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Entry
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- *606097 - PHOSPHATIDYLINOSITOL GLYCAN ANCHOR BIOSYNTHESIS CLASS N PROTEIN; PIGN
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- OMIM
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<p>
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<span class="h4">*606097</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="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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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 role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</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="#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="#molecularGenetics">Molecular Genetics</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/606097">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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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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<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 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=ENSG00000197563;t=ENST00000640252" 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=23556" 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=606097" 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 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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</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=ENSG00000197563;t=ENST00000640252" 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_012327,NM_176787,XM_011525889,XM_011525890,XM_011525891,XM_011525892,XM_011525893,XM_011525894,XM_011525895,XM_011525896,XM_011525898,XM_017025685,XM_047437430,XM_047437431,XM_047437432,XM_047437433,XM_047437434,XM_047437435,XM_047437436,XM_047437437,XM_047437438,XM_047437439,XM_047437440,XM_047437441,XM_047437442,XM_047437443,XM_047437444,XM_047437445,XM_047437446,XM_047437447,XM_047437448,XM_047437449,XM_047437450,XM_047437451,XM_047437452,XM_047437453,XM_047437454,XM_047437455,XM_047437456,XM_047437457,XM_047437458,XM_047437459,XM_047437460,XM_047437461,XM_047437462,XM_047437463,XM_047437464" 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_176787" 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=606097" 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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</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=12085&isoform_id=12085_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/PIGN" 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/4206155,6808356,6912500,20306653,29029537,74706012,119583520,119583521,119583522,119583523,189054763,767998469,767998471,767998473,767998476,767998478,767998480,767998482,767998484,767998488,1034603808,2217316552,2217316554,2217316556,2217316558,2217316560,2217316563,2217316565,2217316567,2217316569,2217316571,2217316573,2217316575,2217316577,2217316579,2217316581,2217316583,2217316585,2217316587,2217316589,2217316591,2217316594,2217316596,2217316598,2217316600,2217316602,2217316604,2217316606,2217316608,2217316610,2217316612,2217316614,2217316616,2217316618,2217316620,2217316622,2462560073,2462560075,2462560077,2462560079,2462560081,2462560083,2462560085,2462560087,2462560089,2462560091,2462560093,2462560095,2462560097,2462560099,2462560101,2462560103,2462560105,2462560107,2462560109,2462560111,2462560113,2462560115,2462560117,2462560119,2462560121,2462560123,2462560125,2462560127,2462560129,2462560131,2462560133,2462560135,2462560137,2462560139,2462560141,2462560143,2462560145,2462560147,2462560149,2462560151,2462560153" 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/O95427" 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=23556" 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=ENSG00000197563;t=ENST00000640252" 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=PIGN" 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=PIGN" 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+23556" 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/PIGN" 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:23556" 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/23556" 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=chr18&hgg_gene=ENST00000640252.2&hgg_start=62017615&hgg_end=62187056&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:8967" 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:8967" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=606097[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=606097[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/PIGN/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/ENSG00000197563" 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=PIGN" 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=PIGN" 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=PIGN" 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="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=PIGN&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/PA33298" 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:8967" 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://flybase.org/reports/FBgn0033479.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1351629" 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/PIGN#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:1351629" 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/23556/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://www.orthodb.org/?ncbi=23556" 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=WBGene00021840;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-080204-114" 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:23556" 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=PIGN&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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</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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606097
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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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PHOSPHATIDYLINOSITOL GLYCAN ANCHOR BIOSYNTHESIS CLASS N PROTEIN; PIGN
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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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<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=PIGN" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PIGN</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/18/223?start=-3&limit=10&highlight=223">18q21.33</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr18:62017615-62187056&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'})">18:62,017,615-62,187,056</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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</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="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/18/223?start=-3&limit=10&highlight=223">
|
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18q21.33
|
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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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Multiple congenital anomalies-hypotonia-seizures 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/614080"> 614080 </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 recessive">AR</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>
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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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<p>The PIGN gene encodes glycosylphosphatidylinositol (GPI) ethanolamine phosphate transferase-1, also called phosphatidylinositol-glycan biosynthesis class N protein, which is involved in GPI-anchor biosynthesis. GPI-anchored proteins comprise a well-characterized family of proteins that must acquire a GPI anchor and traffic from their site of synthesis, i.e., the endoplasmic reticulum (ER), to their final destination, the cell surface (summary by <a href="#6" class="mim-tip-reference" title="Maydan, G., Noyman, I., Har-Zahav, A., Neriah, Z. B., Pasmanik-Chor, M., Yeheskel, A., Albin-Kaplanski, A., Maya, I., Magal, N., Birk, E., Simon, A. J., Halevy, A., Rechavi, G., Shohat, M., Straussberg, R., Basel-Vanagaite, L. <strong>Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN.</strong> J. Med. Genet. 48: 383-389, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21493957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21493957</a>] [<a href="https://doi.org/10.1136/jmg.2010.087114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21493957">Maydan et al., 2011</a>). The common backbone of GPIs is assembled by the sequential additions of sugar and phosphoethanolamine (EtNP) components to phosphatidylinositol (summary by <a href="#3" class="mim-tip-reference" title="Gaynor, E. C., Mondesert, G., Grimme, S. J., Reed, S. I., Orlean, P., Emr, S. D. <strong>MCD4 encodes a conserved endoplasmic reticulum membrane protein essential for glycosylphosphatidylinositol anchor synthesis in yeast.</strong> Molec. Biol. Cell 10: 627-648, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10069808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10069808</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10069808[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/10.1091/mbc.10.3.627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10069808">Gaynor et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21493957+10069808" 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>For information on the PIG gene family and the roles of PIG proteins in GPI biosynthesis, see PIGA (<a href="/entry/311770">311770</a>).</p>
