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<title>
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Entry
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- #616249 - LONG QT SYNDROME 15; LQT15
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- OMIM
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<span class="h4">#616249</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/phenotypicSeries/PS192500"> <strong>Phenotypic Series</strong> </a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div><a href="#mimEuroGentestFold" id="mimEuroGentestToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A list of European laboratories that offer genetic testing."><span id="mimEuroGentestToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>EuroGentest</div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=14727&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Romano-Ward syndrome </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=658&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Familial long QT syndrome </a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1129/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=616249[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><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Orphanet</div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=101016" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Romano-Ward syndrome</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Familial long QT syndrome</a></div>
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<span class="small">
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<div style="display: table-cell;">Animal Models</div>
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</span>
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<div><a href="https://www.alliancegenome.org/disease/DOID:0110656" 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="http://www.informatics.jax.org/disease/616249" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0110656" 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': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></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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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 101016, 768<br />
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<strong>DO:</strong> 0110656<br />
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">ICD+</a>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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616249
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</span>
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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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LONG QT SYNDROME 15; LQT15
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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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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene 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 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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</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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<th>
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Gene/Locus
|
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</th>
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<th>
|
|
Gene/Locus <br /> MIM number
|
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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>
|
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<span class="mim-font">
|
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<a href="/geneMap/2/236?start=-3&limit=10&highlight=236">
|
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2p21
|
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</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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Long QT syndrome 15
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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/616249"> 616249 </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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<td>
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<span class="mim-font">
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CALM2
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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/114182"> 114182 </a>
|
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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>
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<div>
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<div class="btn-group ">
|
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<a href="/clinicalSynopsis/616249" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
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<span class="caret"></span>
|
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<span class="sr-only">Toggle Dropdown</span>
|
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</button>
|
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</div>
|
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|
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<div class="btn-group">
|
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|
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<a href="/phenotypicSeries/PS192500" class="btn btn-info" role="button"> Phenotypic Series </a>
|
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|
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
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<span class="sr-only">Toggle Dropdown</span>
|
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</button>
|
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</div>
|
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/616249" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/616249" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<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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<p />
|
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
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<strong> INHERITANCE </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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|
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<div>
|
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<span class="mim-font">
|
|
|
|
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
|
|
|
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</span>
|
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</div>
|
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|
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</div>
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</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Heart </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Recurrent episodes of ventricular fibrillation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4015672&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4015672</a>]</span><br /> -
|
|
