the silent paternal alleles of imprinted genes are marked in the trophoblast by repressive histone modifications (dimethylation at lys9 of histone H3 and trimethylation at lys27 of histone H3), which were disrupted when imprinting center-2 (IC2) on mouse distal chromosome 7 was deleted. The deletion led to reactivation of the paternal alleles. Lewis et al. (2004) proposed that an evolutionarily older imprinting mechanism limited to extraembryonic tissues was based on histone modifications. </p><p>Elso et al. (2004) characterized 2 mouse lines carrying mutant alleles of Kcnq1, which very rapidly established chronic gastritis in a bacterial pathogen-exposed environment. Independent of infection, mutant mice developed gastric hyperplasia, hypochlorhydria, and mucin dysregulation, as well as metaplasia, dysplasia, and premalignant adenomatous hyperplasia of the stomach. </p><p>Using pharmacologic inhibition and gene knockout in mice, Vallon et al. (2005) demonstrated the importance of Kcnq1 channel complexes in maintenance of the driving force for proximal tubular and intestinal Na+ absorption, gastric acid secretion, and cAMP-induced jejunal Cl- secretion. In the kidney, Kcnq1 was dispensable under basal conditions; however, luminal Kcnq1 repolarized the proximal tubule and stabilized the driving force for Na+ reabsorption under conditions of increased glucose or amino acid resorption. In mice lacking functional Kcnq1, impaired intestinal absorption was associated with reduced serum vitamin B12 concentrations, mild macrocytic anemia, and fecal loss of Na+ and K+, the latter affecting K+ homeostasis. </p><p>In studies of Drosophila, Ocorr et al. (2007) observed a markedly elevated incidence of cardiac dysfunction and arrhythmias in aging fruit fly hearts and a concomitant decrease in expression of Kcnq, which is the Drosophila homolog of human KCNQ1. Hearts from young Kcnq-mutant fruit flies exhibited arrhythmias reminiscent of torsade de pointes and had severely increased susceptibility to pacing-induced cardiac dysfunction at young ages, characteristics that are observed only at advanced ages in wildtype flies. Alterations in rhythmicity of the mutant flies was rescued by transgenic wildtype Kcnq, and heart-specific Kcnq overexpression in old wildtype flies reversed the age-dependent increase in arrhythmias. Ocorr et al. (2007) suggested that an age-dependent decrease in KCNQ1 expression within the heart may contribute to the increased incidence of arrhythmia observed with age. </p>
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</span>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>46 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 LONG QT SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, 3-BP DEL
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<br />
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SNP: rs397508113,
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ClinVar: RCV000003259
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Using SSCP analysis, Wang et al. (1996) demonstrated a deletion in the KVLQT1 gene in a sporadic case of long QT syndrome-1 (LQT1; 192500). Deletion of 3 nucleotides, TCG, changed codon 72 from TTC (phe) to TGG (trp) and deleted the first G of codon 73. (Codon 72 used to be known as codon 38 and codon 73 as codon 39.) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 LONG QT SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, ALA178PRO
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<br />
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SNP: rs120074177,
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gnomAD: rs120074177,
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ClinVar: RCV000003260, RCV000057693
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Using SSCP analysis, Wang et al. (1996) found a GCC (ala) to CCC (pro) transversion in codon 83 of the KVLQT1 gene in a sporadic case of LQT1 (192500). (This variant used to be known as ALA49PRO and ALA83PRO.) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 LONG QT SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, GLY189ARG
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<br />
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SNP: rs104894252, rs104894255,
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ClinVar: RCV000003261, RCV000057702, RCV000223880, RCV001383882
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family in which 3 members had LQT1 (192500), Wang et al. (1996) demonstrated a GGG (gly) to AGG (arg) transition in codon 189 of the KVLQT1 gene. Jongbloed et al. (1999) identified this mutation in 2 families with LQT1. (This variant used to be known as GLY60ARG and GLY94ARG.) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 LONG QT SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, ARG190GLN
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<br />
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SNP: rs120074178,
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gnomAD: rs120074178,
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ClinVar: RCV000003264, RCV000046088, RCV000057706, RCV000182086, RCV000588393, RCV001841223
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family with 2 members affected by LQT1 (192500), Wang et al. (1996) used SSCP analysis to demonstrate a CGG (arg) to CAG (gln) transition in codon 95 of the KVLQT1 gene. (This variant used to be known as ARG61GLN and ARG95GLN.) </p><p>Moretti et al. (2010) reported the creation of patient-specific induced pluripotent stem (IPS) cells containing the R190Q mutation in KCNQ1. They compared IPS cells derived from dermal fibroblasts from 2 patients with this mutation with those from 2 control individuals. The cells were able to generate functional myocytes that showed a ventricular, atrial, or nodal phenotype, as evidenced by expression of cell type-specific markers and as seen in recordings of the action potentials in single cells. The duration of the action potential was markedly prolonged in ventricular and atrial cells derived from patients with LQTS1, as compared with cells from control subjects. Further characterization of the role of the R190Q KCNQ1 mutation in the pathogenesis of LQTS1 revealed a dominant-negative trafficking defect associated with a 70 to 80% reduction in I(Ks) current and altered channel activation and deactivation properties. Moreover, Moretti et al. (2010) showed that myocytes derived from patients with LQTS1 had an increased susceptibility to catecholamine-induced tachyarrhythmia and that beta-blockade attenuated this phenotype, as was demonstrated in the patients themselves. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 LONG QT SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, VAL254MET
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<br />
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SNP: rs120074179,
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ClinVar: RCV000003265, RCV000003296, RCV000057749, RCV000182109, RCV000190212, RCV000619506
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a kindred in which 70 members were affected by LQT1 (192500), Wang et al. (1996) used SSCP analysis to demonstrate a GTG (val) to ATG (met) transition in codon 159 of the KVLQT1 gene. (This variant used to be known as VAL125MET and VAL159MET.) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0006 LONG QT SYNDROME 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, LEU273PHE
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<br />