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<p>In a screen to isolate yeast mutants defective for bud emergence and polarized growth, <a href="#3" class="mim-tip-reference" title="Gaynor, E. C., Mondesert, G., Grimme, S. J., Reed, S. I., Orlean, P., Emr, S. D. <strong>MCD4 encodes a conserved endoplasmic reticulum membrane protein essential for glycosylphosphatidylinositol anchor synthesis in yeast.</strong> Molec. Biol. Cell 10: 627-648, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10069808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10069808</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10069808[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/10.1091/mbc.10.3.627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10069808">Gaynor et al. (1999)</a> identified yeast Mcd4. By database searching, they identified cDNA clones encoding human PIGN, which they called MCD4. PIGN encodes a deduced 931-amino acid protein with 14 predicted transmembrane domains, potential N-linked glycosylation sites, an ER retrieval motif, and a stop-transfer sequence predicted to direct translocation into the ER. PIGN has a hydrophilic N-terminal ER luminal domain that contains motifs conserved in mammalian phosphodiesterases and pyrophosphatases. PIGN shares sequence identity with its counterparts in S. cerevisiae (35%), S. pombe (34%), and mouse (87%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10069808" 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 subcellular fractionation and sucrose density gradient experiments, <a href="#3" class="mim-tip-reference" title="Gaynor, E. C., Mondesert, G., Grimme, S. J., Reed, S. I., Orlean, P., Emr, S. D. <strong>MCD4 encodes a conserved endoplasmic reticulum membrane protein essential for glycosylphosphatidylinositol anchor synthesis in yeast.</strong> Molec. Biol. Cell 10: 627-648, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10069808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10069808</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10069808[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/10.1091/mbc.10.3.627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10069808">Gaynor et al. (1999)</a> demonstrated that yeast Mcd4 is localized in the ER. Using tunicamycin and endo H treatment, they showed that the 6 N-terminal N-linked glycosylation sites of Mcd4 are utilized. They hypothesized that MCD4 is retained in the ER and is unlikely to cycle through the Golgi. Yeast Mcd4 mutants exhibited marked morphologic defects as well as an ER-to-Golgi transport defect specific for GPI-anchored proteins. <a href="#3" class="mim-tip-reference" title="Gaynor, E. C., Mondesert, G., Grimme, S. J., Reed, S. I., Orlean, P., Emr, S. D. <strong>MCD4 encodes a conserved endoplasmic reticulum membrane protein essential for glycosylphosphatidylinositol anchor synthesis in yeast.</strong> Molec. Biol. Cell 10: 627-648, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10069808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10069808</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10069808[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/10.1091/mbc.10.3.627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10069808">Gaynor et al. (1999)</a> concluded that MCD4 is a component of the eukaryotic GPI anchor synthesis pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10069808" 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="#4" class="mim-tip-reference" title="Hong, Y., Maeda, Y., Watanabe, R., Ohishi, K., Mishkind, M., Riezman, H., Kinoshita, T. <strong>Pig-n, a mammalian homologue of yeast Mcd4p, is involved in transferring phosphoethanolamine to the first mannose of the glycosylphosphatidylinositol.</strong> J. Biol. Chem. 274: 35099-35106, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10574991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10574991</a>] [<a href="https://doi.org/10.1074/jbc.274.49.35099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10574991">Hong et al. (1999)</a> cloned mouse Pign and disrupted the protein in F9 embryonal carcinoma cells. The first mannose (Man1) in the GPI precursors was not modified by phosphoethanolamine in the knockout cells, but these cells were still capable of generating further modified GPI species. <a href="#4" class="mim-tip-reference" title="Hong, Y., Maeda, Y., Watanabe, R., Ohishi, K., Mishkind, M., Riezman, H., Kinoshita, T. <strong>Pig-n, a mammalian homologue of yeast Mcd4p, is involved in transferring phosphoethanolamine to the first mannose of the glycosylphosphatidylinositol.</strong> J. Biol. Chem. 274: 35099-35106, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10574991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10574991</a>] [<a href="https://doi.org/10.1074/jbc.274.49.35099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10574991">Hong et al. (1999)</a> concluded that Pign is involved in the addition of EtNP to Man1 but that its modification is not essential for the surface expression of GPI-anchored proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10574991" 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="#1" class="mim-tip-reference" title="Burrell, R. A., McClelland, S. E., Endesfelder, D., Groth, P., Weller, M.-C., Shaikh, N., Domingo, E., Kanu, N., Dewhurst, S. M., Gronroos, E., Chew, S. K., Rowan, A. J., and 9 others. <strong>Replication stress links structural and numerical cancer chromosomal instability.</strong> Nature 494: 492-496, 2013. Note: Erratum: Nature 500: 490 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23446422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23446422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23446422[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/nature11935" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23446422">Burrell et al. (2013)</a> found evidence for impaired replication fork progression and increased DNA replication stress in cancer chromosomal instability (CIN)+ colorectal cancer cells relative to CIN- colorectal cancer cells, with structural chromosome abnormalities precipitating chromosome missegregation in mitosis. <a href="#1" class="mim-tip-reference" title="Burrell, R. A., McClelland, S. E., Endesfelder, D., Groth, P., Weller, M.-C., Shaikh, N., Domingo, E., Kanu, N., Dewhurst, S. M., Gronroos, E., Chew, S. K., Rowan, A. J., and 9 others. <strong>Replication stress links structural and numerical cancer chromosomal instability.</strong> Nature 494: 492-496, 2013. Note: Erratum: Nature 500: 490 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23446422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23446422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23446422[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/nature11935" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23446422">Burrell et al. (2013)</a> identified 3 CIN suppressor genes (PIGN; MEX3C, <a href="/entry/606097">606097</a>; and ZNF516, <a href="/entry/615114">615114</a>) encoded on chromosome 18q that are subject to frequent copy number loss in CIN+ colorectal cancer cells. Chromosome 18q loss was temporally associated with aneuploidy onset at the adenoma-carcinoma transition. CIN suppressor gene silencing led to DNA replication stress, structural chromosome abnormalities, and chromosome missegregation. Supplementing cells with nucleosides, to alleviate replication-associated damage, reduced the frequency of chromosome segregation errors after CIN suppressor gene silencing, and attenuated segregation errors and DNA damage in CIN+ cells. <a href="#1" class="mim-tip-reference" title="Burrell, R. A., McClelland, S. E., Endesfelder, D., Groth, P., Weller, M.-C., Shaikh, N., Domingo, E., Kanu, N., Dewhurst, S. M., Gronroos, E., Chew, S. K., Rowan, A. J., and 9 others. <strong>Replication stress links structural and numerical cancer chromosomal instability.</strong> Nature 494: 492-496, 2013. Note: Erratum: Nature 500: 490 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23446422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23446422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23446422[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/nature11935" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23446422">Burrell et al. (2013)</a> concluded that their data implicated a central role for replication stress in the generation of structural and numerical CIN. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23446422" 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="#6" class="mim-tip-reference" title="Maydan, G., Noyman, I., Har-Zahav, A., Neriah, Z. B., Pasmanik-Chor, M., Yeheskel, A., Albin-Kaplanski, A., Maya, I., Magal, N., Birk, E., Simon, A. J., Halevy, A., Rechavi, G., Shohat, M., Straussberg, R., Basel-Vanagaite, L. <strong>Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN.</strong> J. Med. Genet. 48: 383-389, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21493957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21493957</a>] [<a href="https://doi.org/10.1136/jmg.2010.087114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21493957">Maydan et al. (2011)</a> determined that the PIGN gene contains 31 exons spanning 142.8 kb. There are 29 coding exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21493957" 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="#6" class="mim-tip-reference" title="Maydan, G., Noyman, I., Har-Zahav, A., Neriah, Z. B., Pasmanik-Chor, M., Yeheskel, A., Albin-Kaplanski, A., Maya, I., Magal, N., Birk, E., Simon, A. J., Halevy, A., Rechavi, G., Shohat, M., Straussberg, R., Basel-Vanagaite, L. <strong>Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN.</strong> J. Med. Genet. 48: 383-389, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21493957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21493957</a>] [<a href="https://doi.org/10.1136/jmg.2010.087114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21493957">Maydan et al. (2011)</a> stated that the PIGN gene maps to chromosome 18q21.33. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21493957" 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>By homozygosity mapping followed by candidate gene sequencing in affected members of a consanguineous Arab Israeli family with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; <a href="/entry/614080">614080</a>), <a href="#6" class="mim-tip-reference" title="Maydan, G., Noyman, I., Har-Zahav, A., Neriah, Z. B., Pasmanik-Chor, M., Yeheskel, A., Albin-Kaplanski, A., Maya, I., Magal, N., Birk, E., Simon, A. J., Halevy, A., Rechavi, G., Shohat, M., Straussberg, R., Basel-Vanagaite, L. <strong>Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN.</strong> J. Med. Genet. 48: 383-389, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21493957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21493957</a>] [<a href="https://doi.org/10.1136/jmg.2010.087114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21493957">Maydan et al. (2011)</a> identified a homozygous mutation in the PIGN gene (R709Q; <a href="#0001">606097.0001</a>). Fibroblasts from 2 patients showed a 10-fold reduction in expression of the GPI-linked protein CD59 (<a href="/entry/107271">107271</a>), confirming a pathogenic influence of the mutation on GPI function. The phenotype was characterized by lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. The abundant expression of PIGN in various tissues was compatible with diverse phenotypic features and with involvement of multiple body systems in the patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21493957" 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 Japanese sibs with severely delayed psychomotor development, hypotonia, nystagmus, seizures, and dysmorphic features, <a href="#9" class="mim-tip-reference" title="Ohba, C., Okamoto, N., Murakami, Y., Suzuki, Y., Tsurusaki, Y., Nakashima, M., Miyake, N., Tanaka, F., Kinoshita, T., Matsumoto, N., Saitsu, H. <strong>PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy.</strong> Neurogenetics 15: 85-92, 2014. Note: Erratum: Neurogenetics 15: 93 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24253414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24253414</a>] [<a href="https://doi.org/10.1007/s10048-013-0384-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24253414">Ohba et al. (2014)</a> identified compound heterozygous mutations in the PIGN gene (<a href="#0002">606097.0002</a> and <a href="#0003">606097.0003</a>). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient granulocytes showed 26 to 54% levels of GPI-anchored proteins CD16 (see <a href="/entry/146740">146740</a>) and CD24 (<a href="/entry/600074">600074</a>). Transient expression of the mutations in PIGN-null HEK293 cells showed decreased expression of CD59, consistent with severe or complete loss of PIGN activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24253414" 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 6-year-old girl, born of consanguineous Israeli Arab parents, with MCAHS1, <a href="#5" class="mim-tip-reference" title="Khayat, M., Tilghman, J. M., Chervinsky, I., Zalman, L., Chakravarti, A., Shalev, S. A. <strong>A PIGN mutation responsible for multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) in an Israeli-Arab family.</strong> Am. J. Med. Genet. 170A: 176-182, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26364997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26364997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26364997[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/10.1002/ajmg.a.37375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26364997">Khayat et al. (2016)</a> identified a homozygous missense mutation in the PIGN gene (D252V; <a href="#0004">606097.0004</a>). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient granulocytes showed significantly decreased expression of the GPI-anchored protein CD24 (<a href="/entry/600074">600074</a>) compared to controls, suggesting that the mutation was deleterious to PIGN function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26364997" 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 sisters with MCAHS1, <a href="#2" class="mim-tip-reference" title="Fleming, L., Lemmon, M., Beck, N., Johnson, M., Mu, W., Murdock, D., Bodurtha, J., Hoover-Fong, J., Cohn, R., Bosemani, T., Baranano, K., Hamosh, A. <strong>Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy.</strong> Am. J. Med. Genet. 170A: 77-86, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26394714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26394714</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26394714[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/10.1002/ajmg.a.37369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26394714">Fleming et al. (2016)</a> identified compound heterozygosity for a truncating and splice site mutation in the PIGN gene (<a href="#0005">606097.0005</a> and <a href="#0006">606097.0006</a>). An unrelated patient with a less severe phenotype was compound heterozygous for 2 missense variants in the PIGN gene. In addition, a severely affected infant was compound heterozygous for a frameshift mutation (<a href="#0007">606097.0007</a>) and an intragenic deletion (<a href="#0008">606097.0008</a>), predicted to result in a complete loss of PIGN. The findings suggested a genotype/phenotype correlation with truncating or loss of function mutations resulting in a more severe phenotype compared to missense mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26394714" 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>By homozygosity mapping followed by candidate gene sequencing in affected members of a consanguineous Arab Israeli family with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; <a href="/entry/614080">614080</a>), <a href="#6" class="mim-tip-reference" title="Maydan, G., Noyman, I., Har-Zahav, A., Neriah, Z. B., Pasmanik-Chor, M., Yeheskel, A., Albin-Kaplanski, A., Maya, I., Magal, N., Birk, E., Simon, A. J., Halevy, A., Rechavi, G., Shohat, M., Straussberg, R., Basel-Vanagaite, L. <strong>Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN.</strong> J. Med. Genet. 48: 383-389, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21493957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21493957</a>] [<a href="https://doi.org/10.1136/jmg.2010.087114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21493957">Maydan et al. (2011)</a> identified a homozygous 2126G-A transition in exon 23 of the PIGN gene, resulting in an arg709-to-gln (R709Q) substitution in a highly conserved residue in the PigN domain. The mutation was not found in 438 Arab controls, but was identified in heterozygosity in 1 individual from the same geographic region, representing carrier status. Fibroblasts from 2 patients showed a 10-fold reduction in expression of the GPI-linked protein CD59, confirming a pathogenic influence of the mutation on GPI function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21493957" 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 2 Japanese sibs with MCAHS1 (<a href="/entry/614080">614080</a>), <a href="#9" class="mim-tip-reference" title="Ohba, C., Okamoto, N., Murakami, Y., Suzuki, Y., Tsurusaki, Y., Nakashima, M., Miyake, N., Tanaka, F., Kinoshita, T., Matsumoto, N., Saitsu, H. <strong>PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy.</strong> Neurogenetics 15: 85-92, 2014. Note: Erratum: Neurogenetics 15: 93 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24253414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24253414</a>] [<a href="https://doi.org/10.1007/s10048-013-0384-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24253414">Ohba et al. (2014)</a> identified compound heterozygous mutations in the PIGN gene. One was a c.808T-C transition, resulting in a ser270-to-pro (S270P) substitution at a highly conserved residue, and the other was a c.963G-A transition at the last base of exon 10, resulting in abnormal splicing. RT-PCR analysis showed that the c.963G-A transition led to 2 aberrant transcripts causing premature termination: Ala322ValfsTer24 and Glu308GlyfsTer2. The 2 aberrant transcripts were degraded by nonsense-mediated mRNA decay. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family and were present in less than 1% of the dbSNP (build 135) database and absent in the Exome Variant Server database. S270P was absent from 406 in-house control exomes, but c.963G-A was found in the heterozygous state in 1 control. Patient granulocytes showed 26 to 54% levels of GPI-anchored proteins CD16 and CD24. Transient expression of the mutations in PIGN-null HEK293 cells showed decreased expression of CD59, consistent with severe or complete loss of PIGN activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24253414" 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 6-year-old Japanese boy with MCAHS1, <a href="#8" class="mim-tip-reference" title="Nakagawa, T., Taniguchi-Ikeda, M., Murakami, Y., Nakamura, S., Motooka, D., Emoto, T., Satake, W., Nishiyama, M., Toyoshima, D., Morisada, N., Takada, S., Tairaku, S., Okamoto, N., Morioka, I., Kurahashi, H., Toda, T., Kinoshita, T., Iijima, K. <strong>A novel PIGN mutation and prenatal diagnosis of inherited glycosylphosphatidylinositol deficiency.</strong> Am. J. Med. Genet. 170A: 183-188, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26419326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26419326</a>] [<a href="https://doi.org/10.1002/ajmg.a.37397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26419326">Nakagawa et al. (2016)</a> identified a heterozygous S270P substitution in the PIGN gene, inherited from the unaffected father, and an intragenic microdeletion encompassing exons 2 to 14 of the PIGN gene, inherited from the unaffected mother. The missense mutation, which was found by targeted exome sequencing, was not found in 451 in-house Japanese control exomes. The deletion was found by PCR analysis. This information was used for prenatal genetic testing of amniotic fluid in a subsequent pregnancy: the fetus carried only the S270P mutation in the heterozygous state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26419326" 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>For discussion of the c.963G-A transition in the PIGN gene that was found in compound heterozygous state in 2 patients with MCAHS1 (<a href="/entry/614080">614080</a>) by <a href="#9" class="mim-tip-reference" title="Ohba, C., Okamoto, N., Murakami, Y., Suzuki, Y., Tsurusaki, Y., Nakashima, M., Miyake, N., Tanaka, F., Kinoshita, T., Matsumoto, N., Saitsu, H. <strong>PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy.</strong> Neurogenetics 15: 85-92, 2014. Note: Erratum: Neurogenetics 15: 93 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24253414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24253414</a>] [<a href="https://doi.org/10.1007/s10048-013-0384-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24253414">Ohba et al. (2014)</a>, see <a href="#0002">606097.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24253414" 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 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES 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">rs886039216 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886039216;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=rs886039216" 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=rs886039216" 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=RCV000253807" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000253807" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000253807</a>
