4679 lines
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- *300040 - STRUCTURAL MAINTENANCE OF CHROMOSOMES 1A; SMC1A
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300040</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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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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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li 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="#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/300040">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>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000072501;t=ENST00000322213" 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=8243" 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=300040" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000072501;t=ENST00000322213" 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_001281463,NM_006306" 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_006306" 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=300040" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=02077&isoform_id=02077_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/SMC1A" 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/999380,20521836,29336622,30581135,33338074,39963673,51327185,52545917,57209018,57210024,57210025,85567570,119613555,119613556,119613557,158257274,221043536,308219106,527317371" 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/Q14683" 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=8243" 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=ENSG00000072501;t=ENST00000322213" 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=SMC1A" 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=SMC1A" 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+8243" 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/SMC1A" 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:8243" 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/8243" 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=chrX&hgg_gene=ENST00000322213.9&hgg_start=53374149&hgg_end=53422728&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:11111" 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:11111" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/smc1a" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300040[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=300040[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/SMC1A/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/ENSG00000072501" 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.gwascentral.org/search?q=SMC1A" 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=SMC1A" 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="http://www.LOVD.nl/SMC1A" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SMC1A&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/PA35961" 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:11111" 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/FBgn0040283.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:1344345" 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/SMC1A#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:1344345" 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/8243/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=8243" 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=WBGene00001860;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-040426-57" 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="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:300040" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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:8243" 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=SMC1A&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 55016009<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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300040
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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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STRUCTURAL MAINTENANCE OF CHROMOSOMES 1A; SMC1A
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
SMC1-ALPHA<br />
|
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STRUCTURAL MAINTENANCE OF CHROMOSOMES 1-LIKE 1; SMC1L1<br />
|
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SMC1<br />
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DXS423E<br />
|
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KIAA0178
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SMC1A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SMC1A</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>
|
|
Cytogenetic location: <a href="/geneMap/X/325?start=-3&limit=10&highlight=325">Xp11.22</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:53374149-53422728&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'})">X:53,374,149-53,422,728</a> </span>
|
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</em>
|
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</strong>
|
|
<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>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<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>
|
|
Location
|
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</th>
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<th>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=300590,301044" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/X/325?start=-3&limit=10&highlight=325">
|
|
Xp11.22
|
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</a>
|
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</span>
|
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</td>
|
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|
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<td>
|
|
<span class="mim-font">
|
|
Cornelia de Lange syndrome 2
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/300590"> 300590 </a>
|
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|
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</span>
|
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</td>
|
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<p>Eukaryotic sister chromatids remain connected from the time of synthesis until they are separated in anaphase. This cohesion depends on a complex of proteins known as cohesins. In vertebrates, unlike in yeast, the cohesins dissociate from chromosome arms earlier in M phase, during prophase. Small amounts of cohesin remain near the centromere until metaphase, with complete removal at the beginning of anaphase. Cohesin complexes contain SMC1, SCC1 (RAD21), SMC3 (<a href="/entry/606062">606062</a>), and either SA1 (STAG1; <a href="/entry/604358">604358</a>) or SA2 (STAG2; <a href="/entry/300826">300826</a>). The complexes, in turn, interact with PDS5 (see <a href="/entry/613200">613200</a>), a protein implicated in chromosome cohesion, condensation, and recombination in yeast (summary by <a href="#20" class="mim-tip-reference" title="Sumara, I., Vorlaufer, E., Gieffers, C., Peters, B. H., Peters, J.-M. <strong>Characterization of vertebrate cohesin complexes and their regulation in prophase.</strong> J. Cell Biol. 151: 749-761, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11076961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11076961</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11076961[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/10.1083/jcb.151.4.749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11076961">Sumara et al., 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11076961" 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>Genetic marker SB1.8 (DXS423E) was originally identified as a cross-reacting clone during the screening of a human lymphocyte cDNA library with an oligonucleotide probe corresponding to the CYBB (<a href="/entry/300481">300481</a>) gene, which maps to Xp21.1. <a href="#18" class="mim-tip-reference" title="Rocques, P. J., Clark, J., Ball, S., Crew, J., Gill, S., Christodoulou, Z., Borts, R. H., Louis, E. J., Davies, K. E., Cooper, C. S. <strong>The human SB1.8 gene (DXS423E) encodes a putative chromosome segregation protein conserved in lower eukaryotes and prokaryotes.</strong> Hum. Molec. Genet. 4: 243-249, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7757074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7757074</a>] [<a href="https://doi.org/10.1093/hmg/4.2.243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7757074">Rocques et al. (1995)</a> found that the DXS423E gene encodes a protein of 1,233 amino acids that is 30% identical to the essential yeast protein SMC1 (structural maintenance of chromosomes-1), which is required for the segregation of chromosomes at mitosis. Both the human protein, called SB1.8, and SMC1 contain an N-terminal NTP-binding site, a central coiled-coil region, and a C-terminal helix-loop-helix domain, and both have structural features in common with the force-generating proteins myosin and kinesin. SB1.8 also exhibits regions of homology and overall structural similarity to protein 115p of the prokaryote Mycoplasma hyorhinis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7757074" 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 mouse embryos, <a href="#11" class="mim-tip-reference" title="Kruszka, P., Berger, S. I., Casa, V., Dekker, M. R., Gaesser, J., Weiss, K., Martinez, A. F., Murdock, D. R, Louie, R. J., Prijoles, E. J., Lichty, A. W., Brouwer, O. F., and 23 others. <strong>Cohesin complex-associated holoprosencephaly.</strong> Brain 142: 2631-2643, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31334757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31334757</a>] [<a href="https://doi.org/10.1093/brain/awz210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31334757">Kruszka et al. (2019)</a> found expression of the Smc1a gene in anterior neural folds, the neuroectoderm, and adjacent mesenchyme of the developing brain. The findings suggested a role in forebrain patterning. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31334757" 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 yeast, the cohesin complex is essential for sister chromatid cohesion during mitosis. The Smc1 and Smc3 subunits are rod-shaped molecules with globular ABC-like ATPases at one end and dimerization domains at the other, connected by long coiled coils. Smc1 and Smc3 associate to form V-shaped heterodimers. Their ATPase heads are thought to be bridged by a third subunit, Scc1, creating a huge triangular ring that can trap sister DNA molecules. <a href="#6" class="mim-tip-reference" title="Gruber, S., Haering, C. H., Nasmyth, K. <strong>Chromosomal cohesin forms a ring.</strong> Cell 112: 765-777, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12654244/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12654244</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00162-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12654244">Gruber et al. (2003)</a> studied whether cohesin forms such rings in vivo. Proteolytic cleavage of Scc1 by separase at the onset of anaphase triggers its dissociation from chromosomes. The authors showed that N- and C-terminal Scc1 cleavage fragments remain connected due to their association with different heads of a single Smc1/Smc3 heterodimer. Cleavage of the Smc3 coiled coil was sufficient to trigger cohesin release from chromosomes and loss of sister cohesion, consistent with a topologic association with chromatin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12654244" 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>By yeast 2-hybrid screening of a human fetal brain expression cDNA library using the hinge domain of SMC1 as bait, followed by immunoprecipitation analysis, <a href="#16" class="mim-tip-reference" title="Patel, C. A., Ghiselli, G. <strong>Hinderin, a five-domains protein including coiled-coil motifs that binds to SMC3.</strong> BMC Cell Biol. 6: 3, 2005. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15656913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15656913</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15656913[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/10.1186/1471-2121-6-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15656913">Patel and Ghiselli (2005)</a> found that SMC1 interacted with hinderin (KIAA1328; <a href="/entry/616480">616480</a>). Hinderin did not interact with SMC3. Interaction of hinderin with SMC1 precluded dimerization of SMC1 and SMC3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15656913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Musio, A., Montagna, C., Mariani, T., Tilenni, M., Focarelli, M. L., Brait, L., Indino, E., Benedetti, P. A., Chessa, L., Albertini, A., Ried, T., Vezzoni, P. <strong>SMC1 involvement in fragile site expression.</strong> Hum. Molec. Genet. 14: 525-533, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15640246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15640246</a>] [<a href="https://doi.org/10.1093/hmg/ddi049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15640246">Musio et al. (2005)</a> demonstrated that RNA interference (RNAi) of SMC1 was sufficient to induce fragile site expression in normal human fibroblasts. They showed that aphidicolin treatment led to an increase in SMC1 synthesis, SMC1 phosphorylation via an ATR (<a href="/entry/601215">601215</a>)-dependent pathway, and enhanced double-stranded break induction as visualized by immunohistochemical studies with phosphorylated H2AX (<a href="/entry/601772">601772</a>). Discrete nuclear foci were absent or very rare after 1 or 2 hours exposure to aphidicolin and/or RNAi of SMC1 but became more numerous and distinct after 6 hours. <a href="#14" class="mim-tip-reference" title="Musio, A., Montagna, C., Mariani, T., Tilenni, M., Focarelli, M. L., Brait, L., Indino, E., Benedetti, P. A., Chessa, L., Albertini, A., Ried, T., Vezzoni, P. <strong>SMC1 involvement in fragile site expression.</strong> Hum. Molec. Genet. 14: 525-533, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15640246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15640246</a>] [<a href="https://doi.org/10.1093/hmg/ddi049" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15640246">Musio et al. (2005)</a> proposed that fragile sites might be viewed as an in vitro phenomenon originating from double-strand breaks formed because of stalled DNA replication that lasted too long to be rescued via the ATR/SMC1 axis, whereas in vivo, following an extreme replication block, rare cells could escape checkpoint mechanisms and enter mitosis with a defect in genome assembly, eventually leading to neoplastic transformation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15640246" 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>Cohesin's Scc1, Smc1, and Smc3 subunits form a tripartite ring structure, and it had been proposed that cohesin holds sister DNA molecules together by trapping them inside its ring. To test this, <a href="#7" class="mim-tip-reference" title="Haering, C. H., Farcas, A.