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|
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SNP: rs120074180,
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gnomAD: rs120074180,
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ClinVar: RCV000003266, RCV000057769, RCV000182120, RCV000620696, RCV001192509
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a kindred in which 2 members were affected by LQT1 (192500), Wang et al. (1996) demonstrated a CTC (leu) to TTC (phe) transition in codon 273 of the KVLQT1 gene. (This variant used to be known as LEU144PHE and LEU178PHE.) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0007 LONG QT SYNDROME 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
|
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<span class="mim-text-font">
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KCNQ1, GLY306ARG
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<br />
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SNP: rs120074181,
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ClinVar: RCV000003262, RCV000057797, RCV000182132
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic case of LQT1 (192500), Wang et al. (1996) demonstrated a GGG (gly) to AGG (arg) transition in codon 211 of the KVLQT1 gene. (This mutation used to be known as GLY177ARG and GLY211ARG.) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0008 LONG QT SYNDROME 1</strong>
|
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</span>
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</h4>
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</div>
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<div>
|
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<span class="mim-text-font">
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KCNQ1, THR312ILE
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<br />
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SNP: rs120074182,
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ClinVar: RCV000003263, RCV000057808, RCV000182136, RCV001386969, RCV001841222, RCV002444417
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic case of LQT1 (192500), Wang et al. (1996) demonstrated a ACC (thr) to ATC (ile) transition in codon 217 of the KVLQT1 gene. (This mutation used to be known as THR183ILE and THR217ILE.) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 LONG QT SYNDROME 1</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
LONG QT SYNDROME 1/2, DIGENIC, INCLUDED
|
|
</span>
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</div>
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<div>
|
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<span class="mim-text-font">
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KCNQ1, ALA341GLU
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<br />
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SNP: rs12720459,
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ClinVar: RCV000003267, RCV000003268, RCV000045932, RCV000057526, RCV000182154, RCV000621485, RCV003591617
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 kindreds with 8 members affected by LQT1 (192500), Wang et al. (1996) demonstrated a GCG (ala) to GAG (glu) transversion in codon 341 (A341E) of the KCNQ1 gene. (This variant used to be known as ALA212GLU and ALA246GLU.) </p><p>In 2 severely affected sisters from a large Belgian family with long QT syndrome (see 192500), Berthet et al. (1999) identified biallelic digenic mutations: the A341E substitution in exon 6, within the S6 transmembrane domain of KCNQ1; and a splice site mutation in the KCNH2 gene (2592+1G-A; 152427.0019). The father and his affected relatives were heterozygous for the A341E mutation in KCNQ1; the mother, a more mildly affected sister, and a grandson were heterozygous for the splice site mutation in KCNH2. Neither mutation was found in 2 unaffected sibs or in other unaffected family members. Berthet et al. (1999) stated that this was the first description of double heterozygosity in long QT syndrome. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 LONG QT SYNDROME 1</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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KCNQ1, ALA341VAL
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<br />
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SNP: rs12720459,
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ClinVar: RCV000003269, RCV000057528, RCV000171124, RCV000619686
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In 5 kindreds (K1807, K161, K162, K163, and K164) with 47 members affected by LQT1 (192500), Wang et al. (1996) demonstrated a GCG (ala) to GTG (val) transversion in codon 341 of the KVLQT1 gene. The mutation segregated with disease in the families and was not found in DNA samples from 200 unrelated controls. </p><p>In affected members of a South African family of Afrikaner origin with LQT (pedigree 166), de Jager et al. (1996) identified heterozygosity for the A341V mutation in the KVLQT1 gene. Haplotype analysis of this family and 4 Afrikaner families previously studied by Wang et al. (1996) (pedigrees 161, 162, 163, and 164) revealed that all 5 families shared a common haplotype, indicating a founder effect. Noting differences in severity of disease between the 2 largest families, 161 and 162, de Jager et al. (1996) suggested that the spectrum of clinical symptoms might reflect the influence of different modulating environmental or genetic backgrounds on expression of the same mutant allele. </p><p>Russell et al. (1996) detected this mutation in the spontaneous occurrence of LQT in monozygotic twin offspring of normal parents. This mutation would be expected to encode a potassium channel with altered conductance properties. They noted that mutations at this same nucleotide have been observed in 8 of 19 LQT families determined to have KVLQT1 mutations to that time, suggesting a mutation hotspot. (This variant used to be known as ALA212VAL and ALA246VAL.) </p><p>Brink et al. (2005) studied an LQTS founder population (SA-A341V) consisting of 22 apparently unrelated South African kindreds of Afrikaner origin (including pedigrees 161, 162, 163, 164, and 166), all of which could be traced to a single founding couple of mixed Dutch and French Huguenot origin who married in approximately 1730. Comparing the Afrikaner patients to the general LQT1 population, Brink et al. (2005) found that the SA-A341V group exhibited a significantly more severe form of the disease, with an earlier age of onset, longer QTc intervals, and an increased incidence of first cardiac event by age 20 years. Functional analysis in CHO cells demonstrated that coexpression of the A341V mutant reduced the magnitude of wildtype channel repolarizing current by approximately 50%, indicating that the mutation exerts a dominant-negative effect. </p><p><strong><em>Modifier Effects of Variation in the AKAP9 Gene</em></strong></p><p>
|
|
In 349 members of a South African founder population of Afrikaner origin with LQT1, 168 of whom carried an identical-by-descent A341V mutation, de Villiers et al. (2014) genotyped 4 SNPs in the AKAP9 gene (604001) and found statistically significant associations between certain alleles, genotypes, and haplotypes and phenotypic traits such as QTc interval length, risk of cardiac events, and/or disease severity. De Villiers et al. (2014) stated that these results clearly demonstrated that AKAP9 contributes to LQTS phenotypic variability; however, the authors noted that because these SNPs are located in intronic regions of the gene, functional or regulatory variants in linkage disequilibrium with the SNPs were likely to be responsible for the modifying effects. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0011 LONG QT SYNDROME 1</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, GLY345GLU