Bradycardia (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48867003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48867003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R00.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R00.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0428977&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0428977</a>, <a href="https://bioportal.bioontology.org/search?q=C3812171&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3812171</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001662" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001662</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001662" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001662</a>]</span><br /> -
|
|
Cardiac arrest (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397829000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397829000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/410429000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">410429000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I46" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I46</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/427.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">427.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018790&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018790</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001695" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001695</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001695" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001695</a>]</span><br /> -
|
|
Sudden death (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26636000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26636000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011071&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011071</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001699" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001699</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001699" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001699</a>]</span><br /> -
|
|
Prolonged QTc interval on electrocardiogram (ECG) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4015677&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4015677</a>]</span><br /> -
|
|
Notched T waves on ECG (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4015698&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4015698</a>]</span><br /> -
|
|
Exercise-induced polymorphic ventricular ectopy on ECG (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4015699&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4015699</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
|
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|
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|
|
|
|
|
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|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> PRENATAL MANIFESTATIONS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Fetal bradycardia (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/240299002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">240299002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0410919&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0410919</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Onset at birth or in early childhood<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the calmodulin-2 gene (CALM2, <a href="/entry/114182#0001">114182.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Long QT syndrome
|
|
- <a href="/phenotypicSeries/PS192500">PS192500</a>
|
|
- 21 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/236?start=-3&limit=10&highlight=236"> 2p21 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616249"> Long QT syndrome 15 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/616249"> 616249 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114182"> CALM2 </a>
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114182"> 114182 </a>
|
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</span>
|
|
</td>
|
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</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/3/27?start=-3&limit=10&highlight=27"> 3p25.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611818"> Long QT syndrome 9 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611818"> 611818 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601253"> CAV3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/601253"> 601253 </a>
|
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</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/3/181?start=-3&limit=10&highlight=181"> 3p22.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603830"> Long QT syndrome 3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603830"> 603830 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600163"> SCN5A </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600163"> 600163 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/4/502?start=-3&limit=10&highlight=502"> 4q25-q26 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600919"> Long QT syndrome 4 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600919"> 600919 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/106410"> ANK2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/106410"> 106410 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/4/502?start=-3&limit=10&highlight=502"> 4q25-q26 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600919"> Cardiac arrhythmia, ankyrin-B-related </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600919"> 600919 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/106410"> ANK2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/106410"> 106410 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/404?start=-3&limit=10&highlight=404"> 7q21.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611820"> ?Long QT syndrome 11 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611820"> 611820 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604001"> AKAP9 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/604001"> 604001 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/821?start=-3&limit=10&highlight=821"> 7q36.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613688"> Long QT syndrome 2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613688"> 613688 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/152427"> KCNH2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/152427"> 152427 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/11/82?start=-3&limit=10&highlight=82"> 11p15.5-p15.4 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/192500"> {Long QT syndrome 1, acquired, susceptibility to} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/192500"> 192500 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607542"> KCNQ1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607542"> 607542 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/11/82?start=-3&limit=10&highlight=82"> 11p15.5-p15.4 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/192500"> Long QT syndrome 1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/192500"> 192500 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607542"> KCNQ1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607542"> 607542 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/11/976?start=-3&limit=10&highlight=976"> 11q23.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611819"> Atrial fibrillation, familial, 17 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611819"> 611819 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608256"> SCN4B </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608256"> 608256 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/11/976?start=-3&limit=10&highlight=976"> 11q23.