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<p>In a 6-year-old girl, born of consanguineous Israeli Arab parents, with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; <a href="/entry/614080">614080</a>), <a href="#5" class="mim-tip-reference" title="Khayat, M., Tilghman, J. M., Chervinsky, I., Zalman, L., Chakravarti, A., Shalev, S. A. <strong>A PIGN mutation responsible for multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) in an Israeli-Arab family.</strong> Am. J. Med. Genet. 170A: 176-182, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26364997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26364997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26364997[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/10.1002/ajmg.a.37375" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26364997">Khayat et al. (2016)</a> identified a homozygous c.755A-T transversion (chr18.59,814,254A-T) in exon 9 of the PIGN gene, resulting in an asp252-to-val (D252V) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases, and found to segregate with the disorder in the family. Patient granulocytes showed significantly decreased expression of the GPI-anchored protein CD24 (<a href="/entry/600074">600074</a>) compared to controls, suggesting that the mutation was deleterious to PIGN function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26364997" 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>.0005 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES 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> rs749334082 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs749334082;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/rs749334082?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=rs749334082" 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=rs749334082" 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=RCV000245624 OR RCV001815303" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000245624, RCV001815303" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000245624...</a>
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<p>In 2 sisters (patients 1 and 2), born of unrelated Caucasian parents, with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; <a href="/entry/614080">614080</a>), <a href="#2" class="mim-tip-reference" title="Fleming, L., Lemmon, M., Beck, N., Johnson, M., Mu, W., Murdock, D., Bodurtha, J., Hoover-Fong, J., Cohn, R., Bosemani, T., Baranano, K., Hamosh, A. <strong>Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy.</strong> Am. J. Med. Genet. 170A: 77-86, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26394714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26394714</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26394714[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/10.1002/ajmg.a.37369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26394714">Fleming et al. (2016)</a> identified compound heterozygous mutations in the PIGN gene: a c.2340T-A transversion (c.2340T-A, NM_176787) in exon 25, resulting in a tyr780-to-ter (Y780X) substitution in the PIGN domain inherited from the unaffected mother, and a c.1434+5G-A transition (<a href="#0006">606097.0006</a>) in intron 17 inherited from the unaffected father. The mutations were found by whole-exome sequencing. The Y780X mutation was not found in the Exome Sequencing Project (ESP) database, but was found in 1 of 13,412 alleles in the ExAC database. The paternally inherited splice site mutation was found in 1 of 3,039 African American alleles in the ESP, but not in 6,595 European American alleles in the ESP. In the ExAC database, the splice site mutation was found in 1 of 5,512 African alleles and 1 in 28,268 European alleles. Functional studies of the variants and studies of patient cells were not performed. The sisters also carried a paternally inherited mutation in the SCN1B gene (<a href="/entry/600235">600235</a>), which is associated with GEFS+ (<a href="/entry/604233">604233</a>), and a maternally inherited mutation in the CPA6 gene (<a href="/entry/609562">609562</a>), which is associated with febrile seizures (<a href="/entry/614418">614418</a>). There was no family history of seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26394714" 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 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1</strong>
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PIGN, IVS17DS, G-A, +5
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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> rs369486176 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs369486176;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/rs369486176?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=rs369486176" 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=rs369486176" 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=RCV000250290 OR RCV001091656" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000250290, RCV001091656" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000250290...</a>
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<p>For discussion of the c.1434+5G-A transition (c.1434+5G-A, NM_176787) in intron 17 of the PIGN gene, predicted to result in a splice site mutation, that was found in compound heterozygous state in 2 sisters with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; <a href="/entry/614080">614080</a>) by <a href="#2" class="mim-tip-reference" title="Fleming, L., Lemmon, M., Beck, N., Johnson, M., Mu, W., Murdock, D., Bodurtha, J., Hoover-Fong, J., Cohn, R., Bosemani, T., Baranano, K., Hamosh, A. <strong>Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy.</strong> Am. J. Med. Genet. 170A: 77-86, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26394714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26394714</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26394714[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/10.1002/ajmg.a.37369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26394714">Fleming et al. (2016)</a>, see <a href="#0005">606097.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26394714" 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 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES 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> rs779636222 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs779636222;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/rs779636222?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=rs779636222" 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=rs779636222" 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=RCV000242057 OR RCV000609184 OR RCV000727335 OR RCV002347968" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000242057, RCV000609184, RCV000727335, RCV002347968" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000242057...</a>
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<p>In an infant (patient 4) with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; <a href="/entry/614080">614080</a>), <a href="#2" class="mim-tip-reference" title="Fleming, L., Lemmon, M., Beck, N., Johnson, M., Mu, W., Murdock, D., Bodurtha, J., Hoover-Fong, J., Cohn, R., Bosemani, T., Baranano, K., Hamosh, A. <strong>Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy.</strong> Am. J. Med. Genet. 170A: 77-86, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26394714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26394714</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26394714[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/10.1002/ajmg.a.37369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26394714">Fleming et al. (2016)</a> identified compound heterozygous mutations in the PIGN gene: a maternally inherited c.548_549+6del (c.548_549+6del, NM_176787), resulting in a frameshift (Leu183fs), and a paternally inherited intragenic deletion of part of exon 5 as well as exons 6 and 7 (<a href="#0008">606097.0008</a>). The maternal mutation, which was found by whole-exome sequencing, was not found in the Exome Sequencing Project or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26394714" 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>.0008 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000246837" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000246837" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000246837</a>
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<p>For discussion of the intragenic deletion of part of exon 5 as well as exons 6 and 7 (chr18.59,821,582_59,824,939del, GRCh37) of the PIGN gene that was found in compound heterozygous state in a patient with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; <a href="/entry/614080">614080</a>) by <a href="#2" class="mim-tip-reference" title="Fleming, L., Lemmon, M., Beck, N., Johnson, M., Mu, W., Murdock, D., Bodurtha, J., Hoover-Fong, J., Cohn, R., Bosemani, T., Baranano, K., Hamosh, A. <strong>Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy.</strong> Am. J. Med. Genet. 170A: 77-86, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26394714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26394714</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26394714[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/10.1002/ajmg.a.37369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26394714">Fleming et al. (2016)</a>, see <a href="#0007">606097.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26394714" 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>.0009 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES 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> rs886039217 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886039217;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/rs886039217?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=rs886039217" 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=rs886039217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 sibs (NSGC7.3 and NSGC7.4), who were fetuses, with a severe form of multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; <a href="/entry/614080">614080</a>), but with a clinical diagnosis of Fryns syndrome (FRNS; <a href="/entry/229850">229850</a>), <a href="#7" class="mim-tip-reference" title="McInerney-Leo, A. M., Harris, J. E., Gattas, M., Peach, E. E., Sinnott, S., Dudding-Byth, T., Rajagopalan, S., Barnett, C. P., Anderson, L. K., Wheeler, L., Brown, M. A., Leo, P. J., Wicking, C., Duncan, E. L. <strong>Fryns syndrome associated with recessive mutations in PIGN in two separate families.</strong> Hum. Mutat. 37: 695-702, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27038415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27038415</a>] [<a href="https://doi.org/10.1002/humu.22994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27038415">McInerney-Leo et al. (2016)</a> identified compound heterozygous mutations in the PIGN gene: a c.1966C-T transition (c.1966C-T, NM_176787.4) in exon 21, resulting in a glu656-to-ter (E656X) substitution in a highly conserved region, and a G-to-C transversion in intron 18 (c.1674+1G-C), resulting in aberrant splicing and premature termination. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. They were filtered against the dbSNP, 1000 Genomes Project, and ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27038415" 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> rs376355678 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs376355678;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/rs376355678?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=rs376355678" 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=rs376355678" 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=RCV000241768 OR RCV000579091" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000241768, RCV000579091" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000241768...</a>