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<br />
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SNP: rs120074183,
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ClinVar: RCV000003270, RCV000057536, RCV002512696
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a family with 11 members affected by LQT1 (192500), Wang et al. (1996) demonstrated a GGG (gly) to GAG (glu) transversion in codon 250 of the KVLQT1 gene. (This variant used to be known as GLY216GLU and GLY250GLU.) </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
|
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<div>
|
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<span class="mim-text-font">
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|
|
|
KCNQ1, GLY314SER
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|
<br />
|
|
|
|
SNP: rs120074184,
|
|
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|
|
|
|
|
ClinVar: RCV000003271, RCV000057810, RCV000182137, RCV000852434, RCV002371756
|
|
|
|
|
|
</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Russell et al. (1996) reported a mutation resulting in a gly219-to-ser substitution in 2 LQT1 (192500) families. (This variant used to be known as GLY185SER and GLY219SER.) This mutation would be expected to encode a potassium channel with altered conductance properties. </p>
|
|
</span>
|
|
</div>
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|
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<div>
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|
<br />
|
|
</div>
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|
|
</div>
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|
|
<div>
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|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 JERVELL AND LANGE-NIELSEN SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, 7-BP DEL/8-BP INS, NT1244
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|
|
|
<br />
|
|
|
|
SNP: rs397515637,
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|
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|
|
|
|
ClinVar: RCV000003272
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 3 children with Jervell and Lange-Nielsen cardioauditory syndrome (JLNS1; 220400) from 2 consanguineous families, Neyroud et al. (1997) found homozygosity for a deletion-insertion mutation in the C-terminal domain of the KVLQT1 gene. At nucleotide 1244, a deletion of 7 bp and an insertion of 8 bp was found in affected individuals. The mutation resulted in a frameshift from codon 415, leading to a premature stop signal at codon 522 close to the end of the coding sequence, which is at codon 547. Several other members of the 2 families were heterozygous for the mutation. Both families originated from Kabylia, which suggested founder effect. </p>
|
|
</span>
|
|
</div>
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 JERVELL AND LANGE-NIELSEN SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, 1-BP INS, 282G
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|
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|
|
<br />
|
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|
|
SNP: rs397508117,
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|
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|
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|
|
|
ClinVar: RCV000003273, RCV000046086, RCV000182266, RCV000617403, RCV003319311, RCV004724785
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Jervell and Lange-Nielson syndrome (JLNS1; 220400), Splawski et al. (1997) found homozygosity for a 1-bp insertion (G) after nucleotide 282 of the KVLQT1 gene. The insertion caused a frameshift, disrupting the coding sequence after the second putative membrane-spanning domain of the KVLQT1 protein and leading to a premature stop codon at nucleotide 564. The proband was born to second-cousin parents. At 35 weeks' gestation, the obstetrician informed the mother that the fetal heart rate had dropped to 70 to 80 beats per minute. At 38 weeks, the heart rate continued to be slow, and slow heart rate persisted after birth. One hour after delivery, at the time of the first bottle feeding, the infant had cyanosis and hypotonia. A diagnosis of LQT was made and treatment with propranolol was started. On the eighth day, audiograms indicated bilateral sensory deafness. The family members were not evaluated at that time. Seven months after the delivery of the proband, the mother had a cardiac arrest and died when her alarm clock sounded. She was exhausted and very anxious at the time. Investigation of the family demonstrated an extensive involvement of many members with typical heterozygous LQT. Linkage analysis showed that the disorder mapped to the KVLQT1 region on 11p15.5. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, ARG555CYS
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|
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|
|
|
<br />
|
|
|
|
SNP: rs120074185,
|
|
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|
|
|
gnomAD: rs120074185,
|
|
|
|
|
|
ClinVar: RCV000003274, RCV000046011, RCV000057613, RCV000182211, RCV000618290, RCV001841224
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a study of 20 families originating from France with Romano-Ward syndrome (LQT1; 192500), Donger et al. (1997) identified a C-to-T transition at nucleotide 1663 of the KVLQT1 gene causing a missense arg555-to-cys substitution in the C-terminal domain. In 3 large kindreds, there was a total of 44 carriers of this mutation. Only 5 living subjects experienced syncope and there were 2 sudden deaths. Syncope or death occurred only in the presence of drugs known to modify ventricular repolarization (terfenadine, disopyramide, meflaquine, and diuretics). Carriers of the arg555-to-cys mutation had only minor or no prolongation of the QT interval. Donger et al. (1997) proposed that this allelic variant causes a forme fruste LQT1 phenotype. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 JERVELL AND LANGE-NIELSEN SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, TRP305SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs120074186,
|
|
|
|
|
|
gnomAD: rs120074186,
|
|
|
|
|
|
ClinVar: RCV000003275, RCV000057796, RCV000182130, RCV000622153, RCV001385529
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 consanguineous Jervell and Lange-Nielsen syndrome (JLNS1; 220400) families, Neyroud et al. (1998) identified a trp305-to-ser mutation in the pore region of KCNQ1 by PCR-SSCP analysis. In contrast to several missense mutations found in the same region of the KCNQ1 gene in heterozygous state in Ward-Romano syndrome patients, which are associated with severe cardiac phenotypes, the heterozygous state of the W305S mutation yielded an apparently normal phenotype. This is the same phenomenon as that observed in a number of other situations: different mutations in the same gene produce a phenotype that may be recessive or dominant and the phenotype may be the same or different in the case of the 2 modes of inheritance. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, ALA300THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs120074187,
|
|
|
|
|
|
gnomAD: rs120074187,
|