-M., Arumugam, P., Metson, J., Nasmyth, K. <strong>The cohesin ring concatenates sister DNA molecules.</strong> Nature 454: 297-301, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18596691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18596691</a>] [<a href="https://doi.org/10.1038/nature07098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18596691">Haering et al. (2008)</a> used site-specific crosslinking to create chemical connections at the 3 interfaces between the 3 constituent polypeptides of the ring, thereby creating covalently closed cohesin rings. As predicted by the ring entrapment model, this procedure produced dimeric DNA-cohesin structures that are resistant to protein denaturation. <a href="#7" class="mim-tip-reference" title="Haering, C. H., Farcas, A.-M., Arumugam, P., Metson, J., Nasmyth, K. <strong>The cohesin ring concatenates sister DNA molecules.</strong> Nature 454: 297-301, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18596691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18596691</a>] [<a href="https://doi.org/10.1038/nature07098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18596691">Haering et al. (2008)</a> concluded that cohesin rings concatenate individual sister minichromosome DNA molecules. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18596691" 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="#10" class="mim-tip-reference" title="Kagey, M. H., Newman, J. J., Bilodeau, S., Zhan, Y., Orlando, D. A., van Berkum, N. L., Ebmeier, C. C., Goossens, J., Rahl, P. B., Levine, S. S., Taatjes, D. J., Dekker, J., Young, R. A. <strong>Mediator and cohesin connect gene expression and chromatin architecture.</strong> Nature 467: 430-435, 2010. Note: Erratum: Nature 472: 247 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20720539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20720539</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20720539[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/nature09380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20720539">Kagey et al. (2010)</a> reported that Mediator (see MED8, <a href="/entry/607956">607956</a>) and cohesin physically and functionally connect the enhancers and core promoters of active genes in murine embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with cohesin, which can form rings that connect 2 DNA segments. The cohesin-loading factor NIPBL (<a href="/entry/608667">608667</a>) is associated with Mediator-cohesin complexes, providing a means to load cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by Mediator and cohesin. Mediator and cohesin co-occupy different promoters in different cells, thus generating cell type-specific DNA loops linked to the gene expression program of each cell. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20720539" 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 biochemical reconstitution, <a href="#2" class="mim-tip-reference" title="Davidson, I. F., Bauer, B., Goetz, D., Tang, W., Wutz, G., Peters, J. M. <strong>DNA loop extrusion by human cohesin.</strong> Science 366: 1338-1345, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31753851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31753851</a>] [<a href="https://doi.org/10.1126/science.aaz3418" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31753851">Davidson et al. (2019)</a> found that single human cohesin complexes form DNA loops symmetrically at rates up to 2.1 kilobase pairs per second. Loop formation and maintenance depend on cohesin's ATPase activity and on NIPBL-MAU2 (<a href="/entry/614560">614560</a>), but not on topologic entrapment of DNA by cohesin (components include SMC3, <a href="/entry/606062">606062</a>; SMC1A; STAG1, <a href="/entry/604358">604358</a>; and STAG2, <a href="/entry/300826">300826</a>). During loop formation, cohesin and NIPBL-MAU2 reside at the base of loops, which indicates that they generate loops by extrusion. <a href="#2" class="mim-tip-reference" title="Davidson, I. F., Bauer, B., Goetz, D., Tang, W., Wutz, G., Peters, J. M. <strong>DNA loop extrusion by human cohesin.</strong> Science 366: 1338-1345, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31753851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31753851</a>] [<a href="https://doi.org/10.1126/science.aaz3418" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31753851">Davidson et al. (2019)</a> concluded that their results showed that cohesin and NIPBL-MAU2 form an active holoenzyme that interacts with DNA either pseudotopologically or nontopologically to extrude genomic interphase DNA into loops. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31753851" 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="#18" class="mim-tip-reference" title="Rocques, P. J., Clark, J., Ball, S., Crew, J., Gill, S., Christodoulou, Z., Borts, R. H., Louis, E. J., Davies, K. E., Cooper, C. S. <strong>The human SB1.8 gene (DXS423E) encodes a putative chromosome segregation protein conserved in lower eukaryotes and prokaryotes.</strong> Hum. Molec. Genet. 4: 243-249, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7757074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7757074</a>] [<a href="https://doi.org/10.1093/hmg/4.2.243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7757074">Rocques et al. (1995)</a> showed that the DXS423E gene maps to a cosmid contig that lies centromeric to the OATL2 locus (see <a href="/entry/258870">258870</a>) at Xp11.2. <a href="#1" class="mim-tip-reference" title="Brown, C. J., Miller, A. P., Carrel, L., Rupert, J. L., Davies, K. E., Willard, H. F. <strong>The DXS423E gene in Xp11.21 escapes X chromosome inactivation.</strong> Hum. Molec. Genet. 4: 251-255, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7757075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7757075</a>] [<a href="https://doi.org/10.1093/hmg/4.2.251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7757075">Brown et al. (1995)</a> showed that SMC1 escapes X-chromosome inactivation. SMC1 and XE169 (<a href="/entry/314690">314690</a>) were thought to define a new region in the proximal short arm of the X chromosome that escapes X inactivation. The corresponding gene in the mouse, Sb1.8, is located at the distal end of the X chromosome and is subject to X inactivation (<a href="#19" class="mim-tip-reference" title="Sultana, R., Adler, D. A., Edelhoff, S., Carrel, L., Lee, K., Chapman, V. C., Willard, H. F., Disteche, C. M. <strong>The mouse Sb1.8 gene located at the distal end of the X chromosome is subject to X inactivation.</strong> Hum. Molec. Genet. 4: 257-263, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7757076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7757076</a>] [<a href="https://doi.org/10.1093/hmg/4.2.257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7757076">Sultana et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7757074+7757076+7757075" 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><strong><em>Cornelia de Lange Syndrome 2</em></strong></p><p>
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A female with a Cornelia de Lange syndrome (<a href="/entry/122470">122470</a>) phenotype carrying an apparently balanced X;8 translocation involving the Xp11.2 band, to which the SMC1L1 gene maps, was described by <a href="#4" class="mim-tip-reference" title="Egemen, A., Ulger, Z., Ozkinay, F., Gulen, F., Cogulu, O. <strong>A de novo t(X;8)(p11.2;q24.3) demonstrating Cornelia de Lange syndrome phenotype.</strong> Genet. Counsel. 16: 27-30, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15844775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15844775</a>]" pmid="15844775">Egemen et al. (2005)</a>. The findings were consistent with the location of the SMC1L1 gene at Xp11.2 and the involvement of that gene in X-linked Cornelia de Lange syndrome-2 (CDLS2; <a href="/entry/300590">300590</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15844775" 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="#15" class="mim-tip-reference" title="Musio, A., Selicorni, A., Focarelli, M. L., Gervasini, C., Milani, D., Russo, S., Vezzoni, P., Larizza, L. <strong>X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations.</strong> Nature Genet. 38: 528-530, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16604071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16604071</a>] [<a href="https://doi.org/10.1038/ng1779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16604071">Musio et al. (2006)</a> recruited 53 unrelated and 4 related individuals with a diagnosis of Cornelia de Lange syndrome, encompassing the entire spectrum of phenotypes. They found pathogenic NIPBL (<a href="/entry/608667">608667</a>) mutations in 24 of them, whereas the remaining 33 cases did not bear any NIPBL mutation. Of these 33 individuals, there was only 1 instance of familial occurrence, with 2 male sibs, their mother, and a first cousin affected. Involvement of the NIPBL gene was excluded in this family, but the affected individuals were found to carry a 3-bp deletion in the SMC1L1 gene (<a href="#0001">300040.0001</a>). In addition, a sporadic case was found to have a de novo missense mutation in the SMC1L1 gene (<a href="#0002">300040.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16604071" 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="#3" class="mim-tip-reference" title="Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D. <strong>Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation.</strong> Am. J. Hum. Genet. 80: 485-494, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273969[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/10.1086/511888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273969">Deardorff et al. (2007)</a> identified 14 additional SMC1A mutations in patients with a mild variant of Cornelia de Lange syndrome with predominant mental retardation. Analysis of the mutant SMC1A proteins indicated that they were likely to produce functional cohesin complexes; however, <a href="#3" class="mim-tip-reference" title="Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D. <strong>Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation.</strong> Am. J. Hum. Genet. 80: 485-494, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273969[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/10.1086/511888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273969">Deardorff et al. (2007)</a> posited that they mutations may alter their chromosome binding dynamics. Ten of 14 SMC1A-mutation-positive individuals with CDLS identified by <a href="#3" class="mim-tip-reference" title="Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D. <strong>Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation.</strong> Am. J. Hum. Genet. 80: 485-494, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273969[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/10.1086/511888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273969">Deardorff et al. (2007)</a> were female. Furthermore, their series included similarly affected male and female probands, implying an X-linked dominant mode of expression. Several males were rather mildly affected and no more severely affected than many of the SMC1A mutation-positive females. Since the SMC1A gene escapes X inactivation (<a href="#1" class="mim-tip-reference" title="Brown, C. J., Miller, A. P., Carrel, L., Rupert, J. L., Davies, K. E., Willard, H. F. <strong>The DXS423E gene in Xp11.21 escapes X chromosome inactivation.</strong> Hum. Molec. Genet. 4: 251-255, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7757075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7757075</a>] [<a href="https://doi.org/10.1093/hmg/4.2.251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7757075">Brown et al., 1995</a>), it is likely that the mechanism in affected females is due to a dominant-negative effect of the altered protein and less likely that it is due to decreased protein levels or skewed X inactivation. Consistent with this dominant-negative effect on cohesin, <a href="#3" class="mim-tip-reference" title="Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D. <strong>Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation.</strong> Am. J. Hum. Genet. 80: 485-494, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273969[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/10.1086/511888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273969">Deardorff et al. (2007)</a> described a single amino acid deletion mutation in the SMC3 gene underlying a variant Cornelia de Lange syndrome (<a href="/entry/606062#0001">606062.0001</a>). The data indicated that SMC3 and SMC1A mutations contribute to approximately 5% of cases of Cornelia de Lange syndrome, result in a consistently mild phenotype with absence of major structural anomalies typically associated with CDLS, such as those of the limbs, and, in some instances, result in a phenotype that approaches that of apparently nonsyndromic mental retardation. <a href="#3" class="mim-tip-reference" title="Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D. <strong>Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation.</strong> Am. J. Hum. Genet. 80: 485-494, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273969[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/10.1086/511888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273969">Deardorff et al. (2007)</a> suggested that it may be found that additional 'cohesinopathies' result from perturbation of the more than 15 additional components of this complex that had yet to be associated with human disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17273969+7757075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Developmental and Epileptic Encephalopathy 85 with or without Midline Brain Defects</em></strong></p><p>
