5148 lines
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- *614982 - STRUCTURAL MAINTENANCE OF CHROMOSOMES FLEXIBLE HINGE DOMAIN-CONTAINING PROTEIN 1; SMCHD1
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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">*614982</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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<li role="presentation">
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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>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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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/614982">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<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=ENSG00000101596;t=ENST00000320876" 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=23347" 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=614982" 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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<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=ENSG00000101596;t=ENST00000320876" 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_015295,XM_011525642,XM_047437425,XM_047437426,XM_047437427,XM_047437428,XM_047437429,XR_001753172,XR_007066135,XR_935055" 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_015295" 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=614982" 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://www.proteinatlas.org/search/SMCHD1" 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/3327114,5262582,10438230,34532781,50949995,148839305,187611512,440576019,767997643,2217316532,2217316534,2217316536,2217316540,2217316542,2462560058,2462560061,2462560063,2462560065,2462560069,2462560071" 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/A6NHR9" 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=23347" 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=ENSG00000101596;t=ENST00000320876" 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=SMCHD1" 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=SMCHD1" 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+23347" 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/SMCHD1" 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:23347" 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/23347" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr18&hgg_gene=ENST00000320876.11&hgg_start=2655726&hgg_end=2805017&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 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/genes/HGNC:29090" 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/smchd1" 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=614982[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=614982[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/SMCHD1/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/ENSG00000101596" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=SMCHD1" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=SMCHD1" 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=SMCHD1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SMCHD1&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/PA128395776" 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:29090" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1921605" 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/SMCHD1#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:1921605" 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/23347/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=23347" 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://zfin.org/ZDB-GENE-050211-6" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=SMCHD1&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> 720511000<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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614982
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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 FLEXIBLE HINGE DOMAIN-CONTAINING PROTEIN 1; SMCHD1
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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SMC HINGE DOMAIN-CONTAINING PROTEIN 1<br />
|
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KIAA0650
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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=SMCHD1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SMCHD1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/18/24?start=-3&limit=10&highlight=24">18p11.32</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr18:2655726-2805017&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">18:2,655,726-2,805,017</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>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</div>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
|
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Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
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<a href="/clinicalSynopsis/table?mimNumber=603457,158901" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
|
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</th>
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<th>
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Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
|
|
|
<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
|
<a href="/geneMap/18/24?start=-3&limit=10&highlight=24">
|
|
18p11.32
|
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</a>
|
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</span>
|
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</td>
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|
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<td>
|
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<span class="mim-font">
|
|
Bosma arhinia microphthalmia syndrome
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<a href="/entry/603457"> 603457 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