|
|
|
|
|
ClinVar: RCV000003276, RCV000057789, RCV000182128, RCV000541920, RCV000621158, RCV001102803, RCV001104722, RCV001841225
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Priori et al. (1998) described a 9-year-old boy with classic Romano-Ward syndrome (LQT1; 192500) (syncope, prolonged QT interval, normal audiogram) born to second cousins. Two brothers of the proband had died suddenly, one at rest and the other while swimming. Sequence analysis in the proband demonstrated a novel homozygous missense mutation, a G-to-A transition resulting in an alanine-to-threonine amino acid substitution at position 300 of the KVLQT1 protein. Both parents were heterozygous for this mutation and had normal QT intervals. None of 100 control chromosomes exhibited this mutation. Coexpression of the mutant KVLQT1 protein with minK (176261) in Xenopus oocytes demonstrated a mild electrophysiologic effect on ion flux. The authors commented that this mutation in the homozygous state caused Romano-Ward syndrome and not Jervell and Lange-Nielson syndrome (220400), citing it as evidence for a recessive variant of Romano-Ward syndrome. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, 3-BP DEL, PHE339DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397508069,
|
|
|
|
|
|
|
|
ClinVar: RCV000003277
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>After identifying a 10-year-old boy with long QT syndrome (192500) after a near-drowning that required defibrillation from torsade de pointes, Ackerman et al. (1998) evaluated first-degree relatives and found a 4-generation family comprising 26 individuals with 4 additional symptomatic and 8 asymptomatic members harboring an abnormally prolonged QT interval. Linkage to the 11p15.5 region was found with a maximum lod score of 3.36. A mutation search revealed a 3-bp deletion resulting in an in-frame deletion of codon 339 for phenylalanine. Ackerman et al. (1998) pointed out that the delF339 mutation is closely situated to codon 341, which is the site of 2 common mutations, A341V (607542.0010) and A341E (607542.0009). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, 9-BP DEL, NT373
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397508107,
|
|
|
|
|
|
|
|
ClinVar: RCV000003278, RCV000692974, RCV001567589, RCV002415390, RCV002476915
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 19-year-old woman with LQT1 (192500) who had been asymptomatic but who died after a near-drowning, Ackerman et al. (1999) demonstrated by molecular tests at autopsy a 9-bp deletion involving nucleotides 373 through 381 of the KCNQ1 gene. The 9-bp deletion (GCCGCGCCC) resulted in an in-frame deletion of 3 amino acids (alanine, alanine, and proline) from position 71 through 73 in the cytoplasmic N-terminal region of the KCNQ1 ion channel subunit. The woman's maternal grandfather, mother, and 18-year-old sister also had the 9-bp deletion. It appears that a substantial number of unexplained drownings may have a basis in the long QT syndrome. Although the mother had electrocardiographic changes of long QT syndrome, the 18-year-old sister who was a carrier had equivocal or normal electrocardiogram in the view of half a panel of expert electrocardiographers. The resuscitation of the proband, although ultimately unsuccessful because of the extended period of anoxia, did allow electrocardiographic documentation of QT prolongation, which was a notable finding, given the entirely asymptomatic personal and family history. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 LONG QT SYNDROME 1, RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, ARG518TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs17215500,
|
|
|
|
|
|
gnomAD: rs17215500,
|
|
|
|
|
|
ClinVar: RCV000003279, RCV000148548, RCV000182196, RCV000251958, RCV000515748, RCV000614524, RCV000779058, RCV000999897, RCV001256915, RCV001841226, RCV001847566
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Larsen et al. (1999) described a Swedish family in which the proband and his brother suffered from severe Romano-Ward syndrome (LQT1; 192500) associated with compound heterozygosity for 2 mutations in the KCNQ1 gene: R518X and A525T. The mutations were found to segregate in heterozygosity in the maternal and paternal lineage, respectively. None of the those heterozygous for a mutation exhibited clinical long QT syndrome. No hearing defects were found in the proband. The data strongly indicated that compound heterozygosity for these 2 mutations is the cause of the autosomal recessive form of RWS in this family. A recessive variant of the Ward-Romano long QT syndrome (607542.0017) was suggested by Priori et al. (1998) on the basis of a finding of homozygosity in a consanguineous family. Larsen et al. (1999) suggested that 'sporadic RWS' should be considered as potentially recessive RWS, and efforts made to determine the molecular defects and identify carriers in the family, since they may be at risk of dying suddenly from drug-induced LQTS. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 LONG QT SYNDROME 1, RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, ALA525THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs120074188,
|
|
|
|
|
|
gnomAD: rs120074188,
|
|
|
|
|
|
ClinVar: RCV000003280, RCV000057600, RCV000182202, RCV000622131, RCV001851605
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the ala525-to-thr (A525T) mutation in the KCNQ1 gene that was found in compound heterozygous state in 2 brothers with severe Romano-Ward syndrome (LQT1; 192500) by Larsen et al. (1999), see 607542.0020. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 JERVELL AND LANGE-NIELSEN SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, 2-BP DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397508110,
|
|
|
|
|
|
|
|
ClinVar: RCV000003281, RCV000182294, RCV001061673, RCV004991998
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Chen et al. (1999) reported a small Amish family in which 2 sibs fulfilled the diagnostic criteria for Jervell and Lange-Nielsen syndrome (JLNS1; 220400). Both were homozygous for a novel 2-bp deletion in the S2 transmembrane domain of KVLQT1. This mutation predicts a frameshift leading to protein truncation. The protein product was predicted to be functionless due to most transmembrane domains and the pore region of the KVLQT1 protein having been deleted. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, IVS5, -1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906290,
|
|
|
|
|
|
|
|
ClinVar: RCV000003282, RCV002512697
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Murray et al. (1999) examined a French LQTS (192500) family and found a novel G-to-C transversion at position 922 -1 in the splice acceptor site of intron 5 of the KCNQ1 gene. The effect on splicing efficiency was not determined. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, CODON 344 SPLICE MUTATION
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1800171,
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|
|
gnomAD: rs1800171,
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|
|
ClinVar: RCV000003283, RCV000045941, RCV000182159, RCV000498423, RCV000621184, RCV002247243, RCV004017223
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|
|