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611819"> Long QT syndrome 10 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/611819"> 611819 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608256"> SCN4B </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/608256"> 608256 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/11/1085?start=-3&limit=10&highlight=1085"> 11q24.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613485"> Long QT syndrome 13 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613485"> 613485 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600734"> KCNJ5 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600734"> 600734 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/12/18?start=-3&limit=10&highlight=18"> 12p13.33 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618447"> Long QT syndrome 8 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/618447"> 618447 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114205"> CACNA1C </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/114205"> 114205 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/12/285?start=-3&limit=10&highlight=285"> 12q12 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613688"> {Long QT syndrome, acquired, reduced susceptibility to} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613688"> 613688 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603313"> ALG10B </a>
|
|
</span>
|
|
</td>
|
|
<td>
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<a href="/entry/176261"> KCNE1 </a>
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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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<p>A number sign (#) is used with this entry because of evidence that long QT syndrome-15 (LQT15) is caused by heterozygous mutation in the CALM2 gene (<a href="/entry/114182">114182</a>) on chromosome 2p21.</p><p>For a general phenotypic description and discussion of genetic heterogeneity of long QT syndrome, see LQT1 (<a href="/entry/192500">192500</a>).</p>
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<p>LQT15 is a cardiac arrhythmia disorder characterized by ventricular arrhythmias, often life-threatening, occurring very early in life, frequent episodes of T-wave alternans, markedly prolonged QTc intervals, and intermittent 2:1 atrioventricular block (<a href="#2" class="mim-tip-reference" title="Crotti, L., Johnson, C. N., Graf, E., De Ferrari, G. M., Cuneo, B. F., Ovadia, M., Papagiannis, J., Feldkamp, M. D., Rathi, S. G., Kunic, J. D., Pedrazzini, M., Wieland, T., and 11 others. <strong>Calmodulin mutations associated with recurrent cardiac arrest in infants.</strong> Circulation 127: 1009-1017, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23388215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23388215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23388215[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/CIRCULATIONAHA.112.001216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23388215">Crotti et al., 2013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23388215" 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>Patients with LQT14 (<a href="/entry/616247">616247</a>), LQT15, or LQT16 (<a href="/entry/618782">618782</a>), resulting from mutation in calmodulin genes CALM1 (<a href="/entry/114180">114180</a>), CALM2, or CALM3 (<a href="/entry/114183">114183</a>), respectively, typically have a more severe phenotype, with earlier onset, profound QT prolongation, and a high predilection for cardiac arrest and sudden death, than patients with mutations in other genes (<a href="#1" class="mim-tip-reference" title="Boczek, N. J., Gomez-Hurtado, N., Ye, D., Calvert, M. L., Tester, D. J., Kryshtal, D. O., Hwang, H. S., Johnson, C. N., Chazin, W. J., Loporcaro, C. G., Shah, M., Papez, A. L., Lau, Y. R., Kanter, R., Knollmann, B. C., Ackerman, M. J. <strong>Spectrum and prevalence of CALM1-, CALM2-, and CALM3-encoded calmodulin variants in long QT syndrome and functional characterization of a novel long QT syndrome-associated calmodulin missense variant, E141G.</strong> Circ. Cardiovasc. Genet. 9: 136-146, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26969752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26969752</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.115.001323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26969752">Boczek et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26969752" 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="#2" class="mim-tip-reference" title="Crotti, L., Johnson, C. N., Graf, E., De Ferrari, G. M., Cuneo, B. F., Ovadia, M., Papagiannis, J., Feldkamp, M. D., Rathi, S. G., Kunic, J. D., Pedrazzini, M., Wieland, T., and 11 others. <strong>Calmodulin mutations associated with recurrent cardiac arrest in infants.</strong> Circulation 127: 1009-1017, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23388215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23388215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23388215[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/CIRCULATIONAHA.112.001216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23388215">Crotti et al. (2013)</a> reported a Hispanic girl in whom fetal bradycardia was first noted at 21 weeks' gestation; fetal echocardiogram showed normal cardiac anatomy and function except for bradycardia. Two hours after birth she exhibited sinus bradycardia, T-wave alternans, markedly prolonged corrected QT interval (QTc) of 690 ms, and 2:1 atrioventricular (AV) block. At 3 weeks of age, she underwent cardiac arrest with multiple episodes of ventricular fibrillation (VF), during which time she also suffered a cerebral infarction of the right parietal lobe. She continued to have multiple episodes of VF, and developed seizures at age 2 years that were attributed to the prior brain injury; at age 3, she exhibited developmental delays. Her parents and an older sister were asymptomatic with normal electrocardiograms (ECGs), and there was no history of arrhythmia, miscarriage, sudden death, seizures, or drowning in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23388215" 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="#5" class="mim-tip-reference" title="Makita, N., Yagihara, N., Crotti, L., Johnson, C. N., Beckmann, B.-M., Roh, M. S., Shigemizu, D., Lichtner, P., Ishikawa, T., Aiba, T., Homfray, T., Behr, E. R., and 27 others. <strong>Novel calmodulin mutations associated with congenital arrhythmia susceptibility.</strong> Circ. Cardiovasc. Genet. 