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Facioscapulohumeral muscular dystrophy 2, digenic
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/158901"> 158901 </a>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Digenic dominant">DD</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/614982" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/614982" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>Proteins that contain a structural maintenance of chromosomes (SMC) hinge domain, such as SMCHD1, are typically involved in DNA management. SMCHD1 plays an essential role in X chromosome inactivation (<a href="#2" class="mim-tip-reference" title="Blewitt, M. E., Gendrel, A.-V., Pang, Z., Sparrow, D. B., Whitelaw, N., Craig, J. M., Apedaile, A., Hilton, D. J., Dunwoodie, S. L., Brockdorff, N., Kay, G. F., Whitelaw, E. <strong>SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation.</strong> Nature Genet. 40: 663-669, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18425126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18425126</a>] [<a href="https://doi.org/10.1038/ng.142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18425126">Blewitt et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18425126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By sequencing clones obtained from a size-fractionated human brain cDNA library, <a href="#12" class="mim-tip-reference" title="Ishikawa, K., Nagase, T., Suyama, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong> DNA Res. 5: 169-176, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9734811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9734811</a>] [<a href="https://doi.org/10.1093/dnares/5.3.169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9734811">Ishikawa et al. (1998)</a> obtained a partial SMCHD1 clone, which they designated KIAA0650. RT-PCR analysis detected variable SMCHD1 expression in all tissues examined, with highest expression in testis, ovary, and lung. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9734811" 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="#2" class="mim-tip-reference" title="Blewitt, M. E., Gendrel, A.-V., Pang, Z., Sparrow, D. B., Whitelaw, N., Craig, J. M., Apedaile, A., Hilton, D. J., Dunwoodie, S. L., Brockdorff, N., Kay, G. F., Whitelaw, E. <strong>SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation.</strong> Nature Genet. 40: 663-669, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18425126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18425126</a>] [<a href="https://doi.org/10.1038/ng.142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18425126">Blewitt et al. (2008)</a> cloned mouse Smchd1. The deduced 2,007-amino acid protein has an N-terminal ATPase domain and a C-terminal SMC hinge domain. Database analysis revealed orthologs in amphibians, birds, and eutherian and metatherian mammals. In female mouse embryonic fibroblasts, Smchd1 localized to the inactive X chromosome (Xi). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18425126" 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 histochemical staining of mouse embryos, <a href="#9" class="mim-tip-reference" title="Gordon, C. T., Xue, S., Yigit, G., Filali, H., Chen, K., Rosin, N., Yoshiura, K., Oufadem, M., Beck, T. J., McGowan, R., Magee, A. C., Altmuller, J., and 39 others. <strong>De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.</strong> Nature Genet. 49: 249-255, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067911</a>] [<a href="https://doi.org/10.1038/ng.3765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067911">Gordon et al. (2017)</a> detected Smchd1 expression in the nasal placodes and optic vesicles at embryonic day (E) 9.5 and in the nasal epithelium at E12.5. The authors noted that in situ hybridization data indicated regional expression of Smchd1 in the nasal cavity in E14.5 mice, and that transcriptional profiling of mouse postnatal olfactory epithelium had shown that Smchd1 is specifically expressed in immature olfactory sensory neurons (<a href="#15" class="mim-tip-reference" title="Nickell, M. D., Breheny, P., Stromberg, A. J., McClintock, T. S. <strong>Genomics of mature and immature olfactory sensory neurons.</strong> J. Comp. Neurol. 520: 2608-2629, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22252456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22252456</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22252456[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/cne.23052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22252456">Nickell et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28067911+22252456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By radiation hybrid analysis, <a href="#12" class="mim-tip-reference" title="Ishikawa, K., Nagase, T., Suyama, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.</strong> DNA Res. 5: 169-176, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9734811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9734811</a>] [<a href="https://doi.org/10.1093/dnares/5.3.169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9734811">Ishikawa et al. (1998)</a> mapped the SMCHD1 gene to chromosome 18. <a href="#11" class="mim-tip-reference" title="Hartz, P. A. <strong>Personal Communication.</strong> Baltimore, Md. 12/14/2012."None>Hartz (2012)</a> mapped the SMCHD1 gene to chromosome 18p11.32 based on an alignment of the SMCHD1 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AB014550" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AB014550</a>) with the genomic sequence (GRCh37). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9734811" 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="#2" class="mim-tip-reference" title="Blewitt, M. E., Gendrel, A.-V., Pang, Z., Sparrow, D. B., Whitelaw, N., Craig, J. M., Apedaile, A., Hilton, D. J., Dunwoodie, S. L., Brockdorff, N., Kay, G. F., Whitelaw, E. <strong>SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation.</strong> Nature Genet. 40: 663-669, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18425126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18425126</a>] [<a href="https://doi.org/10.1038/ng.142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18425126">Blewitt et al. (2008)</a> mapped the mouse Smchd1 gene to chromosome 17. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18425126" 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="#7" class="mim-tip-reference" title="Gendrel, A.-V., Apedaile, A., Coker, H., Termanis, A., Zvetkova, I., Godwin, J., Tang, Y. A., Huntley, D., Montana, G., Taylor, S., Giannoulatou, E., Heard, E., Stancheva, I., Brockdorff, N. <strong>Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome.</strong> Dev. Cell 23: 265-279, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22841499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22841499</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22841499[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.devcel.2012.06.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22841499">Gendrel et al. (2012)</a> identified 3 major classes of CpG islands on Xi that showed rapid, intermediate, or slow methylation kinetics during X inactivation in mouse cells. A fourth class consisted of CpG islands on Xi for which methylation dynamics could not be assigned to any of the other classes. CpG islands with slow methylation kinetics were most common. CpG islands showing rapid or intermediate methylation kinetics had higher CpG density and GC content than those with slow methylation kinetics. Fast-methylating CpG islands were associated with fewer genes than slow-methylating CpG islands, and these genes were only weakly expressed in embryonic stem cells. Slow-methylating CpG islands were associated with low CpG density and higher levels of gene expression in embryonic stem cells than fast-methylating CpG islands. CpG islands with intermediate kinetics were located closer to the Xist locus relative to other classes. Use of knockout mouse embryonic fibroblasts revealed that Dnmt3b (<a href="/entry/602900">602900</a>), but not Dnmt3a (<a href="/entry/602769">602769</a>) or Dnmt3l (<a href="/entry/606588">606588</a>), was required for methylation of CpG islands of all classes. Smchd1 was required only for methylation of CpG islands with slow methylation kinetics. Smchd1 was not detected on Xi early during X inactivation, but was highly expressed throughout Xi late during X inactivation. Dnmt3b did not appear to be actively targeted to Xi. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22841499" 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 CRISPR-Cas technology, <a href="#23" class="mim-tip-reference" title="Wang, C.-Y., Jegu, T., Chu, H.-P., Oh, H. J., Lee, J. T. <strong>SMCHD1 merges chromosome compartments and assists formation of super-structures on the inactive X.</strong> Cell 174: 406-421, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29887375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29887375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29887375[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2018.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29887375">Wang et al. (2018)</a> generated Smchd1 -/- clones from a mouse hybrid cell line carrying 1 M. musculus X chromosome and 1 M. castaneus X chromosome. Loss of Smchd1 in mouse cells resulted in failure to silence a large subset of genes, termed 'Smchd1-sensitive genes' by the authors, on Xi. Analysis by allele-specific chromatin immunoprecipitation sequencing (ChIP-seq) showed that failure to silence Smchd1-sensitive genes correlated with an erosion of heterochromatin, indicating that Smchd1 regulates spreading of Xi heterochromatin. Loss of Smchd1 also resulted in regional defects in Xist RNA spreading. In situ high-throughput chromosome conformation capture revealed that the Xi in Smchd1 -/- cells contained unique new compartments, termed S1 and S2 compartments, that were different from the A and B compartments found on the active X chromosome (Xa). Characterization of these new compartments confirmed that Smchd1 played a critical role in organizing Xi structures by merging chromatin compartments. Xi in wildtype mouse cells contained weak but clearly discernible topologically associated domains (TADs) across the entire Xi. Depletion of Smchd1 led to Xi-specific strengthening of TADs, showing that Smchd1 controls TAD strength in an Xi-specific manner. Allele-specific ChIP-seq further demonstrated that Smchd1 suppressed binding of architectural factors to the Xi on a pan-Xi scale, as Ctcf (<a href="/entry/604167">604167</a>) and Rad21 (<a href="/entry/606462">606462</a>) exhibited increased binding to the Xi in Smchd1 -/- cells. Examination of Smchd1 genomic binding sites showed that Smchd1 was enriched in both gene-rich and gene-poor regions on Xi and bridged the S1 and S2 compartments. Further investigation demonstrated that S1 and S2 compartments occurred naturally, but only transiently, during de novo inactivation of the X chromosome before Smchd1 bound and facilitated Xist spreading in wildtype mouse cells. Upon recruitment of Smchd1, S1 and S2 compartments were merged by Smchd1 to create a compartmentless Xi, explaining why deletion of Smchd1 in mouse cells resulted in persistent S1 and S2 compartments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29887375" 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>Facioscapulohumeral Muscular Dystrophy 2</em></strong></p><p>