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In a 7-year-old girl, born of unrelated Portuguese parents, with developmental and epileptic encephalopathy-85 with midline brain defects manifest as thin corpus callosum (DEE85; <a href="/entry/301044">301044</a>), <a href="#12" class="mim-tip-reference" title="Lebrun, N., Lebon, S., Jeannet, P.-Y., Jacquemont, S., Billuart, P., Bienvenu, T. <strong>Early-onset encephalopathy with epilepsy associated with a novel splice site mutation in SMC1A.</strong> Am. J. Med. Genet. 167A: 3076-3081, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26358754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26358754</a>] [<a href="https://doi.org/10.1002/ajmg.a.37364" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26358754">Lebrun et al. (2015)</a> identified a de novo heterozygous splice site mutation in the SMC1A gene (<a href="#0007">300040.0007</a>). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Analysis of patient fibroblasts showed the presence of only the mutant transcript, which was significantly reduced compared to controls, suggesting nonsense-mediated mRNA decay and a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26358754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated girls with DEE85, <a href="#5" class="mim-tip-reference" title="Goldstein, J. H. R., Tim-aroon, T., Shieh, J., Merrill, M., Deeb, K. K., Zhang, S., Bass, N. E., Bedoyan, J. K. <strong>Novel SMC1A frameshift mutations in children with developmental delay and epilepsy.</strong> Europ. J. Med. Genet. 58: 562-568, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26386245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26386245</a>] [<a href="https://doi.org/10.1016/j.ejmg.2015.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26386245">Goldstein et al. (2015)</a> identified de novo heterozygous frameshift mutations in the SMC1A gene (<a href="#0008">300040.0008</a> and <a href="#0009">300040.0009</a>). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. X-inactivation studies in peripheral blood cells showed a skewed pattern (93:7) in 1 patient, but a random pattern in the other. Additional functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26386245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated females with DEE85, <a href="#9" class="mim-tip-reference" title="Jansen, S., Kleefstra, T., Willemsen, M. H., de Vries, P., Pfundt, R., Hehir-Kwa, J. Y., Gilissen, C., Veltman, J. A., de Vries, B. B. A., Vissers, L. E. L. M. <strong>De novo loss-of-function mutations in X-linked SMC1A cause severe ID and therapy-resistant epilepsy in females: expanding the phenotypic spectrum.</strong> Clin. Genet. 90: 413-419, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26752331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26752331</a>] [<a href="https://doi.org/10.1111/cge.12729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26752331">Jansen et al. (2016)</a> identified de novo heterozygous loss of function (LOF) mutations in the SMC1A gene (see, e.g., <a href="#0010">300040.0010</a>). The mutations were found by whole-genome sequencing. X-inactivation studies in 1 patient showed a random pattern, whereas it was skewed in the other patient (85:15). Additional functional studies were not performed. <a href="#9" class="mim-tip-reference" title="Jansen, S., Kleefstra, T., Willemsen, M. H., de Vries, P., Pfundt, R., Hehir-Kwa, J. Y., Gilissen, C., Veltman, J. A., de Vries, B. B. A., Vissers, L. E. L. M. <strong>De novo loss-of-function mutations in X-linked SMC1A cause severe ID and therapy-resistant epilepsy in females: expanding the phenotypic spectrum.</strong> Clin. Genet. 90: 413-419, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26752331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26752331</a>] [<a href="https://doi.org/10.1111/cge.12729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26752331">Jansen et al. (2016)</a> concluded that the de novo LOF mutations in the SMC1A gene in females cause an abnormal dosage effect and that the resulting phenotype is distinct from CDLS2. The authors further suggested that LOF mutations in males may be embryonic lethal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26752331" 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 10 unrelated females with DEE85, <a href="#21" class="mim-tip-reference" title="Symonds, J. D., Joss, S., Metcalfe, K. A., Somarathi, S., Cruden, J., Devlin, A. M., Donaldson, A., DiDonato, N., Fitzpatrick, D., Kaiser, F. J., Lampe, A. K., Lees, M. M., and 13 others. <strong>Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: detailed phenotyping of 10 new cases.</strong> Epilepsia 58: 565-575, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28166369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28166369</a>] [<a href="https://doi.org/10.1111/epi.13669" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28166369">Symonds et al. (2017)</a> identified de novo heterozygous nonsense, frameshift, or splice site mutations in the SMC1A gene (see, e.g., <a href="#0011">300040.0011</a>-<a href="#0013">300040.0013</a>). Functional studies of the variants were not performed. X-inactivation studies, performed in some patients, had variable results: some showed a random pattern, whereas others had a skewed pattern. <a href="#21" class="mim-tip-reference" title="Symonds, J. D., Joss, S., Metcalfe, K. A., Somarathi, S., Cruden, J., Devlin, A. M., Donaldson, A., DiDonato, N., Fitzpatrick, D., Kaiser, F. J., Lampe, A. K., Lees, M. M., and 13 others. <strong>Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: detailed phenotyping of 10 new cases.</strong> Epilepsia 58: 565-575, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28166369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28166369</a>] [<a href="https://doi.org/10.1111/epi.13669" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28166369">Symonds et al. (2017)</a> speculated that if SMC1A escapes X inactivation, then haploinsufficiency is unlikely to be the causative mechanism; rather, the authors postulated a dominant-negative effect. The findings also suggested that complete SMC1A deficiency is embryonic lethal, as no males with such mutations have been reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28166369" 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 5 unrelated girls (patients 7-11) with DEE85 and variable midline brain defects, including holoprosencephaly (HPE), <a href="#11" class="mim-tip-reference" title="Kruszka, P., Berger, S. I., Casa, V., Dekker, M. R., Gaesser, J., Weiss, K., Martinez, A. F., Murdock, D. R, Louie, R. J., Prijoles, E. J., Lichty, A. W., Brouwer, O. F., and 23 others. <strong>Cohesin complex-associated holoprosencephaly.</strong> Brain 142: 2631-2643, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31334757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31334757</a>] [<a href="https://doi.org/10.1093/brain/awz210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31334757">Kruszka et al. (2019)</a> identified de novo heterozygous mutations in the SMC1A gene (see, e.g., <a href="#0014">300040.0014</a> and <a href="#0015">300040.0015</a>). All mutations except 1 were nonsense, frameshift, or splice site mutations, suggesting a loss-of-function effect; there was 1 missense mutation. Functional studies of the variants and studies of patient cells were not performed. Knockdown of the SMC1A gene in human neural progenitor cells resulted in upregulation of GLI2 (<a href="/entry/165230">165230</a>), ZIC2 (<a href="/entry/603073">603073</a>), and SMAD3 (<a href="/entry/603109">603109</a>) gene expression. Although the significance of these findings was unclear, it demonstrated that loss of SMC1A perturbs the expression of genes involved in HPE. The patients were part of a cohort of 277 individuals with HPE as well as gathered through collaborative efforts such as GeneMatcher. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31334757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>15 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=300040[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1602407457 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1602407457;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=rs1602407457" 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=rs1602407457" 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=RCV000012438" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012438" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012438</a>
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<p><a href="#15" class="mim-tip-reference" title="Musio, A., Selicorni, A., Focarelli, M. L., Gervasini, C., Milani, D., Russo, S., Vezzoni, P., Larizza, L. <strong>X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations.</strong> Nature Genet. 38: 528-530, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16604071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16604071</a>] [<a href="https://doi.org/10.1038/ng1779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16604071">Musio et al. (2006)</a> identified a 3-bp deletion in the SMC1L1 gene in hemizygous state in 2 brothers and a maternal first cousin from a family with X-linked Cornelia de Lange syndrome (<a href="/entry/300590">300590</a>). The mother of the 2 brothers was heterozygous for the mutation and mildly affected. The deletion involved the third nucleotide of codon 831 and the first 2 nucleotides of codon 832, leading to deletion of gln832 and an asp831-to-glu (D831E) substitution. The mutation was not identified in over 600 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16604071" 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">rs122454122 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122454122;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=rs122454122" 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=rs122454122" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a male patient with sporadic X-linked Cornelia de Lange syndrome (<a href="/entry/300590">300590</a>), <a href="#15" class="mim-tip-reference" title="Musio, A., Selicorni, A., Focarelli, M. L., Gervasini, C., Milani, D., Russo, S., Vezzoni, P., Larizza, L. <strong>X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations.</strong> Nature Genet. 38: 528-530, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16604071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16604071</a>] [<a href="https://doi.org/10.1038/ng1779" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16604071">Musio et al. (2006)</a> identified hemizygosity for a 1478A-C transversion in the SMC1L1 gene, resulting in an glu493-to-ala (E493A) substitution. The mutation was not identified in over 400 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16604071" 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="#17" class="mim-tip-reference" title="Revenkova, E., Focarelli, M. L., Susani, L., Paulis, M., Bassi, M. T., Mannini, L., Frattini, A., Delia, D., Krantz, I., Vezzoni, P., Jessberger, R., Musio, A. <strong>Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA.</strong> Hum. Molec. Genet. 18: 418-427, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18996922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18996922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18996922[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18996922">Revenkova et al. (2009)</a> showed that E493A-mutant SMC1A affected the affinity of SMC hinge dimers for DNA. Mutated hinge dimers bound DNA with higher affinity than wildtype proteins. SMC1A-mutated Cornelia de Lange syndrome cell lines displayed genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18996922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a boy with a milder variant of Cornelia de Lange syndrome (CDLS2; <a href="/entry/300590">300590</a>), <a href="#3" class="mim-tip-reference" title="Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D. <strong>Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation.</strong> Am. J. Hum. Genet. 80: 485-494, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273969[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/10.1086/511888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273969">Deardorff et al. (2007)</a> identified a 15-bp deletion in the SMC1A gene, resulting in deletion of 5 amino acids (V58_R62del). Features of CDLS included arched eyebrows and synophrys, anteverted nostrils, long and featureless philtrum, thin lips, downturned corners of the mouth, hearing loss, cutis marmorata, small hands and feet, proximally set thumbs, clinodactyly of fifth finger, and hirsutism. The child had psychomotor delay but was in mainstream second grade schooling. He had mild pulmonic stenosis and gastroesophageal reflux. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17273969" 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">rs122454123 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122454123;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=rs122454123" 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=rs122454123" 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=RCV000012441 OR RCV001577833" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012441, RCV001577833" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012441...</a>
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<p>In 2 sisters with a variant form of Cornelia de Lange syndrome (CDLS2; <a href="/entry/300590">300590</a>), <a href="#3" class="mim-tip-reference" title="Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D. <strong>Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation.</strong> Am. J. Hum. Genet. 80: 485-494, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273969[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/10.1086/511888" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273969">Deardorff et al. (2007)</a> identified a 1487G-A transition in the SMC1A gene that resulted in an arg496-to-his substitution (R496H). Both had psychomotor delay and moderately severe mental retardation. One had pulmonic stenosis. Both had gastroesophageal reflux. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17273969" 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="#17" class="mim-tip-reference" title="Revenkova, E., Focarelli, M. L., Susani, L., Paulis, M., Bassi, M. T., Mannini, L., Frattini, A., Delia, D., Krantz, I., Vezzoni, P., Jessberger, R., Musio, A. <strong>Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA.</strong> Hum. Molec. Genet. 18: 418-427, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18996922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18996922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18996922[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18996922">Revenkova et al. (2009)</a> showed that R496H-mutant SMC1A affected the affinity of SMC hinge dimers for DNA. Mutated hinge dimers bound DNA with higher affinity than wildtype proteins. SMC1A-mutated Cornelia de Lange syndrome cell lines displayed genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18996922" 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">rs387906702 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906702;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=rs387906702" 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=rs387906702" 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=RCV000022820 OR RCV000441375 OR RCV000623393" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022820, RCV000441375, RCV000623393" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022820...</a>