7: 466-474, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24917665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24917665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24917665[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.113.000459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24917665">Makita et al. (2014)</a> studied 5 unrelated patients of varying ancestry who had prolonged QTc intervals and demonstrated congenital arrhythmia susceptibility. The first patient was a 16-year-old Japanese girl with a history of fetal bradycardia who had her first episode of syncope at age 19 months. ECG at that time showed marked QTc prolongation (579 ms) with atypical notched, late-peaking T waves. Subsequently, she experienced multiple episodes of cardiac arrest during exertion when she failed to take her antiarrhythmic medication, prompting placement of an internal cardioverter-defibrillator (ICD) at age 14 years. Family history was negative for LQT syndrome or sudden death, and both parents and 2 brothers had normal QTc intervals. The second patient was a 12-year-old Japanese boy who at age 5 years had 2 episodes of syncope with seizure while running. ECG showed QTc prolongation (478 ms), whereas echocardiogram, electroencephalogram, and brain MRI were normal. There was no family history of arrhythmia or sudden death, and his unaffected parents and brother had normal QTc intervals. The third patient was a 29-year-old German woman who experienced perinatal bradycardia and neonatal LQT syndrome, which was treated with medication. At 9 years of age, following interruption of therapy, she had a syncopal episode while swimming, at which time there was evidence of exercise-induced polymorphic ventricular ectopy. Her resting ECG showed QTc prolongation (465-578 ms) with T-wave abnormalities. Echocardiogram at age 22 was normal, but cardiac MRI revealed features consistent with noncompaction of the left ventricular myocardium (see <a href="/entry/604169">604169</a>). Both parents had normal QTc intervals. The fourth patient was a Moroccan girl who had syncope with prolonged unconsciousness at 8 years of age, at which time prolonged QTc (500 ms) with ventricular bigeminy was noted. She had no neurologic dysfunction, and echocardiogram and head CT were normal. She died at age 11 while dancing at a wedding. Her parents and 4 sisters were asymptomatic. The fifth patient was a 2.5-year-old English boy who had cardiac arrest due to ventricular fibrillation at 17 months of age. ECG showed bradycardia and prolonged QTc interval (555 ms). There was no family history of cardiac arrhythmia, and both parents had normal QTc intervals. The boy underwent placement of an ICD; there were no discharges over the following year. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24917665" 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="#1" class="mim-tip-reference" title="Boczek, N. J., Gomez-Hurtado, N., Ye, D., Calvert, M. L., Tester, D. J., Kryshtal, D. O., Hwang, H. S., Johnson, C. N., Chazin, W. J., Loporcaro, C. G., Shah, M., Papez, A. L., Lau, Y. R., Kanter, R., Knollmann, B. C., Ackerman, M. J. <strong>Spectrum and prevalence of CALM1-, CALM2-, and CALM3-encoded calmodulin variants in long QT syndrome and functional characterization of a novel long QT syndrome-associated calmodulin missense variant, E141G.</strong> Circ. Cardiovasc. Genet. 9: 136-146, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26969752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26969752</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.115.001323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26969752">Boczek et al. (2016)</a> reported a 14-year-old Indian girl who had bradycardia at birth, with an ECG that showed a prolonged QTc (740 ms) and 2:1 AV block. She received treatment with beta blockers and a single-chamber pacemaker in the first week of life, and at age 6 years underwent implantation of an ICD. At 11 years and 14 years of age, she received appropriate ICD discharges for ventricular fibrillation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26969752" 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="#1" class="mim-tip-reference" title="Boczek, N. J., Gomez-Hurtado, N., Ye, D., Calvert, M. L., Tester, D. J., Kryshtal, D. O., Hwang, H. S., Johnson, C. N., Chazin, W. J., Loporcaro, C. G., Shah, M., Papez, A. L., Lau, Y. R., Kanter, R., Knollmann, B. C., Ackerman, M. J. <strong>Spectrum and prevalence of CALM1-, CALM2-, and CALM3-encoded calmodulin variants in long QT syndrome and functional characterization of a novel long QT syndrome-associated calmodulin missense variant, E141G.</strong> Circ. Cardiovasc. Genet. 9: 136-146, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26969752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26969752</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.115.001323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26969752">Boczek et al. (2016)</a> performed whole-exome sequencing in 38 unrelated LQTS patients who were negative for mutation in 14 known LQTS-associated genes and identified 5 patients (13.2%) with mutations in calmodulin genes, 3 with mutations in CALM1 (LQT14) and 2 with mutations in CALM2 (LQT15). Compared to the 33 LQTS patients who did not have a mutation in calmodulin, and to a previously reported cohort of 541 patients with LQTS (<a href="#6" 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>), 272 of whom were found to have mutations in the KCNQ1 (<a href="/entry/607542">607542</a>), KCNH2 (<a href="/entry/152427">152427</a>), or SCN5A (<a href="/entry/600163">600163</a>) genes, the 5 children with calmodulin-associated LQTS had a significantly earlier age of onset (average of 10 months, compared to the third decade of life), longer average QTc (676 ms, versus 470 ms to 514 ms), and higher occurrence of cardiac arrest (100%, versus 12 to 24%). In addition, the authors noted that all calmodulin variants were shown to occur de novo when parental DNA was available for testing, supporting the malignant nature of LQTS-related calmodulin variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26969752+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>
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<p>In a Hispanic girl with markedly prolonged QTc intervals and multiple episodes of ventricular fibrillation, who was negative for mutation in the 5 genes most frequently associated with LQT syndrome, <a href="#2" class="mim-tip-reference" title="Crotti, L., Johnson, C. N., Graf, E., De Ferrari, G. M., Cuneo, B. F., Ovadia, M., Papagiannis, J., Feldkamp, M. D., Rathi, S. G., Kunic, J. D., Pedrazzini, M., Wieland, T., and 11 others. <strong>Calmodulin mutations associated with recurrent cardiac arrest in infants.</strong> Circulation 127: 1009-1017, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23388215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23388215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23388215[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/CIRCULATIONAHA.112.001216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23388215">Crotti et al. (2013)</a> performed exome sequencing and identified a heterozygous de novo missense mutation the CALM2 gene (D96V; <a href="/entry/114182#0001">114182.0001</a>). The mutation was not found in 92 Hispanic American controls or in public databases. Functional analysis demonstrated a several-fold reduction in calcium-binding affinity with the D96V mutant compared to wildtype calmodulin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23388215" 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 12 unrelated Japanese patients with LQTS who were negative for mutation in genes known to be associated with life-threatening arrhythmias, <a href="#5" class="mim-tip-reference" title="Makita, N., Yagihara, N., Crotti, L., Johnson, C. N., Beckmann, B.-M., Roh, M. S., Shigemizu, D., Lichtner, P., Ishikawa, T., Aiba, T., Homfray, T., Behr, E. R., and 27 others. <strong>Novel calmodulin mutations associated with congenital arrhythmia susceptibility.</strong> Circ. Cardiovasc. Genet. 