</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>Murray et al. (1999) found linkage to KCNQ1 in a families with LQTS (192500) and detected a G-to-C transversion at position 1032 within the last codon of exon 6. The coded alanine was conserved. RT-PCR from fresh blood samples from the proband and his affected mother demonstrated transcripts lacking exons 6 and 7. Transcripts lacking exon 7 were also found in lymphocyte DNA from a patient with this mutation and in normal cardiac tissue from a patient without LQTS. The reading frame remained intact, resulting in the deletion of the pore, or S6, domain. These observations suggested that the G-to-C transversion in the exon 6/intron 7 consensus splice donor sequence affects splicing efficiency. </p><p>The authors also found a G-to-A transition at position 1032 in 2 unrelated French families. This had been independently reported in 5 other families by Li et al. (1998) and Kanters et al. (1998). Murray et al. (1999) suggested that base position 1032 represented a mutation hotspot within KCNQ1. The commonest site for mutation is codon 341, in association with a methylated CpG dinucleotide. </p>
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|
</span>
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|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0025 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, 1-BP INS
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<br />
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|
|
SNP: rs397508104,
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|
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ClinVar: RCV000003284, RCV000046040, RCV000182288, RCV000622116, RCV001195549, RCV001841642
|
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|
</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected individuals in a family with Romano-Ward syndrome (LQT1; 192500), Neyroud et al. (1999), detected insertion of a C at nucleotide position 1893 in exon 15. This created a frameshift with a premature stop codon 19 amino acids later, resulting in a largely intact protein. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0026 JERVELL AND LANGE-NIELSEN SYNDROME 1</strong>
|
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</span>
|
|
</h4>
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|
</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, 20-BP DEL, NT1892
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<br />
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|
|
SNP: rs397508103,
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ClinVar: RCV000003285, RCV000182287, RCV001386478, RCV002408547, RCV002490606, RCV003591641, RCV004537220
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|
</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>Neyroud et al. (1999) found that a male with Jervell and Lange-Nielsen syndrome (JLNS1; 220400) was compound heterozygous for a frameshift mutation in exon 15 of the KCNQ1 gene and another mutation that was not identified. The frameshift, caused by a 20-bp deletion at nucleotide position 1892, created a premature stop codon 13 amino acids later. </p>
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|
</span>
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|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 JERVELL AND LANGE-NIELSEN SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, THR587MET
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<br />
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SNP: rs120074189,
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|
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ClinVar: RCV000003286, RCV000046026, RCV000057632, RCV000182221, RCV000619349, RCV003319300, RCV004732528
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|
|
</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Neyroud et al. (1999) reported that a male patient (family JLN12664) with Jervell Lange-Nielsen syndrome (JLNS1; 220400) was compound heterozygous for 2 mutations in the KCNQ1 gene: a de novo 1760C-T transition in exon 14, resulting in a thr587-to-met substitution, on the paternal allele, and a maternally derived splice site mutation in intron 1 (607542.0028). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0028 JERVELL AND LANGE-NIELSEN SYNDROME 1</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, IVS1
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<br />
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ClinVar: RCV000003287
|
|
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|
</span>
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|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Neyroud et al. (1999) reported that a male patient with Jervell Lange-Nielsen syndrome (JLNS1; 220400) was compound heterozygous for 2 mutations in the KCNQ1 gene: a de novo 1760C-T transition in exon 14, resulting in a thr587-to-met substitution (607542.0027), on the paternal allele, and a maternally derived splice mutation in intron 1. No additional information was provided for the intron 1 mutation. </p>
|
|
</span>
|
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</div>
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<div>
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|
<br />
|
|
</div>
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</div>
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<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
JERVELL AND LANGE-NIELSEN SYNDROME 1, INCLUDED
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
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|
KCNQ1, GLY589ASP
|
|
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|
|
<br />
|
|
|
|
SNP: rs120074190,
|
|
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|
|
|
gnomAD: rs120074190,
|
|
|
|
|
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ClinVar: RCV000003288, RCV000003289, RCV000057633, RCV000182223, RCV000622145, RCV000699476, RCV001258106, RCV001841227
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Piippo et al. (2001) identified a novel missense mutation in the KCNQ1 gene in Finns with Jervell and Lange-Nielsen syndrome (JLNS1; 220400) or long QT syndrome (192500). The mutation, a glycine-to-aspartic acid substitution at codon 589 (G589D) in the C terminus, was identified in homozygous state in 2 sibs with Jervell and Lange-Nielsen syndrome and in heterozygous state in 34 of 114 probands with Romano-Ward syndrome and 282 family members. The mean rate-corrected QT intervals of the 316 heterozygous subjects and 423 noncarriers were 460 +/- 40 ms and 410 +/- 20 ms (p less than 0.001), respectively. Piippo et al. (2001) concluded that the G589D mutation accounts for 30% of Finnish cases with long QT syndrome and may be associated with both Romano-Ward and Jervell and Lange-Nielsen phenotypes of the syndrome. They suggested that the relative enrichment of this mutation most likely represents a founder gene effect. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0030 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, PRO117LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs120074191,
|
|
|
|
|
|
|
|
ClinVar: RCV000003290, RCV000057662, RCV001349040
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Schwartz et al. (2001) identified 2 Italian families with LQT1 (192500) with the same heterozygous 350C-T transition in the KCNQ1 gene, resulting in a pro117-to-leu (P117L) substitution. In 1 family, an infant had died of SIDS and was found postmortem to have a de novo mutation. In the other family, several members had long QT syndrome. The mutation was not found in 800 reference alleles of Italian origin. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0031 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