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<p>In a 6-year-old girl with Cornelia de Lange syndrome (CDLS2; <a href="/entry/300590">300590</a>), <a href="#13" class="mim-tip-reference" title="Limongelli, G., Russo, S., Digilio, M. C., Masciadri, M., Pacileo, G., Fratta, F., Martone, F., Maddaloni, V., D'Alessandro, R., Calabro, P., Russo, M. G., Calabro, R., Larizza, L. <strong>Hypertrophic cardiomyopathy in a girl with Cornelia de Lange syndrome due to mutation in SMC1A. (Letter)</strong> Am. J. Med. Genet. 152A: 2127-2129, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20635401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20635401</a>] [<a href="https://doi.org/10.1002/ajmg.a.33486" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20635401">Limongelli et al. (2010)</a> identified a de novo heterozygous 2351T-C transition in exon 15 of the SMC1A gene, resulting in an ile784-to-thr (I784T) substitution in a highly conserved residue in the coiled-coil domain. She had pre- and postnatal growth retardation, developmental delay, characteristic facial features, and concentric left ventricular hypertrophic cardiomyopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20635401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000022821" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000022821" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000022821</a>
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<p>In a girl with a severe form of Cornelia de Lange syndrome-2 (CDLS2; <a href="/entry/300590">300590</a>), <a href="#8" class="mim-tip-reference" title="Hoppman-Chaney, N., Jang, J. S., Jen, J., Babovic-Vuksanovic, D., Hodge, J. C. <strong>In-frame multi-exon deletion of SMC1A in a severely affected female with Cornelia de Lange syndrome.</strong> Am. J. Med. Genet. 158A: 193-198, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22106055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22106055</a>] [<a href="https://doi.org/10.1002/ajmg.a.34360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22106055">Hoppman-Chaney et al. (2012)</a> identified a de novo heterozygous 8.152-kb deletion encompassing exon 13 to intron 16 of the SMC1A gene, resulting in an in-frame deletion of 126 amino acids and insertion of 3 novel amino acids. The mutant mRNA was expressed, and <a href="#8" class="mim-tip-reference" title="Hoppman-Chaney, N., Jang, J. S., Jen, J., Babovic-Vuksanovic, D., Hodge, J. C. <strong>In-frame multi-exon deletion of SMC1A in a severely affected female with Cornelia de Lange syndrome.</strong> Am. J. Med. Genet. 158A: 193-198, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22106055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22106055</a>] [<a href="https://doi.org/10.1002/ajmg.a.34360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22106055">Hoppman-Chaney et al. (2012)</a> concluded that the mutant protein lacking the coiled-coil domain would act in a dominant-negative manner. The patient had dysmorphic facial features, microcephaly, poor growth, profound psychomotor retardation, holoprosencephaly, right hemihypertrophy, and mild distal limb anomalies. The patient was also mosaic for Turner syndrom, 45,X(7)/46,XX(23), which may have accounted for some additional features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22106055" 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">rs2075687835 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2075687835;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=rs2075687835" 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=rs2075687835" 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=RCV001072123" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001072123" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001072123</a>
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<p>In a 7-year-old girl, born of unrelated Portuguese parents, with developmental and epileptic encephalopathy-85 and thin corpus callosum (DEE85; <a href="/entry/301044">301044</a>), <a href="#12" class="mim-tip-reference" title="Lebrun, N., Lebon, S., Jeannet, P.-Y., Jacquemont, S., Billuart, P., Bienvenu, T. <strong>Early-onset encephalopathy with epilepsy associated with a novel splice site mutation in SMC1A.</strong> Am. J. Med. Genet. 167A: 3076-3081, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26358754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26358754</a>] [<a href="https://doi.org/10.1002/ajmg.a.37364" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26358754">Lebrun et al. (2015)</a> identified a de novo heterozygous G-to-T transversion (c.1911+1G-T) in intron 11 of the SMC1A gene, predicted to result in a splicing defect, frameshift, and premature termination (Thr638ValfsTer48). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Analysis of patient fibroblasts showed the presence of only the mutant transcript, which was significantly reduced compared to controls, suggesting nonsense-mediated mRNA decay and a loss of function. The patient had onset of infantile spasms associated with hypsarrhythmia on EEG within the first month of life. She also had microcephaly, dysmorphic facial features, and severe developmental delay. Brain imaging showed a thin corpus callosum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26358754" 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">rs863225458 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225458;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=rs863225458" 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=rs863225458" 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=RCV000202429 OR RCV000394437 OR RCV001072124" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000202429, RCV000394437, RCV001072124" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000202429...</a>
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<p>In a 4-year-old girl (patient A) with developmental and epileptic encephalopathy-85 (DEE85; <a href="/entry/301044">301044</a>) with possible thickening of the insular cortex on brain imaging, <a href="#5" class="mim-tip-reference" title="Goldstein, J. H. R., Tim-aroon, T., Shieh, J., Merrill, M., Deeb, K. K., Zhang, S., Bass, N. E., Bedoyan, J. K. <strong>Novel SMC1A frameshift mutations in children with developmental delay and epilepsy.</strong> Europ. J. Med. Genet. 58: 562-568, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26386245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26386245</a>] [<a href="https://doi.org/10.1016/j.ejmg.2015.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26386245">Goldstein et al. (2015)</a> identified a de novo heterozygous 4-bp deletion (c.2853_2856delTCAG, NM_006306) in exon 18 of the SMC1A gene, resulting in a frameshift and premature termination (Ser951ArgfsTer12). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. X-inactivation studies in peripheral blood cells showed a skewed pattern (93:7), although it was not clear if the mutant allele was expressed. Additional functional studies of the variant and studies of patient cells were not performed. The patient had onset of generalized tonic-clonic seizures at 4 months of age. The seizures became increasingly difficult to control, and she showed severe developmental regression and stagnation with inability to walk or speak. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26386245" 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">rs863225459 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225459;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=rs863225459" 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=rs863225459" 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=RCV000202430 OR RCV001072125" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000202430, RCV001072125" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000202430...</a>
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<p>In a 3-year-old girl (patient B) with developmental and epileptic encephalopathy-85 and slight thinning of the corpus callosum (DEE85; <a href="/entry/301044">301044</a>), <a href="#5" class="mim-tip-reference" title="Goldstein, J. H. R., Tim-aroon, T., Shieh, J., Merrill, M., Deeb, K. K., Zhang, S., Bass, N. E., Bedoyan, J. K. <strong>Novel SMC1A frameshift mutations in children with developmental delay and epilepsy.</strong> Europ. J. Med. Genet. 58: 562-568, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26386245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26386245</a>] [<a href="https://doi.org/10.1016/j.ejmg.2015.09.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26386245">Goldstein et al. (2015)</a> identified a de novo heterozygous 4-bp duplication (c.3549_3552dupGGCC, NM_006306) in exon 24 of the SMC1A gene, resulting in a frameshift and premature termination (Ile1185GlyfsTer23). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. X-inactivation studies in peripheral blood cells showed a random pattern. Additional functional studies of the variant and studies of patient cells were not performed. The patient had onset of tonic-clonic movements at 17 months of age following earlier global developmental delay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26386245" 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>.0010 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITHOUT MIDLINE BRAIN DEFECTS</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">rs2075680107 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2075680107;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=rs2075680107" 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=rs2075680107" 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=RCV001072126" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001072126" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001072126</a>
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<p>In a 46-year-old woman (patient 1) with developmental and epileptic encephalopathy-85 (DEE85; <a href="/entry/301044">301044</a>) without midline brain defects, <a href="#9" class="mim-tip-reference" title="Jansen, S., Kleefstra, T., Willemsen, M. H., de Vries, P., Pfundt, R., Hehir-Kwa, J. Y., Gilissen, C., Veltman, J. A., de Vries, B. B. A., Vissers, L. E. L. M. <strong>De novo loss-of-function mutations in X-linked SMC1A cause severe ID and therapy-resistant epilepsy in females: expanding the phenotypic spectrum.</strong> Clin. Genet. 90: 413-419, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26752331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26752331</a>] [<a href="https://doi.org/10.1111/cge.12729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26752331">Jansen et al. (2016)</a> identified a de novo heterozygous 1-bp deletion (c.2364del, NM_006306) in the SMC1A gene, predicted to result in a frameshift and premature termination (Asn788LysfsTer10). The mutation was found by whole-genome sequencing and was predicted to result in nonsense-mediated mRNA decay and a loss of function. X-inactivation studies showed a random pattern. Additional functional studies were not performed. The patient had severe global developmental delay and onset of intractable seizures at 9 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26752331" 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>.0011 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITHOUT MIDLINE BRAIN DEFECTS</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">rs2075681060 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2075681060;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=rs2075681060" 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=rs2075681060" 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=RCV001072127" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001072127" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001072127</a>
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<p>In an 8-year-old girl (patient 4) with developmental and epileptic encephalopathy-85 (DEE85; <a href="/entry/301044">301044</a>) without midline brain defects, <a href="#21" class="mim-tip-reference" title="Symonds, J. D., Joss, S., Metcalfe, K. A., Somarathi, S., Cruden, J., Devlin, A. M., Donaldson, A., DiDonato, N., Fitzpatrick, D., Kaiser, F. J., Lampe, A. K., Lees, M. M., and 13 others. <strong>Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: detailed phenotyping of 10 new cases.</strong> Epilepsia 58: 565-575, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28166369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28166369</a>] [<a href="https://doi.org/10.1111/epi.13669" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28166369">Symonds et al. (2017)</a> identified a de novo heterozygous c.2197G-T transversion (c.2197G-T, NM_006306) in the SMC1A gene, predicted to result in a glu733-to-ter (E733X) substitution. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed, although X-inactivation studies showed a normal pattern. The patient had onset of focal and generalized seizures that were difficult to control at 5 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28166369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITH OR WITHOUT MIDLINE BRAIN DEFECTS</strong>
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SMC1A, 1-BP DEL, 2477A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2075664229 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2075664229;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=rs2075664229" 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=rs2075664229" 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=RCV001072128" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001072128" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001072128</a>