7: 466-474, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24917665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24917665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24917665[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.113.000459" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24917665">Makita et al. (2014)</a> used next-generation sequencing and identified heterozygosity for a de novo mutation in the CALM2 gene (D134H; <a href="/entry/114182#0002">114182.0002</a>) in a 16-year-old girl. Analysis of exome-sequencing data from 190 unrelated mutation-negative Japanese patients with LQTS revealed another missense mutation in CALM2 (N98S; <a href="/entry/114182#0003">114182.0003</a>) in a 12-year-old boy. Exome sequencing in an affected English boy identified heterozygosity for a different mutation at codon 98 in CALM2 (N98I; <a href="/entry/114182#0004">114182.0004</a>). Candidate gene screening of the 3 calmodulin genes revealed 2 more heterozygous missense mutations in CALM2: D132E (<a href="/entry/114182#0005">114182.0005</a>) in a 29-year-old German woman with LQTS, and Q136P (<a href="/entry/114182#0006">114182.0006</a>) in a Moroccan girl who died suddenly during exertion at age 11 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24917665" 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="#1" class="mim-tip-reference" title="Boczek, N. J., Gomez-Hurtado, N., Ye, D., Calvert, M. L., Tester, D. J., Kryshtal, D. O., Hwang, H. S., Johnson, C. N., Chazin, W. J., Loporcaro, C. G., Shah, M., Papez, A. L., Lau, Y. R., Kanter, R., Knollmann, B. C., Ackerman, M. J. <strong>Spectrum and prevalence of CALM1-, CALM2-, and CALM3-encoded calmodulin variants in long QT syndrome and functional characterization of a novel long QT syndrome-associated calmodulin missense variant, E141G.</strong> Circ. Cardiovasc. Genet. 9: 136-146, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26969752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26969752</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.115.001323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26969752">Boczek et al. (2016)</a> performed whole-exome sequencing in 38 unrelated LQTS patients who were negative for mutation in 14 known LQTS-associated genes and identified a 14-year-old Indian girl and a 7-year-old white boy who were heterozygous for 2 different missense mutations at the same codon in the CALM2 gene, D130G (<a href="/entry/114182#0007">114182.0007</a>) and D130V, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26969752" 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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In a review of 74 patients from the International Calmodulinopathy Registry and from the published literature who had mutations in the CALM1, CALM2, or CALM3 genes, <a href="#3" class="mim-tip-reference" title="Crotti, L., Spazzolini, C., Tester, D. J., Ghidoni, A., Baruteau, A.-E., Beckmann, B.-M., Behr, E. R., Bennet, J. S., Bezzina, C. R., Bhuiyan, Z. A., Celiker, A., Cerrone, M., and 29 others. <strong>Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.</strong> Europ. Heart J. 40: 2964-2975, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31170290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31170290</a>] [<a href="https://doi.org/10.1093/eurheartj/ehz311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31170290">Crotti et al. (2019)</a> stated that beta-blocker therapy and left cardiac sympathetic denervation, effectively used for conventional LQTS and CPVT, offer surprisingly modest benefits in calmodulin-related arrhythmias, with patients often requiring an implantable cardioverter-defibrillator despite optimal medical therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31170290" 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>Gene Therapy</em></strong></p><p>
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In cardiomyocytes differentiated from induced pluripotent stem cells from the 14-year-old Indian girl with LQTS who was originally reported by <a href="#1" class="mim-tip-reference" title="Boczek, N. J., Gomez-Hurtado, N., Ye, D., Calvert, M. L., Tester, D. J., Kryshtal, D. O., Hwang, H. S., Johnson, C. N., Chazin, W. J., Loporcaro, C. G., Shah, M., Papez, A. L., Lau, Y. R., Kanter, R., Knollmann, B. C., Ackerman, M. J. <strong>Spectrum and prevalence of CALM1-, CALM2-, and CALM3-encoded calmodulin variants in long QT syndrome and functional characterization of a novel long QT syndrome-associated calmodulin missense variant, E141G.</strong> Circ. Cardiovasc. Genet. 9: 136-146, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26969752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26969752</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.115.001323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26969752">Boczek et al. (2016)</a>, <a href="#4" class="mim-tip-reference" title="Limpitikul, W. B., Dick, I. E., Tester, D. J., Boczek, N. J., Limphong, P., Yang, W., Choi, M. H., Babich, J., DiSilvestre, D., Kanter, R. J., Tomaselli, G. F., Ackerman, M. J., Yue, D. T. <strong>A precision medicine approach to the rescue of function on malignant calmodulinopathic long-QT syndrome.</strong> Circ. Res. 120: 39-48, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27765793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27765793</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.116.309283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27765793">Limpitikul et al. (2017)</a> used a CRISPR interference (CRISPRi) short guide RNA to selectively reduce expression of both mutant and wildtype CALM2, without appreciable alteration of either CALM1 or CALM3. Monolayers of treated mutant cardiomyocytes showed a substantial shortening of action potential durations (APDs) compared to untreated mutant cardiomyocytes. In addition, the treated cells showed significantly faster Ca(2+)/calmodulin-dependent inactivation (CDI) compared to untreated cells, and CDI in the treated mutant cardiomyocytes was nearly identical to that of wildtype cardiomyocytes. The authors concluded that CRISPRi effectively reduced expression of mutant and wildtype CALM2 alleles, with normalization of the APD and the L-type Ca(2+) channel CDI mechanism. They noted that this treatment strategy would be readily generalizable to the CALM1 or CALM3 genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26969752+27765793" 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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Boczek, N. J., Gomez-Hurtado, N., Ye, D., Calvert, M. L., Tester, D. J., Kryshtal, D. O., Hwang, H. S., Johnson, C. N., Chazin, W. J., Loporcaro, C. G., Shah, M., Papez, A. L., Lau, Y. R., Kanter, R., Knollmann, B. C., Ackerman, M. J.
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Circ. Cardiovasc. Genet. 9: 136-146, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26969752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26969752</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26969752" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Crotti, L., Johnson, C. N., Graf, E., De Ferrari, G. M., Cuneo, B. F., Ovadia, M., Papagiannis, J., Feldkamp, M. D., Rathi, S. G., Kunic, J. D., Pedrazzini, M., Wieland, T., and 11 others.
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<strong>Calmodulin mutations associated with recurrent cardiac arrest in infants.</strong>
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Circulation 127: 1009-1017, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23388215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23388215</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23388215[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=23388215" 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/CIRCULATIONAHA.112.001216" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Crotti2019" class="mim-anchor"></a>
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Crotti, L., Spazzolini, C., Tester, D. J., Ghidoni, A., Baruteau, A.-E., Beckmann, B.-M., Behr, E. R., Bennet, J. S., Bezzina, C. R., Bhuiyan, Z. A., Celiker, A., Cerrone, M., and 29 others.