LONG QT SYNDROME 1, ACQUIRED, SUSCEPTIBILITY TO, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, ARG583CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs17221854,
|
|
|
|
|
|
gnomAD: rs17221854,
|
|
|
|
|
|
ClinVar: RCV000003291, RCV000003292, RCV000057628, RCV000182219, RCV000762837, RCV001824559, RCV001851606, RCV003591618, RCV004018545
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with long QT syndrome (192500), Splawski et al. (2000) identified heterozygosity for a 1747C-T transition in exon 15 of the KCNQ1 gene, resulting in an arg583-to-cys (R583C) substitution. </p><p>In a patient who developed QT prolongation and torsade de pointes while taking the drug dofetilide (see 192500), Yang et al. (2002) identified heterozygosity for an R583C mutation in the KCNQ1 gene. The mutation was not found in 228 controls. In vitro expression studies of the mutant protein confirmed a significant reduction in potassium currents, suggesting that the R583C mutation was responsible for the patient's response to dofetilide. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0032 ATRIAL FIBRILLATION, FAMILIAL, 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, SER140GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs120074192,
|
|
|
|
|
|
|
|
ClinVar: RCV000003293, RCV000057673
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4-generation family with autosomal dominant atrial fibrillation (ATFB3; 607554) from Shandong Province, China, Chen et al. (2003) identified an A-to-G substitution at nucleotide 418 of the KCNQ1 gene leading to a ser-to-gly substitution at codon 140 in all affected family members. This mutation was not observed in normal individuals in the family with 1 exception, which Chen et al. (2003) ascribed to delayed manifestation or incomplete penetrance. A prolonged QTc interval was observed in 9 of the 16 affected family members, ranging from 450 to 530 ms. The mutation was absent in 188 healthy control individuals. The serine at position 140 is well conserved among different species and is located in the S1 transmembrane segment of KCNQ1 in a position close to the extracellular surface of the plasma membrane. </p><p>Using Xenopus oocytes expressing human KCNQ1 in the presence or absence of KCNE1 (176261), Peng et al. (2017) characterized 2 KCNQ1 gain-of-function mutations that cause atrial fibrillation, S140G and val141 to met (V141M; 607542.0045). In the absence of KCNE1, S140G, but not V141M, slowed voltage sensor movement, leading to indirect slowing of current deactivation. Slowing of voltage sensor deactivation by S140G in the absence of KCNE1 was independent of channel opening. When KCNE1 was coexpressed, S140G slowed both current deactivation and voltage sensor movement, whereas V141M slowed current deactivation without slowing voltage sensor movement. Slowing of voltage sensor deactivation by S140G in the presence of KCNE1 was dependent on channel opening. The authors proposed a molecular mechanism underlying the effects of the KCNQ1 mutations on channel gating and suggested that KCNE1 mediates changes in pore movement and voltage sensor-pore coupling to slow channel deactivation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0033 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, GLY269SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs120074193,
|
|
|
|
|
|
gnomAD: rs120074193,
|
|
|
|
|
|
ClinVar: RCV000003294, RCV000057765, RCV000182118, RCV000477568, RCV000762834, RCV001002562, RCV002408447
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Reardon et al. (1993) reported a family in which the proband had a cardiac arrest at 4 years of age; she and her brother were then found to have a QTc of 490 ms. The parents of the proband were first cousins and there were hearing abnormalities reported in several family members. It was uncertain whether the diagnosis should be Romano-Ward syndrome (192500), which is dominant, or Jervell and Lange-Nielsen syndrome (220400), which is recessive. Murray et al. (2002) identified a gly269-to-ser (G269S) mutation in the KCNQ1 gene in homozygous state in the proband and her brother. Functional studies indicated that the mutation had both recessive and dominant characteristics. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0034 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, GLY269ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs120074194,
|
|
|
|
|
|
|
|
ClinVar: RCV000003295, RCV000046133, RCV000057766, RCV000182119, RCV002415391, RCV004540987
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 8 affected members of a family with a severe form of dominantly inherited Romano-Ward syndrome (192500), 5 of whom had sudden deaths, Donger et al. (1997) identified a gly269-to-asp (G269D) mutation in the KCNQ1 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0035 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, VAL254MET AND VAL417MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607197,
|
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|
|
|
|
|
ClinVar: RCV000003265, RCV000003296, RCV000057749, RCV000182109, RCV000190212, RCV000619506, RCV001841405
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Wedekind et al. (2004) described a 4-generation family with long QT syndrome (192500) in which 7 members were carriers of 2 amino acid alterations in cis in the KCNQ1 gene: val254 to met (V254M) and val417 to met (V417M). Voltage clamp recordings of mutant KCNQ1 protein in Xenopus oocytes showed that only the V254M mutation reduced the I(Ks) current and that the effect of the V417M variant was negligible. The family exhibited the complete clinical spectrum of the disease, from asymptomatic patients to victims of sudden death before beta-blocker therapy. Of 9 family members, 1 female died suddenly before treatment, 3 females of the second generation were asymptomatic, and 4 members of the third and fourth generations were symptomatic. All mutation carriers were treated with beta-blockers and remained asymptomatic for a follow-up of up to 23 years. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0036 LONG QT SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, 1-BP DEL/2-BP INS, NT533
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397508115,
|
|
|
|
|
|
|
|
ClinVar: RCV000003297
|
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 13-year-old girl with long QT syndrome (192500), Aizawa et al. (2004) identified a C-to-GG substitution at nucleotide 533 in the KCNQ1 gene, causing a frameshift at alanine-178 and resulting in a truncated protein with elimination of the S3 to S6 domains and the C terminus of the KCNQ1 channel. Coexpression experiments in COS-7 cells showed that mutant and wildtype KCNQ1 remained within the cytoplasm rather than being distributed to the plasma membrane, suggesting that the truncated mutant forms a heteromultimer with wildtype KCNQ1 and causes a dominant-negative effect due to a trafficking defect. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0037 SHORT QT SYNDROME 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, VAL307LEU
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<br />
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SNP: rs120074195,
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gnomAD: rs120074195,
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ClinVar: RCV000003298, RCV000057800, RCV003996077