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<p>In 2 sisters (patients 8 and 9) with developmental and epileptic encephalopathy-85 (DEE85; <a href="/entry/301044">301044</a>), <a href="#21" class="mim-tip-reference" title="Symonds, J. D., Joss, S., Metcalfe, K. A., Somarathi, S., Cruden, J., Devlin, A. M., Donaldson, A., DiDonato, N., Fitzpatrick, D., Kaiser, F. J., Lampe, A. K., Lees, M. M., and 13 others. <strong>Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: detailed phenotyping of 10 new cases.</strong> Epilepsia 58: 565-575, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28166369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28166369</a>] [<a href="https://doi.org/10.1111/epi.13669" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28166369">Symonds et al. (2017)</a> identified a de novo heterozygous 1-bp deletion (c.2477delA, NM_006306) in the SMC1A gene, predicted to result in a frameshift and premature termination. Functional studies of the variant and studies of patient cells were not performed. One sister had normal brain imaging and was less severely affected; she had onset of seizures at about 28 months of age. The other sister showed semilobar holoprosencephaly on brain imaging. She had onset of seizures in the first month of life and died at age 11 months. These findings demonstrated phenotypic variability even within the same family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28166369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITH MIDLINE BRAIN DEFECTS</strong>
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SMC1A, GLN1039TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2075591576 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2075591576;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=rs2075591576" 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=rs2075591576" 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=RCV001072129" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001072129" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001072129</a>
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<p>In a girl (patient 10) who died at age 9 years with developmental and epileptic encephalopathy-85 with abnormal corpus callosum (DEE85; <a href="/entry/301044">301044</a>), <a href="#21" class="mim-tip-reference" title="Symonds, J. D., Joss, S., Metcalfe, K. A., Somarathi, S., Cruden, J., Devlin, A. M., Donaldson, A., DiDonato, N., Fitzpatrick, D., Kaiser, F. J., Lampe, A. K., Lees, M. M., and 13 others. <strong>Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: detailed phenotyping of 10 new cases.</strong> Epilepsia 58: 565-575, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28166369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28166369</a>] [<a href="https://doi.org/10.1111/epi.13669" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28166369">Symonds et al. (2017)</a> identified a de novo heterozygous c.3115C-T transition (c.3115C-T, NM_006306) in the SMC1A gene, predicted to result in a gln1039-to-ter (Q1039X) substitution. Functional studies of the variant and studies in patient cells were not performed, but X-inactivation studies showed a skewed ratio (76:24). The patient had onset of intractable tonic-clonic seizures at 2 months of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28166369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0014" class="mim-anchor"></a>
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<h4>
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<strong>.0014 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITH MIDLINE BRAIN DEFECTS</strong>
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SMC1A, ARG895GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2075651835 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2075651835;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=rs2075651835" 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=rs2075651835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001072130" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001072130" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001072130</a>
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<p>In a 6-year-old girl (patient 9) with developmental and epileptic encephalopathy-85 with semilobar holoprosencephaly (DEE85; <a href="/entry/301044">301044</a>), <a href="#11" class="mim-tip-reference" title="Kruszka, P., Berger, S. I., Casa, V., Dekker, M. R., Gaesser, J., Weiss, K., Martinez, A. F., Murdock, D. R, Louie, R. J., Prijoles, E. J., Lichty, A. W., Brouwer, O. F., and 23 others. <strong>Cohesin complex-associated holoprosencephaly.</strong> Brain 142: 2631-2643, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31334757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31334757</a>] [<a href="https://doi.org/10.1093/brain/awz210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31334757">Kruszka et al. (2019)</a> identified a de novo heterozygous c.2683C-G transversion (chrX.53,423,417G-C, GRCh37) in the SMC1A gene, resulting in an arg895-to-gly (R895G) substitution at a conserved residue in the second coiled-coil domain. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated either a loss-of-function or a dominant-negative effect. The patient had early-onset seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31334757" 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>.0015 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITH MIDLINE BRAIN DEFECTS</strong>
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SMC1A, 1-BP DEL, 2394A
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1569356555 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569356555;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=rs1569356555" 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=rs1569356555" 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=RCV001072131" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001072131" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001072131</a>
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<p>In a 3-year-old girl (patient 10) with developmental and epileptic encephalopathy-85 with semilobar holoprosencephaly (DEE85; <a href="/entry/301044">301044</a>), <a href="#11" class="mim-tip-reference" title="Kruszka, P., Berger, S. I., Casa, V., Dekker, M. R., Gaesser, J., Weiss, K., Martinez, A. F., Murdock, D. R, Louie, R. J., Prijoles, E. J., Lichty, A. W., Brouwer, O. F., and 23 others. <strong>Cohesin complex-associated holoprosencephaly.</strong> Brain 142: 2631-2643, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31334757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31334757</a>] [<a href="https://doi.org/10.1093/brain/awz210" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31334757">Kruszka et al. (2019)</a> identified a de novo heterozygous 1-bp deletion (c.2394delA; chrX.53,430,524delA) in the SMC1A gene, predicted to result in a frameshift and premature termination (Lys798AsnfsTer3). Functional studies of the variant and studies of patient cells were not performed. The patient had early-onset seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31334757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1093/hmg/4.2.251" target="_blank">Full Text</a>]
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Davidson, I. F., Bauer, B., Goetz, D., Tang, W., Wutz, G., Peters, J. M.
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[<a href="https://doi.org/10.1126/science.aaz3418" target="_blank">Full Text</a>]
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Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273969</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273969[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=17273969" 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/10.1086/511888" target="_blank">Full Text</a>]
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Egemen, A., Ulger, Z., Ozkinay, F., Gulen, F., Cogulu, O.
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<strong>A de novo t(X;8)(p11.2;q24.3) demonstrating Cornelia de Lange syndrome phenotype.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15844775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15844775</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15844775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Goldstein, J. H. R., Tim-aroon, T., Shieh, J., Merrill, M., Deeb, K. K., Zhang, S., Bass, N. E., Bedoyan, J. K.
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<strong>Novel SMC1A frameshift mutations in children with developmental delay and epilepsy.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26386245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26386245</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26386245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ejmg.2015.09.007" target="_blank">Full Text</a>]
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Gruber, S., Haering, C. H., Nasmyth, K.
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<strong>Chromosomal cohesin forms a ring.</strong>
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Cell 112: 765-777, 2003.
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[<a href="https://doi.org/10.1016/s0092-8674(03)00162-4" target="_blank">Full Text</a>]
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<a id="Haering2008" class="mim-anchor"></a>
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Haering, C. H., Farcas, A.-M., Arumugam, P., Metson, J., Nasmyth, K.
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[<a href="https://doi.org/10.1038/nature07098" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.34360" target="_blank">Full Text</a>]
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Jansen, S., Kleefstra, T., Willemsen, M. H., de Vries, P., Pfundt, R., Hehir-Kwa, J. Y., Gilissen, C., Veltman, J. A., de Vries, B. B. A., Vissers, L. E. L. M.
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[<a href="https://doi.org/10.1111/cge.12729" target="_blank">Full Text</a>]
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Kagey, M. H., Newman, J. J., Bilodeau, S., Zhan, Y., Orlando, D. A., van Berkum, N. L., Ebmeier, C. C., Goossens, J., Rahl, P. B., Levine, S. S., Taatjes, D. J., Dekker, J., Young, R. A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20720539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20720539</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20720539[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=20720539" 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/nature09380" target="_blank">Full Text</a>]
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Kruszka, P., Berger, S. I., Casa, V., Dekker, M. R., Gaesser, J., Weiss, K., Martinez, A. F., Murdock, D. R, Louie, R. J., Prijoles, E. J., Lichty, A. W., Brouwer, O. F., and 23 others.
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<strong>Cohesin complex-associated holoprosencephaly.</strong>
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Brain 142: 2631-2643, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31334757/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31334757</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31334757" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awz210" target="_blank">Full Text</a>]
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Lebrun, N., Lebon, S., Jeannet, P.-Y., Jacquemont, S., Billuart, P., Bienvenu, T.
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<strong>Early-onset encephalopathy with epilepsy associated with a novel splice site mutation in SMC1A.</strong>
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Am. J. Med. Genet. 167A: 3076-3081, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26358754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26358754</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26358754" 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.37364" target="_blank">Full Text</a>]
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</p>
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<a id="13" class="mim-anchor"></a>
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<a id="Limongelli2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Limongelli, G., Russo, S., Digilio, M. C., Masciadri, M., Pacileo, G., Fratta, F., Martone, F., Maddaloni, V., D'Alessandro, R., Calabro, P., Russo, M. G., Calabro, R., Larizza, L.
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<strong>Hypertrophic cardiomyopathy in a girl with Cornelia de Lange syndrome due to mutation in SMC1A. (Letter)</strong>
|
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Am. J. Med. Genet. 152A: 2127-2129, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20635401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20635401</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20635401" 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.33486" target="_blank">Full Text</a>]
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</p>
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<a id="14" class="mim-anchor"></a>
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<a id="Musio2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Musio, A., Montagna, C., Mariani, T., Tilenni, M., Focarelli, M. L., Brait, L., Indino, E., Benedetti, P. A., Chessa, L., Albertini, A., Ried, T., Vezzoni, P.
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|
<strong>SMC1 involvement in fragile site expression.</strong>
|
|
Hum. Molec. Genet. 14: 525-533, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15640246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15640246</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15640246" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi049" target="_blank">Full Text</a>]
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</p>
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<a id="15" class="mim-anchor"></a>
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<a id="Musio2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Musio, A., Selicorni, A., Focarelli, M. L., Gervasini, C., Milani, D., Russo, S., Vezzoni, P., Larizza, L.
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<strong>X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations.</strong>
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Nature Genet. 38: 528-530, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16604071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16604071</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16604071" 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/ng1779" target="_blank">Full Text</a>]
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<a id="16" class="mim-anchor"></a>
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<a id="Patel2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Patel, C. A., Ghiselli, G.