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<strong>Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.</strong>
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Europ. Heart J. 40: 2964-2975, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31170290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31170290</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31170290" 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/10.1093/eurheartj/ehz311" target="_blank">Full Text</a>]
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<a id="Limpitikul2017" class="mim-anchor"></a>
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Limpitikul, W. B., Dick, I. E., Tester, D. J., Boczek, N. J., Limphong, P., Yang, W., Choi, M. H., Babich, J., DiSilvestre, D., Kanter, R. J., Tomaselli, G. F., Ackerman, M. J., Yue, D. T.
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<strong>A precision medicine approach to the rescue of function on malignant calmodulinopathic long-QT syndrome.</strong>
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Circ. Res. 120: 39-48, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27765793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27765793</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27765793" 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/CIRCRESAHA.116.309283" target="_blank">Full Text</a>]
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<a id="Makita2014" class="mim-anchor"></a>
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Makita, N., Yagihara, N., Crotti, L., Johnson, C. N., Beckmann, B.-M., Roh, M. S., Shigemizu, D., Lichtner, P., Ishikawa, T., Aiba, T., Homfray, T., Behr, E. R., and 27 others.
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<strong>Novel calmodulin mutations associated with congenital arrhythmia susceptibility.</strong>
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Circ. Cardiovasc. Genet. 7: 466-474, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24917665/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24917665</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24917665[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=24917665" 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/CIRCGENETICS.113.000459" target="_blank">Full Text</a>]
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<a id="Tester2005" class="mim-anchor"></a>
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Tester, D. J., Will, M. L., Haglund, C. M., Ackerman, M. J.
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<strong>Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.</strong>
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Heart Rhythm 2: 507-517, 2005.
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[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://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'})">related citations</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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Marla J. F. O'Neill - updated : 02/25/2020
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Marla J. F. O'Neill - updated : 02/21/2020
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Marla J. F. O'Neill : 2/26/2015
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carol : 02/26/2020
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alopez : 02/25/2020<br>alopez : 02/21/2020<br>alopez : 03/02/2015<br>mcolton : 2/27/2015
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<strong>#</strong> 616249
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LONG QT SYNDROME 15; LQT15
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<strong>ORPHA:</strong> 101016, 768;
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<strong>DO:</strong> 0110656;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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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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2p21
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Long QT syndrome 15
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616249
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Autosomal dominant
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3
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CALM2
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<span class="mim-font">
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114182
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<p>A number sign (#) is used with this entry because of evidence that long QT syndrome-15 (LQT15) is caused by heterozygous mutation in the CALM2 gene (114182) on chromosome 2p21.</p><p>For a general phenotypic description and discussion of genetic heterogeneity of long QT syndrome, see LQT1 (192500).</p>
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<strong>Description</strong>
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<p>LQT15 is a cardiac arrhythmia disorder characterized by ventricular arrhythmias, often life-threatening, occurring very early in life, frequent episodes of T-wave alternans, markedly prolonged QTc intervals, and intermittent 2:1 atrioventricular block (Crotti et al., 2013). </p><p>Patients with LQT14 (616247), LQT15, or LQT16 (618782), resulting from mutation in calmodulin genes CALM1 (114180), CALM2, or CALM3 (114183), respectively, typically have a more severe phenotype, with earlier onset, profound QT prolongation, and a high predilection for cardiac arrest and sudden death, than patients with mutations in other genes (Boczek et al., 2016). </p>
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<strong>Clinical Features</strong>