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<p>For discussion of the G-to-C transversion in intron 18 (c.1674+1G-C, NM_176787.4) of the PIGN gene, resulting in aberrant splicing, that was found in compound heterozygous state in 2 fetuses with a severe form of multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; <a href="/entry/614080">614080</a>) by <a href="#7" class="mim-tip-reference" title="McInerney-Leo, A. M., Harris, J. E., Gattas, M., Peach, E. E., Sinnott, S., Dudding-Byth, T., Rajagopalan, S., Barnett, C. P., Anderson, L. K., Wheeler, L., Brown, M. A., Leo, P. J., Wicking, C., Duncan, E. L. <strong>Fryns syndrome associated with recessive mutations in PIGN in two separate families.</strong> Hum. Mutat. 37: 695-702, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27038415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27038415</a>] [<a href="https://doi.org/10.1002/humu.22994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27038415">McInerney-Leo et al. (2016)</a>, see <a href="#0009">606097.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27038415" 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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PIGN, LYS232TER
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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> rs886039218 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886039218;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/rs886039218?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=rs886039218" 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=rs886039218" 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=RCV000246557" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000246557" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000246557</a>
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<p>In a fetus (COLL-2.3) with a severe form of multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; <a href="/entry/614080">614080</a>), but with a clinical diagnosis of Fryns syndrome (FRNS; <a href="/entry/229850">229850</a>), <a href="#7" class="mim-tip-reference" title="McInerney-Leo, A. M., Harris, J. E., Gattas, M., Peach, E. E., Sinnott, S., Dudding-Byth, T., Rajagopalan, S., Barnett, C. P., Anderson, L. K., Wheeler, L., Brown, M. A., Leo, P. J., Wicking, C., Duncan, E. L. <strong>Fryns syndrome associated with recessive mutations in PIGN in two separate families.</strong> Hum. Mutat. 37: 695-702, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27038415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27038415</a>] [<a href="https://doi.org/10.1002/humu.22994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27038415">McInerney-Leo et al. (2016)</a> identified a homozygous c.694A-T transversion (c.694A-T, NM_176787.4) in exon 9 of the PIGN gene, resulting in a lys232-to-ter (K232X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was filtered against the dbSNP, 1000 Genomes Project, and ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27038415" 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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Burrell, R. A., McClelland, S. E., Endesfelder, D., Groth, P., Weller, M.-C., Shaikh, N., Domingo, E., Kanu, N., Dewhurst, S. M., Gronroos, E., Chew, S. K., Rowan, A. J., and 9 others.
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<strong>Replication stress links structural and numerical cancer chromosomal instability.</strong>
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Nature 494: 492-496, 2013. Note: Erratum: Nature 500: 490 only, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23446422/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23446422</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23446422[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=23446422" 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/nature11935" target="_blank">Full Text</a>]
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Fleming, L., Lemmon, M., Beck, N., Johnson, M., Mu, W., Murdock, D., Bodurtha, J., Hoover-Fong, J., Cohn, R., Bosemani, T., Baranano, K., Hamosh, A.
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<strong>Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy.</strong>
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Am. J. Med. Genet. 170A: 77-86, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26394714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26394714</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26394714[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=26394714" 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/10.1002/ajmg.a.37369" target="_blank">Full Text</a>]
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Gaynor, E. C., Mondesert, G., Grimme, S. J., Reed, S. I., Orlean, P., Emr, S. D.
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<strong>MCD4 encodes a conserved endoplasmic reticulum membrane protein essential for glycosylphosphatidylinositol anchor synthesis in yeast.</strong>
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Molec. Biol. Cell 10: 627-648, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10069808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10069808</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10069808[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=10069808" 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/10.1091/mbc.10.3.627" target="_blank">Full Text</a>]
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Hong, Y., Maeda, Y., Watanabe, R., Ohishi, K., Mishkind, M., Riezman, H., Kinoshita, T.
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<strong>Pig-n, a mammalian homologue of yeast Mcd4p, is involved in transferring phosphoethanolamine to the first mannose of the glycosylphosphatidylinositol.</strong>
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J. Biol. Chem. 274: 35099-35106, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10574991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10574991</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10574991" 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/10.1074/jbc.274.49.35099" target="_blank">Full Text</a>]
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</p>
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<a id="5" class="mim-anchor"></a>
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<a id="Khayat2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Khayat, M., Tilghman, J. M., Chervinsky, I., Zalman, L., Chakravarti, A., Shalev, S. A.
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<strong>A PIGN mutation responsible for multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) in an Israeli-Arab family.</strong>
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Am. J. Med. Genet. 170A: 176-182, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26364997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26364997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26364997[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=26364997" 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/10.1002/ajmg.a.37375" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Maydan2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Maydan, G., Noyman, I., Har-Zahav, A., Neriah, Z. B., Pasmanik-Chor, M., Yeheskel, A., Albin-Kaplanski, A., Maya, I., Magal, N., Birk, E., Simon, A. J., Halevy, A., Rechavi, G., Shohat, M., Straussberg, R., Basel-Vanagaite, L.
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<strong>Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN.</strong>
|
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J. Med. Genet. 48: 383-389, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21493957/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21493957</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21493957" 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/10.1136/jmg.2010.087114" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="7" class="mim-anchor"></a>
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<a id="McInerney-Leo2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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McInerney-Leo, A. M., Harris, J. E., Gattas, M., Peach, E. E., Sinnott, S., Dudding-Byth, T., Rajagopalan, S., Barnett, C. P., Anderson, L. K., Wheeler, L., Brown, M. A., Leo, P. J., Wicking, C., Duncan, E. L.
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<strong>Fryns syndrome associated with recessive mutations in PIGN in two separate families.</strong>
|
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Hum. Mutat. 37: 695-702, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27038415/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27038415</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27038415" 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/10.1002/humu.22994" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="8" class="mim-anchor"></a>
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<a id="Nakagawa2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nakagawa, T., Taniguchi-Ikeda, M., Murakami, Y., Nakamura, S., Motooka, D., Emoto, T., Satake, W., Nishiyama, M., Toyoshima, D., Morisada, N., Takada, S., Tairaku, S., Okamoto, N., Morioka, I., Kurahashi, H., Toda, T., Kinoshita, T., Iijima, K.
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<strong>A novel PIGN mutation and prenatal diagnosis of inherited glycosylphosphatidylinositol deficiency.</strong>
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Am. J. Med. Genet. 170A: 183-188, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26419326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26419326</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26419326" 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/10.1002/ajmg.a.37397" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="9" class="mim-anchor"></a>
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<a id="Ohba2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ohba, C., Okamoto, N., Murakami, Y., Suzuki, Y., Tsurusaki, Y., Nakashima, M., Miyake, N., Tanaka, F., Kinoshita, T., Matsumoto, N., Saitsu, H.