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<strong>Hinderin, a five-domains protein including coiled-coil motifs that binds to SMC3.</strong>
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BMC Cell Biol. 6: 3, 2005. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15656913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15656913</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15656913[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=15656913" 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/10.1186/1471-2121-6-3" target="_blank">Full Text</a>]
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<a id="17" class="mim-anchor"></a>
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<a id="Revenkova2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Revenkova, E., Focarelli, M. L., Susani, L., Paulis, M., Bassi, M. T., Mannini, L., Frattini, A., Delia, D., Krantz, I., Vezzoni, P., Jessberger, R., Musio, A.
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<strong>Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA.</strong>
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Hum. Molec. Genet. 18: 418-427, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18996922/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18996922</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18996922[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=18996922" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddn369" target="_blank">Full Text</a>]
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Rocques1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rocques, P. J., Clark, J., Ball, S., Crew, J., Gill, S., Christodoulou, Z., Borts, R. H., Louis, E. J., Davies, K. E., Cooper, C. S.
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<strong>The human SB1.8 gene (DXS423E) encodes a putative chromosome segregation protein conserved in lower eukaryotes and prokaryotes.</strong>
|
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Hum. Molec. Genet. 4: 243-249, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7757074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7757074</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7757074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/4.2.243" target="_blank">Full Text</a>]
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Sultana1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sultana, R., Adler, D. A., Edelhoff, S., Carrel, L., Lee, K., Chapman, V. C., Willard, H. F., Disteche, C. M.
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<strong>The mouse Sb1.8 gene located at the distal end of the X chromosome is subject to X inactivation.</strong>
|
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Hum. Molec. Genet. 4: 257-263, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7757076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7757076</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7757076" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/4.2.257" target="_blank">Full Text</a>]
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<a id="20" class="mim-anchor"></a>
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<a id="Sumara2000" class="mim-anchor"></a>
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Sumara, I., Vorlaufer, E., Gieffers, C., Peters, B. H., Peters, J.-M.
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<strong>Characterization of vertebrate cohesin complexes and their regulation in prophase.</strong>
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J. Cell Biol. 151: 749-761, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11076961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11076961</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11076961[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=11076961" 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/10.1083/jcb.151.4.749" target="_blank">Full Text</a>]
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<a id="21" class="mim-anchor"></a>
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<a id="Symonds2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Symonds, J. D., Joss, S., Metcalfe, K. A., Somarathi, S., Cruden, J., Devlin, A. M., Donaldson, A., DiDonato, N., Fitzpatrick, D., Kaiser, F. J., Lampe, A. K., Lees, M. M., and 13 others.
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<strong>Heterozygous truncation mutations of the SMC1A gene cause a severe early onset epilepsy with cluster seizures in females: detailed phenotyping of 10 new cases.</strong>
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Epilepsia 58: 565-575, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28166369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28166369</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28166369" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/epi.13669" target="_blank">Full Text</a>]
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</ol>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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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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Ada Hamosh - updated : 05/06/2020
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</div>
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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 : 04/10/2020<br>Patricia A. Hartz - updated : 07/24/2015<br>Cassandra L. Kniffin - updated : 2/16/2012<br>Cassandra L. Kniffin - updated : 1/11/2011<br>Ada Hamosh - updated : 10/7/2010<br>George E. Tiller - updated : 7/31/2009<br>Ada Hamosh - updated : 8/12/2008<br>George E. Tiller - updated : 1/3/2008<br>Victor A. McKusick - updated : 2/8/2007<br>Victor A. McKusick - updated : 4/26/2006<br>Stylianos E. Antonarakis - updated : 4/14/2003<br>Paul J. Converse - updated : 11/16/2001
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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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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Victor A. McKusick : 3/14/1996
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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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carol : 12/01/2020
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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ckniffin : 11/25/2020<br>alopez : 05/06/2020<br>carol : 04/16/2020<br>carol : 04/15/2020<br>carol : 04/14/2020<br>ckniffin : 04/10/2020<br>carol : 03/19/2019<br>mgross : 07/24/2015<br>carol : 2/21/2012<br>ckniffin : 2/16/2012<br>alopez : 6/10/2011<br>wwang : 2/1/2011<br>ckniffin : 1/11/2011<br>alopez : 10/8/2010<br>alopez : 10/8/2010<br>terry : 10/7/2010<br>wwang : 8/13/2009<br>terry : 7/31/2009<br>alopez : 8/25/2008<br>terry : 8/12/2008<br>alopez : 3/20/2008<br>terry : 3/7/2008<br>wwang : 1/14/2008<br>terry : 1/3/2008<br>carol : 12/5/2007<br>alopez : 2/13/2007<br>terry : 2/8/2007<br>carol : 8/8/2006<br>wwang : 5/4/2006<br>wwang : 4/27/2006<br>terry : 4/26/2006<br>alopez : 4/6/2005<br>mgross : 5/25/2004<br>mgross : 5/25/2004<br>ckniffin : 3/12/2004<br>mgross : 4/14/2003<br>mgross : 11/16/2001<br>alopez : 8/14/2000<br>alopez : 8/14/2000<br>mark : 3/14/1996<br>mark : 3/14/1996
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<strong>*</strong> 300040
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<div>
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<h3>
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<span class="mim-font">
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STRUCTURAL MAINTENANCE OF CHROMOSOMES 1A; SMC1A
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</h3>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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SMC1-ALPHA<br />
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STRUCTURAL MAINTENANCE OF CHROMOSOMES 1-LIKE 1; SMC1L1<br />
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SMC1<br />
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DXS423E<br />
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KIAA0178
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SMC1A</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 55016009;
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</span>
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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: Xp11.22
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Genomic coordinates <span class="small">(GRCh38)</span> : X:53,374,149-53,422,728 </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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<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-Phenotype Relationships</strong>
|
|
</span>
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
Xp11.22
|
|
</span>
|
|
</td>
|
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Cornelia de Lange syndrome 2
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
300590
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
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</tr>
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Developmental and epileptic encephalopathy 85, with or without midline brain defects
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
301044
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
X-linked dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
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|
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|
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|
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|
|
</tbody>
|
|
</table>
|
|
</div>
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|
</div>
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<div>
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<br />
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|
</div>
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<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Eukaryotic sister chromatids remain connected from the time of synthesis until they are separated in anaphase. This cohesion depends on a complex of proteins known as cohesins. In vertebrates, unlike in yeast, the cohesins dissociate from chromosome arms earlier in M phase, during prophase. Small amounts of cohesin remain near the centromere until metaphase, with complete removal at the beginning of anaphase. Cohesin complexes contain SMC1, SCC1 (RAD21), SMC3 (606062), and either SA1 (STAG1; 604358) or SA2 (STAG2; 300826). The complexes, in turn, interact with PDS5 (see 613200), a protein implicated in chromosome cohesion, condensation, and recombination in yeast (summary by Sumara et al., 2000). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Genetic marker SB1.8 (DXS423E) was originally identified as a cross-reacting clone during the screening of a human lymphocyte cDNA library with an oligonucleotide probe corresponding to the CYBB (300481) gene, which maps to Xp21.1. Rocques et al. (1995) found that the DXS423E gene encodes a protein of 1,233 amino acids that is 30% identical to the essential yeast protein SMC1 (structural maintenance of chromosomes-1), which is required for the segregation of chromosomes at mitosis. Both the human protein, called SB1.8, and SMC1 contain an N-terminal NTP-binding site, a central coiled-coil region, and a C-terminal helix-loop-helix domain, and both have structural features in common with the force-generating proteins myosin and kinesin. SB1.8 also exhibits regions of homology and overall structural similarity to protein 115p of the prokaryote Mycoplasma hyorhinis. </p><p>In mouse embryos, Kruszka et al. (2019) found expression of the Smc1a gene in anterior neural folds, the neuroectoderm, and adjacent mesenchyme of the developing brain. The findings suggested a role in forebrain patterning. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
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|
|
<span class="mim-text-font">
|
|