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<p>Crotti et al. (2013) reported a Hispanic girl in whom fetal bradycardia was first noted at 21 weeks' gestation; fetal echocardiogram showed normal cardiac anatomy and function except for bradycardia. Two hours after birth she exhibited sinus bradycardia, T-wave alternans, markedly prolonged corrected QT interval (QTc) of 690 ms, and 2:1 atrioventricular (AV) block. At 3 weeks of age, she underwent cardiac arrest with multiple episodes of ventricular fibrillation (VF), during which time she also suffered a cerebral infarction of the right parietal lobe. She continued to have multiple episodes of VF, and developed seizures at age 2 years that were attributed to the prior brain injury; at age 3, she exhibited developmental delays. Her parents and an older sister were asymptomatic with normal electrocardiograms (ECGs), and there was no history of arrhythmia, miscarriage, sudden death, seizures, or drowning in the family. </p><p>Makita et al. (2014) studied 5 unrelated patients of varying ancestry who had prolonged QTc intervals and demonstrated congenital arrhythmia susceptibility. The first patient was a 16-year-old Japanese girl with a history of fetal bradycardia who had her first episode of syncope at age 19 months. ECG at that time showed marked QTc prolongation (579 ms) with atypical notched, late-peaking T waves. Subsequently, she experienced multiple episodes of cardiac arrest during exertion when she failed to take her antiarrhythmic medication, prompting placement of an internal cardioverter-defibrillator (ICD) at age 14 years. Family history was negative for LQT syndrome or sudden death, and both parents and 2 brothers had normal QTc intervals. The second patient was a 12-year-old Japanese boy who at age 5 years had 2 episodes of syncope with seizure while running. ECG showed QTc prolongation (478 ms), whereas echocardiogram, electroencephalogram, and brain MRI were normal. There was no family history of arrhythmia or sudden death, and his unaffected parents and brother had normal QTc intervals. The third patient was a 29-year-old German woman who experienced perinatal bradycardia and neonatal LQT syndrome, which was treated with medication. At 9 years of age, following interruption of therapy, she had a syncopal episode while swimming, at which time there was evidence of exercise-induced polymorphic ventricular ectopy. Her resting ECG showed QTc prolongation (465-578 ms) with T-wave abnormalities. Echocardiogram at age 22 was normal, but cardiac MRI revealed features consistent with noncompaction of the left ventricular myocardium (see 604169). Both parents had normal QTc intervals. The fourth patient was a Moroccan girl who had syncope with prolonged unconsciousness at 8 years of age, at which time prolonged QTc (500 ms) with ventricular bigeminy was noted. She had no neurologic dysfunction, and echocardiogram and head CT were normal. She died at age 11 while dancing at a wedding. Her parents and 4 sisters were asymptomatic. The fifth patient was a 2.5-year-old English boy who had cardiac arrest due to ventricular fibrillation at 17 months of age. ECG showed bradycardia and prolonged QTc interval (555 ms). There was no family history of cardiac arrhythmia, and both parents had normal QTc intervals. The boy underwent placement of an ICD; there were no discharges over the following year. </p><p>Boczek et al. (2016) reported a 14-year-old Indian girl who had bradycardia at birth, with an ECG that showed a prolonged QTc (740 ms) and 2:1 AV block. She received treatment with beta blockers and a single-chamber pacemaker in the first week of life, and at age 6 years underwent implantation of an ICD. At 11 years and 14 years of age, she received appropriate ICD discharges for ventricular fibrillation. </p><p>Boczek et al. (2016) performed whole-exome sequencing in 38 unrelated LQTS patients who were negative for mutation in 14 known LQTS-associated genes and identified 5 patients (13.2%) with mutations in calmodulin genes, 3 with mutations in CALM1 (LQT14) and 2 with mutations in CALM2 (LQT15). Compared to the 33 LQTS patients who did not have a mutation in calmodulin, and to a previously reported cohort of 541 patients with LQTS (Tester et al., 2005), 272 of whom were found to have mutations in the KCNQ1 (607542), KCNH2 (152427), or SCN5A (600163) genes, the 5 children with calmodulin-associated LQTS had a significantly earlier age of onset (average of 10 months, compared to the third decade of life), longer average QTc (676 ms, versus 470 ms to 514 ms), and higher occurrence of cardiac arrest (100%, versus 12 to 24%). In addition, the authors noted that all calmodulin variants were shown to occur de novo when parental DNA was available for testing, supporting the malignant nature of LQTS-related calmodulin variants. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>In a Hispanic girl with markedly prolonged QTc intervals and multiple episodes of ventricular fibrillation, who was negative for mutation in the 5 genes most frequently associated with LQT syndrome, Crotti et al. (2013) performed exome sequencing and identified a heterozygous de novo missense mutation the CALM2 gene (D96V; 114182.0001). The mutation was not found in 92 Hispanic American controls or in public databases. Functional analysis demonstrated a several-fold reduction in calcium-binding affinity with the D96V mutant compared to wildtype calmodulin. </p><p>Among 12 unrelated Japanese patients with LQTS who were negative for mutation in genes known to be associated with life-threatening arrhythmias, Makita et al. (2014) used next-generation sequencing and identified heterozygosity for a de novo mutation in the CALM2 gene (D134H; 114182.0002) in a 16-year-old girl. Analysis of exome-sequencing data from 190 unrelated mutation-negative Japanese patients with LQTS revealed another missense mutation in CALM2 (N98S; 114182.0003) in a 12-year-old boy. Exome sequencing in an affected English boy identified heterozygosity for a different mutation at codon 98 in CALM2 (N98I; 114182.0004). Candidate gene screening of the 3 calmodulin genes revealed 2 more heterozygous missense mutations in CALM2: D132E (114182.0005) in a 29-year-old German woman with LQTS, and Q136P (114182.0006) in a Moroccan girl who died suddenly during exertion at age 11 years. </p><p>Boczek et al. (2016) performed whole-exome sequencing in 38 unrelated LQTS patients who were negative for mutation in 14 known LQTS-associated genes and identified a 14-year-old Indian girl and a 7-year-old white boy who were heterozygous for 2 different missense mutations at the same codon in the CALM2 gene, D130G (114182.0007) and D130V, respectively. </p>
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<h4>
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<strong>Clinical Management</strong>
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<p><strong><em>Implantable Cardioverter-Defibrillator</em></strong></p><p>