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 70-year-old man with short QT syndrome-2 (SQT2; 609621) who survived an episode of ventricular fibrillation, Bellocq et al. (2004) identified a 919G-C transversion in the KCNQ1 gene, resulting in a val307-to-leu (V307L) substitution. Functional studies of the mutant channel revealed that both a pronounced shift of the half-activation potential and an acceleration of the activation kinetics led to a gain of function in I(Ks). </p><p>Functional studies of the mutant channel revealed that both a pronounced shift of the half-activation potential and an acceleration of the activation kinetics led to a gain of function in I(Ks).</p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0038 LONG QT SYNDROME 1/2, DIGENIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, 1-BP DEL, 562T
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<br />
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SNP: rs397508116,
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gnomAD: rs397508116,
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ClinVar: RCV000003299
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a female infant with a family history of sudden death, who had severe, continuous bradycardia in utero that was confirmed after birth and a QTc of 485 ms (see 192500), Millat et al. (2006) identified biallelic digenic mutations: a 1-bp deletion (562delT) in exon 2 of the KCNQ1 gene, causing a frameshift at trp188, and an insertion in the KCNH2 gene (2775insG; 152427.0020). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0039 LONG QT SYNDROME 1/2, DIGENIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, ARG243PRO
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<br />
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SNP: rs120074196,
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gnomAD: rs120074196,
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ClinVar: RCV000003300, RCV000057743
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a female infant with fetal and neonatal bradycardia and a QTc of 570 ms (see 192500), Millat et al. (2006) identified biallelic digenic mutations: a 728G-C transversion in exon 4 of the KCNQ1 gene, resulting in an arg243-to-pro (R243P) substitution, and a missense mutation in the KCNH2 gene (R948C; 152427.0022). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0040 LONG QT SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, VAL205MET
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<br />
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SNP: rs151344631,
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gnomAD: rs151344631,
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ClinVar: RCV000030815, RCV000057723, RCV000119056, RCV000148547, RCV000252730
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 severely affected index cases with long QT syndrome (LQT1; 192500) from a First Nations community in northern British Columbia (Gitxsan), Arbour et al. (2008) identified a G-to-A transition in exon 4 of the KCNQ1 gene that resulted in a val-to-met substitution at codon 205 (V205M). Identification of the mutation prompted the ascertainment of 122 relatives using community-based participatory research principles. The 22 further mutation carriers identified had a significantly higher mean corrected QT interval than noncarriers (465 +/- 28 milliseconds vs 434 +/- 26 milliseconds, P less than 0.0001); however, 30% of carriers had a corrected QT interval below 440 milliseconds. In transfected mouse Itk cells this mutation suppressed I(Ks) by causing a dramatic depolarizing shift in activation voltage coupled with acceleration of channel deactivation. Arbour et al. (2008) concluded that this mutation likely conferred increased susceptibility to arrhythmias because of decreased I(Ks) current. Even with a common mutation within a relatively homogeneous population, clinical expression remains variable, supporting the difficulty of definitive diagnosis without genetic testing. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0041 ATRIAL FIBRILLATION, FAMILIAL, 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, 9-BP DUP
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<br />
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SNP: rs397515877,
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gnomAD: rs397515877,
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ClinVar: RCV000035343, RCV000114749, RCV000250643, RCV000852643, RCV001080143, RCV001719723, RCV004534735
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In affected members of a Caucasian kindred segregating autosomal dominant early-onset lone atrial fibrillation (ATFB3; 607554), Abraham et al. (2010) identified heterozygosity for a 9-bp duplication in the KCNQ1 gene, resulting in insertion of isoleucine, alanine, and proline at positions 54 to 56. The duplication was present in all 4 affected family members and in 2 symptomatic family members in whom atrial fibrillation had not yet been documented. It was not found in 3 unaffected family members or in Caucasian, Han Chinese, and Asian population controls; however, the duplication was detected in 2 (2.1%) of 94 African American control chromosomes that had been obtained from the anonymous Coriell repository, for which no clinical information was available. Functional analysis in CHO cells demonstrated that coexpression of mutant KCNQ1 with its ancillary subunit KCNE1 (176261) generated approximately 3-fold larger currents that also activated much earlier than wildtype currents. The mutant accelerated both activation and deactivation over all voltages. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0042 ATRIAL FIBRILLATION, FAMILIAL, 3</strong>
|
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</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNQ1, SER209PRO
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<br />
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SNP: rs199472705,
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ClinVar: RCV000057725, RCV000115006, RCV000232681
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In affected members of a 3-generation family with lone atrial fibrillation (ATFB3; 607554), Das et al. (2009) identified heterozygosity for a c.625C-T transition in the KCNQ1 gene, resulting in a ser209-to-pro (S209P) substitution at a highly conserved residue in the C-terminal half of the third transmembrane region (S3b) of the channel protein. The mutation was incompletely penetrant, as 1 carrier individual with an affected child was unaffected both by history and by longitudinal ECG monitoring; however, the mutation was not found in more than 1,000 control chromosomes. Mutation carriers had a longer QRS duration and a trend toward larger left atrial dimension than noncarriers, but there was no difference in PR or corrected QT interval. Functional analysis in COS-7 cells demonstrated that S209P mutant channels activate more rapidly, deactivate more slowly, and have a hyperpolarizing shift in the voltage deactivation curve compared to wildtype. In addition, a fraction of mutant channels are constitutively open at all voltages, resulting in a net increase in I(Ks) current. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0043 ATRIAL FIBRILLATION, FAMILIAL, 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
LONG QT SYNDROME 1, INCLUDED
|
|
</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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KCNQ1, ARG231HIS
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|
<br />
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|
|
SNP: rs199472709,
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|
|
gnomAD: rs199472709,