<p>In yeast, the cohesin complex is essential for sister chromatid cohesion during mitosis. The Smc1 and Smc3 subunits are rod-shaped molecules with globular ABC-like ATPases at one end and dimerization domains at the other, connected by long coiled coils. Smc1 and Smc3 associate to form V-shaped heterodimers. Their ATPase heads are thought to be bridged by a third subunit, Scc1, creating a huge triangular ring that can trap sister DNA molecules. Gruber et al. (2003) studied whether cohesin forms such rings in vivo. Proteolytic cleavage of Scc1 by separase at the onset of anaphase triggers its dissociation from chromosomes. The authors showed that N- and C-terminal Scc1 cleavage fragments remain connected due to their association with different heads of a single Smc1/Smc3 heterodimer. Cleavage of the Smc3 coiled coil was sufficient to trigger cohesin release from chromosomes and loss of sister cohesion, consistent with a topologic association with chromatin. </p><p>By yeast 2-hybrid screening of a human fetal brain expression cDNA library using the hinge domain of SMC1 as bait, followed by immunoprecipitation analysis, Patel and Ghiselli (2005) found that SMC1 interacted with hinderin (KIAA1328; 616480). Hinderin did not interact with SMC3. Interaction of hinderin with SMC1 precluded dimerization of SMC1 and SMC3. </p><p>Musio et al. (2005) demonstrated that RNA interference (RNAi) of SMC1 was sufficient to induce fragile site expression in normal human fibroblasts. They showed that aphidicolin treatment led to an increase in SMC1 synthesis, SMC1 phosphorylation via an ATR (601215)-dependent pathway, and enhanced double-stranded break induction as visualized by immunohistochemical studies with phosphorylated H2AX (601772). Discrete nuclear foci were absent or very rare after 1 or 2 hours exposure to aphidicolin and/or RNAi of SMC1 but became more numerous and distinct after 6 hours. Musio et al. (2005) proposed that fragile sites might be viewed as an in vitro phenomenon originating from double-strand breaks formed because of stalled DNA replication that lasted too long to be rescued via the ATR/SMC1 axis, whereas in vivo, following an extreme replication block, rare cells could escape checkpoint mechanisms and enter mitosis with a defect in genome assembly, eventually leading to neoplastic transformation. </p><p>Cohesin's Scc1, Smc1, and Smc3 subunits form a tripartite ring structure, and it had been proposed that cohesin holds sister DNA molecules together by trapping them inside its ring. To test this, Haering et al. (2008) used site-specific crosslinking to create chemical connections at the 3 interfaces between the 3 constituent polypeptides of the ring, thereby creating covalently closed cohesin rings. As predicted by the ring entrapment model, this procedure produced dimeric DNA-cohesin structures that are resistant to protein denaturation. Haering et al. (2008) concluded that cohesin rings concatenate individual sister minichromosome DNA molecules. </p><p>Kagey et al. (2010) reported that Mediator (see MED8, 607956) and cohesin physically and functionally connect the enhancers and core promoters of active genes in murine embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with cohesin, which can form rings that connect 2 DNA segments. The cohesin-loading factor NIPBL (608667) is associated with Mediator-cohesin complexes, providing a means to load cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by Mediator and cohesin. Mediator and cohesin co-occupy different promoters in different cells, thus generating cell type-specific DNA loops linked to the gene expression program of each cell. </p><p>Using biochemical reconstitution, Davidson et al. (2019) found that single human cohesin complexes form DNA loops symmetrically at rates up to 2.1 kilobase pairs per second. Loop formation and maintenance depend on cohesin's ATPase activity and on NIPBL-MAU2 (614560), but not on topologic entrapment of DNA by cohesin (components include SMC3, 606062; SMC1A; STAG1, 604358; and STAG2, 300826). During loop formation, cohesin and NIPBL-MAU2 reside at the base of loops, which indicates that they generate loops by extrusion. Davidson et al. (2019) concluded that their results showed that cohesin and NIPBL-MAU2 form an active holoenzyme that interacts with DNA either pseudotopologically or nontopologically to extrude genomic interphase DNA into loops. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Rocques et al. (1995) showed that the DXS423E gene maps to a cosmid contig that lies centromeric to the OATL2 locus (see 258870) at Xp11.2. Brown et al. (1995) showed that SMC1 escapes X-chromosome inactivation. SMC1 and XE169 (314690) were thought to define a new region in the proximal short arm of the X chromosome that escapes X inactivation. The corresponding gene in the mouse, Sb1.8, is located at the distal end of the X chromosome and is subject to X inactivation (Sultana et al., 1995). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Cornelia de Lange Syndrome 2</em></strong></p><p>
|
|
A female with a Cornelia de Lange syndrome (122470) phenotype carrying an apparently balanced X;8 translocation involving the Xp11.2 band, to which the SMC1L1 gene maps, was described by Egemen et al. (2005). The findings were consistent with the location of the SMC1L1 gene at Xp11.2 and the involvement of that gene in X-linked Cornelia de Lange syndrome-2 (CDLS2; 300590). </p><p>Musio et al. (2006) recruited 53 unrelated and 4 related individuals with a diagnosis of Cornelia de Lange syndrome, encompassing the entire spectrum of phenotypes. They found pathogenic NIPBL (608667) mutations in 24 of them, whereas the remaining 33 cases did not bear any NIPBL mutation. Of these 33 individuals, there was only 1 instance of familial occurrence, with 2 male sibs, their mother, and a first cousin affected. Involvement of the NIPBL gene was excluded in this family, but the affected individuals were found to carry a 3-bp deletion in the SMC1L1 gene (300040.0001). In addition, a sporadic case was found to have a de novo missense mutation in the SMC1L1 gene (300040.0002). </p><p>Deardorff et al. (2007) identified 14 additional SMC1A mutations in patients with a mild variant of Cornelia de Lange syndrome with predominant mental retardation. Analysis of the mutant SMC1A proteins indicated that they were likely to produce functional cohesin complexes; however, Deardorff et al. (2007) posited that they mutations may alter their chromosome binding dynamics. Ten of 14 SMC1A-mutation-positive individuals with CDLS identified by Deardorff et al. (2007) were female. Furthermore, their series included similarly affected male and female probands, implying an X-linked dominant mode of expression. Several males were rather mildly affected and no more severely affected than many of the SMC1A mutation-positive females. Since the SMC1A gene escapes X inactivation (Brown et al., 1995), it is likely that the mechanism in affected females is due to a dominant-negative effect of the altered protein and less likely that it is due to decreased protein levels or skewed X inactivation. Consistent with this dominant-negative effect on cohesin, Deardorff et al. (2007) described a single amino acid deletion mutation in the SMC3 gene underlying a variant Cornelia de Lange syndrome (606062.0001). The data indicated that SMC3 and SMC1A mutations contribute to approximately 5% of cases of Cornelia de Lange syndrome, result in a consistently mild phenotype with absence of major structural anomalies typically associated with CDLS, such as those of the limbs, and, in some instances, result in a phenotype that approaches that of apparently nonsyndromic mental retardation. Deardorff et al. (2007) suggested that it may be found that additional 'cohesinopathies' result from perturbation of the more than 15 additional components of this complex that had yet to be associated with human disorders. </p><p><strong><em>Developmental and Epileptic Encephalopathy 85 with or without Midline Brain Defects</em></strong></p><p>
|
|
In a 7-year-old girl, born of unrelated Portuguese parents, with developmental and epileptic encephalopathy-85 with midline brain defects manifest as thin corpus callosum (DEE85; 301044), Lebrun et al. (2015) identified a de novo heterozygous splice site mutation in the SMC1A gene (300040.0007). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Analysis of patient fibroblasts showed the presence of only the mutant transcript, which was significantly reduced compared to controls, suggesting nonsense-mediated mRNA decay and a loss of function. </p><p>In 2 unrelated girls with DEE85, Goldstein et al. (2015) identified de novo heterozygous frameshift mutations in the SMC1A gene (300040.0008 and 300040.0009). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. X-inactivation studies in peripheral blood cells showed a skewed pattern (93:7) in 1 patient, but a random pattern in the other. Additional functional studies of the variants and studies of patient cells were not performed. </p><p>In 2 unrelated females with DEE85, Jansen et al. (2016) identified de novo heterozygous loss of function (LOF) mutations in the SMC1A gene (see, e.g., 300040.0010). The mutations were found by whole-genome sequencing. X-inactivation studies in 1 patient showed a random pattern, whereas it was skewed in the other patient (85:15). Additional functional studies were not performed. Jansen et al. (2016) concluded that the de novo LOF mutations in the SMC1A gene in females cause an abnormal dosage effect and that the resulting phenotype is distinct from CDLS2. The authors further suggested that LOF mutations in males may be embryonic lethal. </p><p>In 10 unrelated females with DEE85, Symonds et al. (2017) identified de novo heterozygous nonsense, frameshift, or splice site mutations in the SMC1A gene (see, e.g., 300040.0011-300040.0013). Functional studies of the variants were not performed. X-inactivation studies, performed in some patients, had variable results: some showed a random pattern, whereas others had a skewed pattern. Symonds et al. (2017) speculated that if SMC1A escapes X inactivation, then haploinsufficiency is unlikely to be the causative mechanism; rather, the authors postulated a dominant-negative effect. The findings also suggested that complete SMC1A deficiency is embryonic lethal, as no males with such mutations have been reported. </p><p>In 5 unrelated girls (patients 7-11) with DEE85 and variable midline brain defects, including holoprosencephaly (HPE), Kruszka et al. (2019) identified de novo heterozygous mutations in the SMC1A gene (see, e.g., 300040.0014 and 300040.0015). All mutations except 1 were nonsense, frameshift, or splice site mutations, suggesting a loss-of-function effect; there was 1 missense mutation. Functional studies of the variants and studies of patient cells were not performed. Knockdown of the SMC1A gene in human neural progenitor cells resulted in upregulation of GLI2 (165230), ZIC2 (603073), and SMAD3 (603109) gene expression. Although the significance of these findings was unclear, it demonstrated that loss of SMC1A perturbs the expression of genes involved in HPE. The patients were part of a cohort of 277 individuals with HPE as well as gathered through collaborative efforts such as GeneMatcher. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
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|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>15 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 CORNELIA DE LANGE SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMC1A, 3-BP DEL, 2493CCA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1602407457,
|
|
|
|
|
|
|
|
ClinVar: RCV000012438
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Musio et al. (2006) identified a 3-bp deletion in the SMC1L1 gene in hemizygous state in 2 brothers and a maternal first cousin from a family with X-linked Cornelia de Lange syndrome (300590). The mother of the 2 brothers was heterozygous for the mutation and mildly affected. The deletion involved the third nucleotide of codon 831 and the first 2 nucleotides of codon 832, leading to deletion of gln832 and an asp831-to-glu (D831E) substitution. The mutation was not identified in over 600 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 CORNELIA DE LANGE SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMC1A, GLU493ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122454122,
|
|
|
|
|
|
|
|
ClinVar: RCV000012439
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male patient with sporadic X-linked Cornelia de Lange syndrome (300590), Musio et al. (2006) identified hemizygosity for a 1478A-C transversion in the SMC1L1 gene, resulting in an glu493-to-ala (E493A) substitution. The mutation was not identified in over 400 control chromosomes. </p><p>Revenkova et al. (2009) showed that E493A-mutant SMC1A affected the affinity of SMC hinge dimers for DNA. Mutated hinge dimers bound DNA with higher affinity than wildtype proteins. SMC1A-mutated Cornelia de Lange syndrome cell lines displayed genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
|
|
|
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 CORNELIA DE LANGE SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMC1A, 15-BP DEL, NT173
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000012440
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a boy with a milder variant of Cornelia de Lange syndrome (CDLS2; 300590), Deardorff et al. (2007) identified a 15-bp deletion in the SMC1A gene, resulting in deletion of 5 amino acids (V58_R62del). Features of CDLS included arched eyebrows and synophrys, anteverted nostrils, long and featureless philtrum, thin lips, downturned corners of the mouth, hearing loss, cutis marmorata, small hands and feet, proximally set thumbs, clinodactyly of fifth finger, and hirsutism. The child had psychomotor delay but was in mainstream second grade schooling. He had mild pulmonic stenosis and gastroesophageal reflux. </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 CORNELIA DE LANGE SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMC1A, ARG496HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122454123,
|
|
|
|
|
|
|
|
ClinVar: RCV000012441, RCV001577833
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters with a variant form of Cornelia de Lange syndrome (CDLS2; 300590), Deardorff et al. (2007) identified a 1487G-A transition in the SMC1A gene that resulted in an arg496-to-his substitution (R496H). Both had psychomotor delay and moderately severe mental retardation. One had pulmonic stenosis. Both had gastroesophageal reflux. </p><p>Revenkova et al. (2009) showed that R496H-mutant SMC1A affected the affinity of SMC hinge dimers for DNA. Mutated hinge dimers bound DNA with higher affinity than wildtype proteins. SMC1A-mutated Cornelia de Lange syndrome cell lines displayed genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</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>.0005 CORNELIA DE LANGE SYNDROME 2</strong>
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|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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SMC1A, ILE784THR