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In a review of 74 patients from the International Calmodulinopathy Registry and from the published literature who had mutations in the CALM1, CALM2, or CALM3 genes, Crotti et al. (2019) stated that beta-blocker therapy and left cardiac sympathetic denervation, effectively used for conventional LQTS and CPVT, offer surprisingly modest benefits in calmodulin-related arrhythmias, with patients often requiring an implantable cardioverter-defibrillator despite optimal medical therapy. </p><p><strong><em>Gene Therapy</em></strong></p><p>
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In cardiomyocytes differentiated from induced pluripotent stem cells from the 14-year-old Indian girl with LQTS who was originally reported by Boczek et al. (2016), Limpitikul et al. (2017) used a CRISPR interference (CRISPRi) short guide RNA to selectively reduce expression of both mutant and wildtype CALM2, without appreciable alteration of either CALM1 or CALM3. Monolayers of treated mutant cardiomyocytes showed a substantial shortening of action potential durations (APDs) compared to untreated mutant cardiomyocytes. In addition, the treated cells showed significantly faster Ca(2+)/calmodulin-dependent inactivation (CDI) compared to untreated cells, and CDI in the treated mutant cardiomyocytes was nearly identical to that of wildtype cardiomyocytes. The authors concluded that CRISPRi effectively reduced expression of mutant and wildtype CALM2 alleles, with normalization of the APD and the L-type Ca(2+) channel CDI mechanism. They noted that this treatment strategy would be readily generalizable to the CALM1 or CALM3 genes. </p>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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Boczek, N. J., Gomez-Hurtado, N., Ye, D., Calvert, M. L., Tester, D. J., Kryshtal, D. O., Hwang, H. S., Johnson, C. N., Chazin, W. J., Loporcaro, C. G., Shah, M., Papez, A. L., Lau, Y. R., Kanter, R., Knollmann, B. C., Ackerman, M. J.
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<strong>Spectrum and prevalence of CALM1-, CALM2-, and CALM3-encoded calmodulin variants in long QT syndrome and functional characterization of a novel long QT syndrome-associated calmodulin missense variant, E141G.</strong>
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Circ. Cardiovasc. Genet. 9: 136-146, 2016.
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[PubMed: 26969752]
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[Full Text: https://doi.org/10.1161/CIRCGENETICS.115.001323]
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<li>
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Crotti, L., Johnson, C. N., Graf, E., De Ferrari, G. M., Cuneo, B. F., Ovadia, M., Papagiannis, J., Feldkamp, M. D., Rathi, S. G., Kunic, J. D., Pedrazzini, M., Wieland, T., and 11 others.
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<strong>Calmodulin mutations associated with recurrent cardiac arrest in infants.</strong>
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Circulation 127: 1009-1017, 2013.
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[PubMed: 23388215]
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[Full Text: https://doi.org/10.1161/CIRCULATIONAHA.112.001216]
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Crotti, L., Spazzolini, C., Tester, D. J., Ghidoni, A., Baruteau, A.-E., Beckmann, B.-M., Behr, E. R., Bennet, J. S., Bezzina, C. R., Bhuiyan, Z. A., Celiker, A., Cerrone, M., and 29 others.
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<strong>Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.</strong>
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Europ. Heart J. 40: 2964-2975, 2019.
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[PubMed: 31170290]
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[Full Text: https://doi.org/10.1093/eurheartj/ehz311]
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</li>
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<li>
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<p class="mim-text-font">
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Limpitikul, W. B., Dick, I. E., Tester, D. J., Boczek, N. J., Limphong, P., Yang, W., Choi, M. H., Babich, J., DiSilvestre, D., Kanter, R. J., Tomaselli, G. F., Ackerman, M. J., Yue, D. T.
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<strong>A precision medicine approach to the rescue of function on malignant calmodulinopathic long-QT syndrome.</strong>
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Circ. Res. 120: 39-48, 2017.
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[PubMed: 27765793]
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[Full Text: https://doi.org/10.1161/CIRCRESAHA.116.309283]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Makita, N., Yagihara, N., Crotti, L., Johnson, C. N., Beckmann, B.-M., Roh, M. S., Shigemizu, D., Lichtner, P., Ishikawa, T., Aiba, T., Homfray, T., Behr, E. R., and 27 others.
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<strong>Novel calmodulin mutations associated with congenital arrhythmia susceptibility.</strong>
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Circ. Cardiovasc. Genet. 7: 466-474, 2014.
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[PubMed: 24917665]
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[Full Text: https://doi.org/10.1161/CIRCGENETICS.113.000459]
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<p class="mim-text-font">
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Tester, D. J., Will, M. L., Haglund, C. M., Ackerman, M. J.
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<strong>Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.</strong>
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Heart Rhythm 2: 507-517, 2005.
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[PubMed: 15840476]
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[Full Text: https://doi.org/10.1016/j.hrthm.2005.01.020]
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Marla J. F. O'Neill - updated : 02/25/2020<br>Marla J. F. O'Neill - updated : 02/21/2020
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Marla J. F. O'Neill : 2/26/2015
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