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<strong>PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy.</strong>
|
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Neurogenetics 15: 85-92, 2014. Note: Erratum: Neurogenetics 15: 93 only, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24253414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24253414</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24253414" 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/s10048-013-0384-7" target="_blank">Full Text</a>]
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</p>
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</ol>
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Matthew B. Gross - updated : 01/10/2018
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</span>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 09/27/2016<br>Cassandra L. Kniffin - updated : 2/27/2014<br>Ada Hamosh - updated : 3/7/2013<br>Cassandra L. Kniffin - updated : 7/8/2011
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</span>
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</div>
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</div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Dawn Watkins-Chow : 7/10/2001
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 01/10/2018
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 09/29/2016<br>carol : 09/28/2016<br>ckniffin : 09/27/2016<br>mgross : 04/25/2016<br>carol : 6/4/2015<br>carol : 2/2/2015<br>mcolton : 2/2/2015<br>carol : 1/29/2015<br>mcolton : 8/12/2014<br>carol : 3/4/2014<br>carol : 3/4/2014<br>mcolton : 2/27/2014<br>ckniffin : 2/27/2014<br>mgross : 10/9/2013<br>carol : 9/3/2013<br>alopez : 3/8/2013<br>terry : 3/7/2013<br>terry : 4/12/2012<br>wwang : 7/18/2011<br>ckniffin : 7/8/2011<br>terry : 7/26/2006<br>carol : 7/11/2001<br>carol : 7/11/2001
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</span>
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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 class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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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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<strong>*</strong> 606097
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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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PHOSPHATIDYLINOSITOL GLYCAN ANCHOR BIOSYNTHESIS CLASS N PROTEIN; PIGN
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PIGN</em></strong>
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</span>
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</p>
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</div>
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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: 18q21.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 18:62,017,615-62,187,056 </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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</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-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="1">
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<span class="mim-font">
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18q21.33
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</td>
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<td>
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<span class="mim-font">
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Multiple congenital anomalies-hypotonia-seizures 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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614080
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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 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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</span>
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</td>
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</tr>
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</tbody>
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<div>
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<br />
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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>The PIGN gene encodes glycosylphosphatidylinositol (GPI) ethanolamine phosphate transferase-1, also called phosphatidylinositol-glycan biosynthesis class N protein, which is involved in GPI-anchor biosynthesis. GPI-anchored proteins comprise a well-characterized family of proteins that must acquire a GPI anchor and traffic from their site of synthesis, i.e., the endoplasmic reticulum (ER), to their final destination, the cell surface (summary by Maydan et al., 2011). The common backbone of GPIs is assembled by the sequential additions of sugar and phosphoethanolamine (EtNP) components to phosphatidylinositol (summary by Gaynor et al., 1999). </p><p>For information on the PIG gene family and the roles of PIG proteins in GPI biosynthesis, see PIGA (311770).</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>In a screen to isolate yeast mutants defective for bud emergence and polarized growth, Gaynor et al. (1999) identified yeast Mcd4. By database searching, they identified cDNA clones encoding human PIGN, which they called MCD4. PIGN encodes a deduced 931-amino acid protein with 14 predicted transmembrane domains, potential N-linked glycosylation sites, an ER retrieval motif, and a stop-transfer sequence predicted to direct translocation into the ER. PIGN has a hydrophilic N-terminal ER luminal domain that contains motifs conserved in mammalian phosphodiesterases and pyrophosphatases. PIGN shares sequence identity with its counterparts in S. cerevisiae (35%), S. pombe (34%), and mouse (87%). </p><p>Using subcellular fractionation and sucrose density gradient experiments, Gaynor et al. (1999) demonstrated that yeast Mcd4 is localized in the ER. Using tunicamycin and endo H treatment, they showed that the 6 N-terminal N-linked glycosylation sites of Mcd4 are utilized. They hypothesized that MCD4 is retained in the ER and is unlikely to cycle through the Golgi. Yeast Mcd4 mutants exhibited marked morphologic defects as well as an ER-to-Golgi transport defect specific for GPI-anchored proteins. Gaynor et al. (1999) concluded that MCD4 is a component of the eukaryotic GPI anchor synthesis pathway. </p><p>Hong et al. (1999) cloned mouse Pign and disrupted the protein in F9 embryonal carcinoma cells. The first mannose (Man1) in the GPI precursors was not modified by phosphoethanolamine in the knockout cells, but these cells were still capable of generating further modified GPI species. Hong et al. (1999) concluded that Pign is involved in the addition of EtNP to Man1 but that its modification is not essential for the surface expression of GPI-anchored proteins. </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>Burrell et al. (2013) found evidence for impaired replication fork progression and increased DNA replication stress in cancer chromosomal instability (CIN)+ colorectal cancer cells relative to CIN- colorectal cancer cells, with structural chromosome abnormalities precipitating chromosome missegregation in mitosis. Burrell et al. (2013) identified 3 CIN suppressor genes (PIGN; MEX3C, 606097; and ZNF516, 615114) encoded on chromosome 18q that are subject to frequent copy number loss in CIN+ colorectal cancer cells. Chromosome 18q loss was temporally associated with aneuploidy onset at the adenoma-carcinoma transition. CIN suppressor gene silencing led to DNA replication stress, structural chromosome abnormalities, and chromosome missegregation. Supplementing cells with nucleosides, to alleviate replication-associated damage, reduced the frequency of chromosome segregation errors after CIN suppressor gene silencing, and attenuated segregation errors and DNA damage in CIN+ cells. Burrell et al. (2013) concluded that their data implicated a central role for replication stress in the generation of structural and numerical CIN. </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">
|
|
<strong>Gene Structure</strong>
|
|
</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>Maydan et al. (2011) determined that the PIGN gene contains 31 exons spanning 142.8 kb. There are 29 coding exons. </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>Maydan et al. (2011) stated that the PIGN gene maps to chromosome 18q21.33. </p>
|
|
</span>
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<div>
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|
<br />
|
|
</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</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 homozygosity mapping followed by candidate gene sequencing in affected members of a consanguineous Arab Israeli family with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), Maydan et al. (2011) identified a homozygous mutation in the PIGN gene (R709Q; 606097.0001). Fibroblasts from 2 patients showed a 10-fold reduction in expression of the GPI-linked protein CD59 (107271), confirming a pathogenic influence of the mutation on GPI function. The phenotype was characterized by lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. The abundant expression of PIGN in various tissues was compatible with diverse phenotypic features and with involvement of multiple body systems in the patients. </p><p>In 2 Japanese sibs with severely delayed psychomotor development, hypotonia, nystagmus, seizures, and dysmorphic features, Ohba et al. (2014) identified compound heterozygous mutations in the PIGN gene (606097.0002 and 606097.0003). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient granulocytes showed 26 to 54% levels of GPI-anchored proteins CD16 (see 146740) and CD24 (600074). Transient expression of the mutations in PIGN-null HEK293 cells showed decreased expression of CD59, consistent with severe or complete loss of PIGN activity. </p><p>In a 6-year-old girl, born of consanguineous Israeli Arab parents, with MCAHS1, Khayat et al. (2016) identified a homozygous missense mutation in the PIGN gene (D252V; 606097.0004). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient granulocytes showed significantly decreased expression of the GPI-anchored protein CD24 (600074) compared to controls, suggesting that the mutation was deleterious to PIGN function. </p><p>In 2 sisters with MCAHS1, Fleming et al. (2016) identified compound heterozygosity for a truncating and splice site mutation in the PIGN gene (606097.0005 and 606097.0006). An unrelated patient with a less severe phenotype was compound heterozygous for 2 missense variants in the PIGN gene. In addition, a severely affected infant was compound heterozygous for a frameshift mutation (606097.0007) and an intragenic deletion (606097.0008), predicted to result in a complete loss of PIGN. The findings suggested a genotype/phenotype correlation with truncating or loss of function mutations resulting in a more severe phenotype compared to missense mutations. </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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<h4>
|
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<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
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<strong>11 Selected Examples):</strong>
|
|
</span>
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</h4>
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<div>
|
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<p />
|
|
</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