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|
|
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|
|
ClinVar: RCV000046107, RCV000057734, RCV000115007, RCV000115008, RCV000182101, RCV000762833, RCV002371883
|
|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Johnson et al. (2008) reported a female patient with onset of atrial fibrillation (ATFB3; 607554) in the first year of life who was heterozygous for a c.692G-A transition in exon 5 of the KCNQ1 gene, resulting in an arg231-to-his (R231H) substitution. The patient was also found to have a long QT interval (see 192500) at 1 year of age, with a QTc of 479 ms. </p><p>In affected members of 4 families with early-onset atrial fibrillation, Bartos et al. (2013) identified heterozygosity for the R231H mutation in KCNQ1. Twelve of 13 mutation-positive individuals had a normal QTc, and 1 had a prolonged QT interval. Functional analysis indicated that the R231H mutation increases the amount of KCNQ1 current during the atrial action potential, thus dramatically shortening its duration. R231H also disrupts PKA (see 188830) regulation of the KCNQ1 current and is associated with borderline and adrenergic-induced QT interval prolongation in patients. </p><p>In affected members of a family with atrial fibrillation, Guerrier et al. (2013) identified heterozygosity for the R231H missense mutation in KCNQ1. Guerrier et al. (2013) noted that the R231H mutation had previously been identified by Napolitano et al. (2005) in a study of patients with long QT syndrome, but stated that none of the family members with atrial fibrillation had documented prolonged QT intervals. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0044 ATRIAL FIBRILLATION, FAMILIAL, 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
KCNQ1, GLY229ASP
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|
<br />
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|
|
SNP: rs199472708,
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|
|
ClinVar: RCV000057732, RCV000115009, RCV000182099, RCV001320480, RCV003335080
|
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|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese boy who was diagnosed at 16 years of age with atrial fibrillation (ATFB3; 607554), Hasegawa et al. (2014) identified heterozygosity for a c.686G-A transition in the KCNQ1 gene, resulting in a gly229-to-asp (G229D) substitution at a highly conserved residue in the fourth transmembrane segment (S4), which is known to be a voltage sensor. Although ECG at the time of diagnosis showed a normal QT interval, the proband was later found to have borderline QT prolongation (QTc 452 ms to 480 ms), and the mutation was detected in his asymptomatic mother, who also had borderline QT prolongation (QTc 468 ms). The mutation was not found in 400 Japanese control alleles or in the NHLBI Exome Sequencing Project Exome Variant Server database. G229D mutant channels in CHO cells displayed unique functional properties, including a large instantaneous activating component without deactivation after repolarization. Hasegawa et al. (2014) concluded that G229D alters I(Ks) activity and kinetics, thereby increasing arrhythmogenicity to atrial fibrillation. </p>
|
|
</span>
|
|
</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0045 SHORT QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNQ1, VAL141MET
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|
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<br />
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|
|
SNP: rs199472687,
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ClinVar: RCV000057674, RCV000417071, RCV000468931, RCV000494365, RCV000621525
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a female infant with short QT interval, atrial fibrillation, and bradycardia (SQT2; 609621), Hong et al. (2005) identified heterozygosity for a c.421G-A transition in the KCNQ1 gene, resulting in a val141-to-met (V141M) substitution within transmembrane domain S1. Functional analysis in Xenopus oocytes demonstrated that in contrast to wildtype channels, which exhibited a slowly activating and deactivating voltage-dependent and K(+)-selective current, the V141M mutant channel current developed instantly at all voltages tested, consistent with a constitutively open channel. </p><p>In 2 unrelated girls with short QT syndrome, AF, and bradycardia, Villafane et al. (2014) identified heterozygosity for the V141M mutation in the KCNQ1 gene. </p><p>Using Xenopus oocytes expressing human KCNQ1 in the presence or absence of KCNE1 (176261), Peng et al. (2017) characterized 2 KCNQ1 gain-of-function mutations that cause atrial fibrillation, ser140 to gly (S140G; 607542.0032) and V141M. In the absence of KCNE1, S140G, but not V141M, slowed voltage sensor movement, leading to indirect slowing of current deactivation. Slowing of voltage sensor deactivation by S140G in the absence of KCNE1 was independent of channel opening. When KCNE1 was coexpressed, S140G slowed both current deactivation and voltage sensor movement, whereas V141M slowed current deactivation without slowing voltage sensor movement. Slowing of voltage sensor deactivation by S140G in the presence of KCNE1 was dependent on channel opening. The authors proposed a molecular mechanism underlying the effects of the KCNQ1 mutations on channel gating and suggested that KCNE1 mediates changes in pore movement and voltage sensor-pore coupling to slow channel deactivation. </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0046 SHORT QT SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
KCNQ1, PHE279ILE
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<br />
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SNP: rs1057519584,
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ClinVar: RCV000417068
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a 23-year-old man with a slightly shortened QT interval and a family history of sudden cardiac death (SQT2; 609621), Moreno et al. (2015) identified heterozygosity for a c.127910T-A transversion in exon 6 of the KCNQ1 gene, resulting in a phe279-to-ile (F279I) substitution at a conserved residue within the S5 transmembrane segment. The mutation was not present in his unaffected sister or mother; no DNA was available from his father, who had died unexpectedly at age 37 years. Functional analysis of the F279I mutant in the presence of KCNE1 (176261) showed a negative shift in the activation curve and an acceleration of the activation kinetics resulting in a gain of function in I(Ks). In addition, coimmunoprecipitation studies and Foster resonance energy transfer (FRET) experiments demonstrated that coassembly between F279I channels and KCNE1 was markedly decreased compared to wildtype channels. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Abraham, R. L., Yang, T., Blair, M., Roden, D. M., Darbar, D.
|
|
<strong>Augmented potassium current is a shared phenotype for two genetic defects associated with familial atrial fibrillation.</strong>
|
|
J. Molec. Cell. Cardiol. 48: 181-190, 2010.
|
|
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|
|
[PubMed: 19646991]
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[Full Text: https://doi.org/10.1016/j.yjmcc.2009.07.020]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ackerman, M. J., Clapham, D. E.
|
|
<strong>Ion channels--basic science and clinical disease.</strong>
|
|
New Eng. J. Med. 336: 1575-1586, 1997. Note: Erratum: New Eng. J. Med. 337: 579 only, 1997.
|
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