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|
<br />
|
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|
|
SNP: rs387906702,
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|
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|
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|
|
ClinVar: RCV000022820, RCV000441375, RCV000623393
|
|
|
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|
|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a 6-year-old girl with Cornelia de Lange syndrome (CDLS2; 300590), Limongelli et al. (2010) identified a de novo heterozygous 2351T-C transition in exon 15 of the SMC1A gene, resulting in an ile784-to-thr (I784T) substitution in a highly conserved residue in the coiled-coil domain. She had pre- and postnatal growth retardation, developmental delay, characteristic facial features, and concentric left ventricular hypertrophic cardiomyopathy. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0006 CORNELIA DE LANGE SYNDROME 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMC1A, 8.152-KB DEL
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<br />
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ClinVar: RCV000022821
|
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a girl with a severe form of Cornelia de Lange syndrome-2 (CDLS2; 300590), Hoppman-Chaney et al. (2012) identified a de novo heterozygous 8.152-kb deletion encompassing exon 13 to intron 16 of the SMC1A gene, resulting in an in-frame deletion of 126 amino acids and insertion of 3 novel amino acids. The mutant mRNA was expressed, and Hoppman-Chaney et al. (2012) concluded that the mutant protein lacking the coiled-coil domain would act in a dominant-negative manner. The patient had dysmorphic facial features, microcephaly, poor growth, profound psychomotor retardation, holoprosencephaly, right hemihypertrophy, and mild distal limb anomalies. The patient was also mosaic for Turner syndrom, 45,X(7)/46,XX(23), which may have accounted for some additional features. </p>
|
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</span>
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|
</div>
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<div>
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<br />
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</div>
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</div>
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|
<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITH MIDLINE BRAIN DEFECTS</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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|
SMC1A, IVS11DS, G-T, +1
|
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<br />
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|
|
SNP: rs2075687835,
|
|
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|
ClinVar: RCV001072123
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 7-year-old girl, born of unrelated Portuguese parents, with developmental and epileptic encephalopathy-85 and thin corpus callosum (DEE85; 301044), Lebrun et al. (2015) identified a de novo heterozygous G-to-T transversion (c.1911+1G-T) in intron 11 of the SMC1A gene, predicted to result in a splicing defect, frameshift, and premature termination (Thr638ValfsTer48). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Analysis of patient fibroblasts showed the presence of only the mutant transcript, which was significantly reduced compared to controls, suggesting nonsense-mediated mRNA decay and a loss of function. The patient had onset of infantile spasms associated with hypsarrhythmia on EEG within the first month of life. She also had microcephaly, dysmorphic facial features, and severe developmental delay. Brain imaging showed a thin corpus callosum. </p>
|
|
</span>
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|
</div>
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<div>
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|
<br />
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|
</div>
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|
</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITH MIDLINE BRAIN DEFECTS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMC1A, 4-BP DEL, 2853TCAG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs863225458,
|
|
|
|
|
|
|
|
ClinVar: RCV000202429, RCV000394437, RCV001072124
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4-year-old girl (patient A) with developmental and epileptic encephalopathy-85 (DEE85; 301044) with possible thickening of the insular cortex on brain imaging, Goldstein et al. (2015) identified a de novo heterozygous 4-bp deletion (c.2853_2856delTCAG, NM_006306) in exon 18 of the SMC1A gene, resulting in a frameshift and premature termination (Ser951ArgfsTer12). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. X-inactivation studies in peripheral blood cells showed a skewed pattern (93:7), although it was not clear if the mutant allele was expressed. Additional functional studies of the variant and studies of patient cells were not performed. The patient had onset of generalized tonic-clonic seizures at 4 months of age. The seizures became increasingly difficult to control, and she showed severe developmental regression and stagnation with inability to walk or speak. </p>
|
|
</span>
|
|
</div>
|
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITH MIDLINE BRAIN DEFECTS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMC1A, 4-BP DUP, 3549GGCC
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs863225459,
|
|
|
|
|
|
|
|
ClinVar: RCV000202430, RCV001072125
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-year-old girl (patient B) with developmental and epileptic encephalopathy-85 and slight thinning of the corpus callosum (DEE85; 301044), Goldstein et al. (2015) identified a de novo heterozygous 4-bp duplication (c.3549_3552dupGGCC, NM_006306) in exon 24 of the SMC1A gene, resulting in a frameshift and premature termination (Ile1185GlyfsTer23). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. X-inactivation studies in peripheral blood cells showed a random pattern. Additional functional studies of the variant and studies of patient cells were not performed. The patient had onset of tonic-clonic movements at 17 months of age following earlier global developmental delay. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITHOUT MIDLINE BRAIN DEFECTS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMC1A, 1-BP DEL, NT2364
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2075680107,
|
|
|
|
|
|
|
|
ClinVar: RCV001072126
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 46-year-old woman (patient 1) with developmental and epileptic encephalopathy-85 (DEE85; 301044) without midline brain defects, Jansen et al. (2016) identified a de novo heterozygous 1-bp deletion (c.2364del, NM_006306) in the SMC1A gene, predicted to result in a frameshift and premature termination (Asn788LysfsTer10). The mutation was found by whole-genome sequencing and was predicted to result in nonsense-mediated mRNA decay and a loss of function. X-inactivation studies showed a random pattern. Additional functional studies were not performed. The patient had severe global developmental delay and onset of intractable seizures at 9 months of age. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITHOUT MIDLINE BRAIN DEFECTS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMC1A, GLU733TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2075681060,
|
|
|
|
|
|
|
|
ClinVar: RCV001072127
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 8-year-old girl (patient 4) with developmental and epileptic encephalopathy-85 (DEE85; 301044) without midline brain defects, Symonds et al. (2017) identified a de novo heterozygous c.2197G-T transversion (c.2197G-T, NM_006306) in the SMC1A gene, predicted to result in a glu733-to-ter (E733X) substitution. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed, although X-inactivation studies showed a normal pattern. The patient had onset of focal and generalized seizures that were difficult to control at 5 months of age. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITH OR WITHOUT MIDLINE BRAIN DEFECTS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMC1A, 1-BP DEL, 2477A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2075664229,
|
|
|
|
|
|
|
|
ClinVar: RCV001072128
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters (patients 8 and 9) with developmental and epileptic encephalopathy-85 (DEE85; 301044), Symonds et al. (2017) identified a de novo heterozygous 1-bp deletion (c.2477delA, NM_006306) in the SMC1A gene, predicted to result in a frameshift and premature termination. Functional studies of the variant and studies of patient cells were not performed. One sister had normal brain imaging and was less severely affected; she had onset of seizures at about 28 months of age. The other sister showed semilobar holoprosencephaly on brain imaging. She had onset of seizures in the first month of life and died at age 11 months. These findings demonstrated phenotypic variability even within the same family. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITH MIDLINE BRAIN DEFECTS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMC1A, GLN1039TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2075591576,
|
|
|
|
|
|
|
|
ClinVar: RCV001072129
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl (patient 10) who died at age 9 years with developmental and epileptic encephalopathy-85 with abnormal corpus callosum (DEE85; 301044), Symonds et al. (2017) identified a de novo heterozygous c.3115C-T transition (c.3115C-T, NM_006306) in the SMC1A gene, predicted to result in a gln1039-to-ter (Q1039X) substitution. Functional studies of the variant and studies in patient cells were not performed, but X-inactivation studies showed a skewed ratio (76:24). The patient had onset of intractable tonic-clonic seizures at 2 months of age. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITH MIDLINE BRAIN DEFECTS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMC1A, ARG895GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2075651835,
|
|
|
|
|
|
|
|
ClinVar: RCV001072130
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-year-old girl (patient 9) with developmental and epileptic encephalopathy-85 with semilobar holoprosencephaly (DEE85; 301044), Kruszka et al. (2019) identified a de novo heterozygous c.2683C-G transversion (chrX.53,423,417G-C, GRCh37) in the SMC1A gene, resulting in an arg895-to-gly (R895G) substitution at a conserved residue in the second coiled-coil domain. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated either a loss-of-function or a dominant-negative effect. The patient had early-onset seizures. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 85 WITH MIDLINE BRAIN DEFECTS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMC1A, 1-BP DEL, 2394A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1569356555,
|
|
|
|
|
|
|
|
ClinVar: RCV001072131
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-year-old girl (patient 10) with developmental and epileptic encephalopathy-85 with semilobar holoprosencephaly (DEE85; 301044), Kruszka et al. (2019) identified a de novo heterozygous 1-bp deletion (c.2394delA; chrX.53,430,524delA) in the SMC1A gene, predicted to result in a frameshift and premature termination (Lys798AsnfsTer3). Functional studies of the variant and studies of patient cells were not performed. The patient had early-onset seizures. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
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|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Brown, C. J., Miller, A. P., Carrel, L., Rupert, J. L., Davies, K. E., Willard, H. F.
|
|
<strong>The DXS423E gene in Xp11.21 escapes X chromosome inactivation.</strong>
|
|
Hum. Molec. Genet. 4: 251-255, 1995.
|
|
|
|
|
|
[PubMed: 7757075]
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|
|
[Full Text: https://doi.org/10.1093/hmg/4.2.251]
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|
|
</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Davidson, I. F., Bauer, B., Goetz, D., Tang, W., Wutz, G., Peters, J. M.
|
|
<strong>DNA loop extrusion by human cohesin.</strong>
|
|
Science 366: 1338-1345, 2019.
|
|
|
|
|
|
[PubMed: 31753851]
|
|
|
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|
|
[Full Text: https://doi.org/10.1126/science.aaz3418]
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Deardorff, M. A., Kaur, M., Yaeger, D., Rampuria, A., Korolev, S., Pie, J., Gil-Rodriguez, C., Arnedo, M., Loeys, B., Kline, A. D., Wilson, M., Lillquist, K., Siu, V., Ramos, F. J., Musio, A., Jackson, L. S., Dorsett, D., Krantz, I. D.
|
|
<strong>Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of Cornelia de Lange syndrome with predominant mental retardation.</strong>
|
|
Am. J. Hum. Genet. 80: 485-494, 2007.
|
|
|
|
|
|
[PubMed: 17273969]
|
|
|
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|
|
[Full Text: https://doi.org/10.1086/511888]
|
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|
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|
|
</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
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Symonds, J. D., Joss, S., Metcalfe, K. A., Somarathi, S., Cruden, J., Devlin, A. M., Donaldson, A., DiDonato, N., Fitzpatrick, D., Kaiser, F. J., Lampe, A. K., Lees, M. M., and 13 others.
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