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|
PIGN, ARG709GLN
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|
<br />
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SNP: rs397514475,
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gnomAD: rs397514475,
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|
|
ClinVar: RCV000023506
|
|
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|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>By homozygosity mapping followed by candidate gene sequencing in affected members of a consanguineous Arab Israeli family with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), Maydan et al. (2011) identified a homozygous 2126G-A transition in exon 23 of the PIGN gene, resulting in an arg709-to-gln (R709Q) substitution in a highly conserved residue in the PigN domain. The mutation was not found in 438 Arab controls, but was identified in heterozygosity in 1 individual from the same geographic region, representing carrier status. Fibroblasts from 2 patients showed a 10-fold reduction in expression of the GPI-linked protein CD59, confirming a pathogenic influence of the mutation on GPI function. </p>
|
|
</span>
|
|
</div>
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|
|
|
|
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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>.0002 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1</strong>
|
|
</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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|
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|
PIGN, SER270PRO
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|
<br />
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SNP: rs587777186,
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gnomAD: rs587777186,
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ClinVar: RCV000087305
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|
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|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Japanese sibs with MCAHS1 (614080), Ohba et al. (2014) identified compound heterozygous mutations in the PIGN gene. One was a c.808T-C transition, resulting in a ser270-to-pro (S270P) substitution at a highly conserved residue, and the other was a c.963G-A transition at the last base of exon 10, resulting in abnormal splicing. RT-PCR analysis showed that the c.963G-A transition led to 2 aberrant transcripts causing premature termination: Ala322ValfsTer24 and Glu308GlyfsTer2. The 2 aberrant transcripts were degraded by nonsense-mediated mRNA decay. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family and were present in less than 1% of the dbSNP (build 135) database and absent in the Exome Variant Server database. S270P was absent from 406 in-house control exomes, but c.963G-A was found in the heterozygous state in 1 control. Patient granulocytes showed 26 to 54% levels of GPI-anchored proteins CD16 and CD24. Transient expression of the mutations in PIGN-null HEK293 cells showed decreased expression of CD59, consistent with severe or complete loss of PIGN activity. </p><p>In a 6-year-old Japanese boy with MCAHS1, Nakagawa et al. (2016) identified a heterozygous S270P substitution in the PIGN gene, inherited from the unaffected father, and an intragenic microdeletion encompassing exons 2 to 14 of the PIGN gene, inherited from the unaffected mother. The missense mutation, which was found by targeted exome sequencing, was not found in 451 in-house Japanese control exomes. The deletion was found by PCR analysis. This information was used for prenatal genetic testing of amniotic fluid in a subsequent pregnancy: the fetus carried only the S270P mutation in the heterozygous state. </p>
|
|
</span>
|
|
</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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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PIGN, 963G-A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587777187,
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|
|
|
|
|
gnomAD: rs587777187,
|
|
|
|
|
|
ClinVar: RCV000087306, RCV001548501
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.963G-A transition in the PIGN gene that was found in compound heterozygous state in 2 patients with MCAHS1 (614080) by Ohba et al. (2014), see 606097.0002. </p>
|
|
</span>
|
|
</div>
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|
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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>.0004 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PIGN, ASP252VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs886039216,
|
|
|
|
|
|
|
|
ClinVar: RCV000253807
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-year-old girl, born of consanguineous Israeli Arab parents, with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), Khayat et al. (2016) identified a homozygous c.755A-T transversion (chr18.59,814,254A-T) in exon 9 of the PIGN gene, resulting in an asp252-to-val (D252V) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases, and found to segregate with the disorder in the family. Patient granulocytes showed significantly decreased expression of the GPI-anchored protein CD24 (600074) compared to controls, suggesting that the mutation was deleterious to PIGN function. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PIGN, TYR780TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs749334082,
|
|
|
|
|
|
gnomAD: rs749334082,
|
|
|
|
|
|
ClinVar: RCV000245624, RCV001815303
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters (patients 1 and 2), born of unrelated Caucasian parents, with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), Fleming et al. (2016) identified compound heterozygous mutations in the PIGN gene: a c.2340T-A transversion (c.2340T-A, NM_176787) in exon 25, resulting in a tyr780-to-ter (Y780X) substitution in the PIGN domain inherited from the unaffected mother, and a c.1434+5G-A transition (606097.0006) in intron 17 inherited from the unaffected father. The mutations were found by whole-exome sequencing. The Y780X mutation was not found in the Exome Sequencing Project (ESP) database, but was found in 1 of 13,412 alleles in the ExAC database. The paternally inherited splice site mutation was found in 1 of 3,039 African American alleles in the ESP, but not in 6,595 European American alleles in the ESP. In the ExAC database, the splice site mutation was found in 1 of 5,512 African alleles and 1 in 28,268 European alleles. Functional studies of the variants and studies of patient cells were not performed. The sisters also carried a paternally inherited mutation in the SCN1B gene (600235), which is associated with GEFS+ (604233), and a maternally inherited mutation in the CPA6 gene (609562), which is associated with febrile seizures (614418). There was no family history of seizures. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PIGN, IVS17DS, G-A, +5
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs369486176,
|
|
|
|
|
|
gnomAD: rs369486176,
|
|
|
|
|
|
ClinVar: RCV000250290, RCV001091656
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.1434+5G-A transition (c.1434+5G-A, NM_176787) in intron 17 of the PIGN gene, predicted to result in a splice site mutation, that was found in compound heterozygous state in 2 sisters with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080) by Fleming et al. (2016), see 606097.0005. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PIGN, 548_549+6DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs779636222,
|
|
|
|
|
|
gnomAD: rs779636222,
|
|
|
|
|
|
ClinVar: RCV000242057, RCV000609184, RCV000727335, RCV002347968
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an infant (patient 4) with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), Fleming et al. (2016) identified compound heterozygous mutations in the PIGN gene: a maternally inherited c.548_549+6del (c.548_549+6del, NM_176787), resulting in a frameshift (Leu183fs), and a paternally inherited intragenic deletion of part of exon 5 as well as exons 6 and 7 (606097.0008). The maternal mutation, which was found by whole-exome sequencing, was not found in the Exome Sequencing Project or ExAC databases. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PIGN, EX5-7DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000246837
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the intragenic deletion of part of exon 5 as well as exons 6 and 7 (chr18.59,821,582_59,824,939del, GRCh37) of the PIGN gene that was found in compound heterozygous state in a patient with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080) by Fleming et al. (2016), see 606097.0007. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PIGN, GLU656TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs886039217,
|
|
|
|
|
|
gnomAD: rs886039217,
|
|
|
|
|
|
ClinVar: RCV000249988
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs (NSGC7.3 and NSGC7.4), who were fetuses, with a severe form of multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), but with a clinical diagnosis of Fryns syndrome (FRNS; 229850), McInerney-Leo et al. (2016) identified compound heterozygous mutations in the PIGN gene: a c.1966C-T transition (c.1966C-T, NM_176787.4) in exon 21, resulting in a glu656-to-ter (E656X) substitution in a highly conserved region, and a G-to-C transversion in intron 18 (c.1674+1G-C), resulting in aberrant splicing and premature termination. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. They were filtered against the dbSNP, 1000 Genomes Project, and ExAC databases. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PIGN, IVS18DS, G-C, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs376355678,
|
|
|
|
|
|
gnomAD: rs376355678,
|
|
|
|
|
|
ClinVar: RCV000241768, RCV000579091
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the G-to-C transversion in intron 18 (c.1674+1G-C, NM_176787.4) of the PIGN gene, resulting in aberrant splicing, that was found in compound heterozygous state in 2 fetuses with a severe form of multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080) by McInerney-Leo et al. (2016), see 606097.0009. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 MULTIPLE CONGENITAL ANOMALIES-HYPOTONIA-SEIZURES SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
PIGN, LYS232TER
|
|
|
|
|
|
<br />
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SNP: rs886039218,
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gnomAD: rs886039218,
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ClinVar: RCV000246557
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<p>In a fetus (COLL-2.3) with a severe form of multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), but with a clinical diagnosis of Fryns syndrome (FRNS; 229850), McInerney-Leo et al. (2016) identified a homozygous c.694A-T transversion (c.694A-T, NM_176787.4) in exon 9 of the PIGN gene, resulting in a lys232-to-ter (K232X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was filtered against the dbSNP, 1000 Genomes Project, and ExAC databases. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<p />
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</div>
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<ol>
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<p class="mim-text-font">
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Burrell, R. A., McClelland, S. E., Endesfelder, D., Groth, P., Weller, M.-C., Shaikh, N., Domingo, E., Kanu, N., Dewhurst, S. M., Gronroos, E., Chew, S. K., Rowan, A. J., and 9 others.
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<strong>Replication stress links structural and numerical cancer chromosomal instability.</strong>
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Nature 494: 492-496, 2013. Note: Erratum: Nature 500: 490 only, 2013.
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[PubMed: 23446422]
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[Full Text: https://doi.org/10.1038/nature11935]
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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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Fleming, L., Lemmon, M., Beck, N., Johnson, M., Mu, W., Murdock, D., Bodurtha, J., Hoover-Fong, J., Cohn, R., Bosemani, T., Baranano, K., Hamosh, A.
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<strong>Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy.</strong>
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Am. J. Med. Genet. 170A: 77-86, 2016.
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[PubMed: 26394714]
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[Full Text: https://doi.org/10.1002/ajmg.a.37369]
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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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Gaynor, E. C., Mondesert, G., Grimme, S. J., Reed, S. I., Orlean, P., Emr, S. D.
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<strong>MCD4 encodes a conserved endoplasmic reticulum membrane protein essential for glycosylphosphatidylinositol anchor synthesis in yeast.</strong>
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Molec. Biol. Cell 10: 627-648, 1999.
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[PubMed: 10069808]
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[Full Text: https://doi.org/10.1091/mbc.10.3.627]
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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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Hong, Y., Maeda, Y., Watanabe, R., Ohishi, K., Mishkind, M., Riezman, H., Kinoshita, T.
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<strong>Pig-n, a mammalian homologue of yeast Mcd4p, is involved in transferring phosphoethanolamine to the first mannose of the glycosylphosphatidylinositol.</strong>
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J. Biol. Chem. 274: 35099-35106, 1999.
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[PubMed: 10574991]
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[Full Text: https://doi.org/10.1074/jbc.274.49.35099]
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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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Khayat, M., Tilghman, J. M., Chervinsky, I., Zalman, L., Chakravarti, A., Shalev, S. A.
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<strong>A PIGN mutation responsible for multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) in an Israeli-Arab family.</strong>
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Am. J. Med. Genet. 170A: 176-182, 2016.
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[PubMed: 26364997]
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[Full Text: https://doi.org/10.1002/ajmg.a.37375]
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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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Maydan, G., Noyman, I., Har-Zahav, A., Neriah, Z. B., Pasmanik-Chor, M., Yeheskel, A., Albin-Kaplanski, A., Maya, I., Magal, N., Birk, E., Simon, A. J., Halevy, A., Rechavi, G., Shohat, M., Straussberg, R., Basel-Vanagaite, L.
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<strong>Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN.</strong>
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J. Med. Genet. 48: 383-389, 2011.
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[PubMed: 21493957]
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[Full Text: https://doi.org/10.1136/jmg.2010.087114]
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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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McInerney-Leo, A. M., Harris, J. E., Gattas, M., Peach, E. E., Sinnott, S., Dudding-Byth, T., Rajagopalan, S., Barnett, C. P., Anderson, L. K., Wheeler, L., Brown, M. A., Leo, P. J., Wicking, C., Duncan, E. L.
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<strong>Fryns syndrome associated with recessive mutations in PIGN in two separate families.</strong>
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Hum. Mutat. 37: 695-702, 2016.
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[PubMed: 27038415]
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[Full Text: https://doi.org/10.1002/humu.22994]
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</li>
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<li>
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<p class="mim-text-font">
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Nakagawa, T., Taniguchi-Ikeda, M., Murakami, Y., Nakamura, S., Motooka, D., Emoto, T., Satake, W., Nishiyama, M., Toyoshima, D., Morisada, N., Takada, S., Tairaku, S., Okamoto, N., Morioka, I., Kurahashi, H., Toda, T., Kinoshita, T., Iijima, K.
|
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<strong>A novel PIGN mutation and prenatal diagnosis of inherited glycosylphosphatidylinositol deficiency.</strong>
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Am. J. Med. Genet. 170A: 183-188, 2016.
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[PubMed: 26419326]
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[Full Text: https://doi.org/10.1002/ajmg.a.37397]
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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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Ohba, C., Okamoto, N., Murakami, Y., Suzuki, Y., Tsurusaki, Y., Nakashima, M., Miyake, N., Tanaka, F., Kinoshita, T., Matsumoto, N., Saitsu, H.
|
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<strong>PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy.</strong>
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Neurogenetics 15: 85-92, 2014. Note: Erratum: Neurogenetics 15: 93 only, 2014.
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[PubMed: 24253414]
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[Full Text: https://doi.org/10.1007/s10048-013-0384-7]
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</p>
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</li>
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</ol>
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<span class="mim-text-font">
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Matthew B. Gross - updated : 01/10/2018<br>Cassandra L. Kniffin - updated : 09/27/2016<br>Cassandra L. Kniffin - updated : 2/27/2014<br>Ada Hamosh - updated : 3/7/2013<br>Cassandra L. Kniffin - updated : 7/8/2011
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<span class="mim-text-font">
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Dawn Watkins-Chow : 7/10/2001
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mgross : 01/10/2018<br>carol : 09/29/2016<br>carol : 09/28/2016<br>ckniffin : 09/27/2016<br>mgross : 04/25/2016<br>carol : 6/4/2015<br>carol : 2/2/2015<br>mcolton : 2/2/2015<br>carol : 1/29/2015<br>mcolton : 8/12/2014<br>carol : 3/4/2014<br>carol : 3/4/2014<br>mcolton : 2/27/2014<br>ckniffin : 2/27/2014<br>mgross : 10/9/2013<br>carol : 9/3/2013<br>alopez : 3/8/2013<br>terry : 3/7/2013<br>terry : 4/12/2012<br>wwang : 7/18/2011<br>ckniffin : 7/8/2011<br>terry : 7/26/2006<br>carol : 7/11/2001<br>carol : 7/11/2001
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