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In affected members of 15 (79%) of 19 families with facioscapulohumeral muscular dystrophy-2 (FSHD2; <a href="/entry/158901">158901</a>), <a href="#13" class="mim-tip-reference" title="Lemmers, R. J. L. F., Tawil, R., Petek, L. M., Balog, J., Block, G. J., Santen, G. W. E., Amell, A. M., van der Vliet, P. J., Almomani, R., Straasheijm, K. R., Krom, Y. D., Klooster, R., and 18 others. <strong>Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.</strong> Nature Genet. 44: 1370-1374, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23143600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23143600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23143600[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/ng.2454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23143600">Lemmers et al. (2012)</a> identified heterozygous loss-of-function mutations in the SMCHD1 gene (see, e.g., <a href="#0001">614982.0001</a>-<a href="#0005">614982.0005</a>). The mutations in 7 families were initially identified by exome sequencing and confirmed by Sanger sequencing. The mutational spectrum included small deletions, splice site mutations, and missense mutations, resulting in haploinsufficiency. Patients showed D4Z4 (see <a href="/entry/606009">606009</a>) hypomethylation to levels less than 25% (normal being about 50%), and protein blot analysis in several patients showed decreased SMCHD1 protein in fibroblasts. Affected individuals were also heterozygous or homozygous for an FSHD1 (<a href="/entry/158900">158900</a>)-permissive D4Z4 haplotype that contains a polyadenylation signal to stabilize DUX4 (<a href="/entry/606009">606009</a>) mRNA in skeletal muscle. Primary myotubes from a normal individual with a normal-sized and methylated D4Z4 array on a permissive haplotype showed no DUX4 mRNA. However, decreasing SMCHD1 expression to about 50% using RNA interference resulted in transcriptional activation of DUX4 and a variegated pattern of DUX4 protein expression in the myotubes. The pattern of variegated DUX4 expression that resulted was similar to that observed in FSHD1 and FSHD2 myotube cultures. The findings indicated that SMCHD1 activity is necessary for D4Z4 hypermethylation and somatic repression of DUX4, and that reduction of SMCHD1 results in D4Z4 arrays that express DUX4 when a permissive haplotype is present. The SMCHD1 mutation and the permissive D4Z4 haplotype segregated independently in the families, indicating digenic inheritance. Of the 26 individuals with hypomethylation at D4Z4, a SMCHD1 mutation, and a permissive D4Z4 haplotype, 5 (19%) were asymptomatic, indicating incomplete penetrance. <a href="#13" class="mim-tip-reference" title="Lemmers, R. J. L. F., Tawil, R., Petek, L. M., Balog, J., Block, G. J., Santen, G. W. E., Amell, A. M., van der Vliet, P. J., Almomani, R., Straasheijm, K. R., Krom, Y. D., Klooster, R., and 18 others. <strong>Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.</strong> Nature Genet. 44: 1370-1374, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23143600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23143600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23143600[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/ng.2454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23143600">Lemmers et al. (2012)</a> suggested that SMCHD1 mutations may modify the epigenetic repression of other genomic regions and the penetrance of other human diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23143600" 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="#18" class="mim-tip-reference" title="Sacconi, S., Lemmers, R. J. L. F., Balog, J., van der Vliet, P. J., Lahaut, P., van Nieuwenhuizen, M. P., Straasheijm, K. R., Debipersad, R. D., Vos-Versteeg, M., Salviati, L., Casarin, A., Pegoraro, E., Tawil, R., Bakker, E., Tapscott, S. J., Desnuelle, C., van der Maarel, S. M. <strong>The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1.</strong> Am. J. Hum. Genet. 93: 744-751, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24075187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24075187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24075187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.08.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24075187">Sacconi et al. (2013)</a> found that mutation in the SMCHD1 gene is a modifier of disease severity in families affected by FSHD1. Three unrelated families with intrafamilial clinical variability of the disorder were studied. In 1 family, a mildly affected man with FSHD1 carried a 9-unit D4Z4 repeat on a 4A allele with no SMCHD1 mutations, whereas his mildly affected wife carried a SMCHD1 mutation (T527M; <a href="#0006">614982.0006</a>) on a normal-sized 4A allele, consistent with FSHD2. Their more severely affected son and grandson each carried the 9-unit D4Z4 repeat on a 4A allele as well as the T527M SMCHD1 mutation, consistent with having both FSHD1 and FSHD2. In a second family, a man with a severe early-onset phenotype had both a 9-unit D4Z4 repeat on a 4A permissive allele and a mutation in the SMCHD1 gene. Each of his children, who had milder symptoms, inherited 1 of the genetic defects. In a third family, a man with a severe phenotype was also found to carry a 9-unit D4Z4 repeat on a 4A permissive allele with a SMCHD1 mutation. No information from his parents was available. Transduction of SMCHD1 shRNA into FSHD1 myotubes caused increased levels of DUX4 mRNA as well as transcriptional activation of known DUX4 target genes. These findings were consistent with further chromatin relaxation of the contracted FSHD1 repeat upon knockdown of SMCHD1. <a href="#18" class="mim-tip-reference" title="Sacconi, S., Lemmers, R. J. L. F., Balog, J., van der Vliet, P. J., Lahaut, P., van Nieuwenhuizen, M. P., Straasheijm, K. R., Debipersad, R. D., Vos-Versteeg, M., Salviati, L., Casarin, A., Pegoraro, E., Tawil, R., Bakker, E., Tapscott, S. J., Desnuelle, C., van der Maarel, S. M. <strong>The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1.</strong> Am. J. Hum. Genet. 93: 744-751, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24075187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24075187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24075187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.08.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24075187">Sacconi et al. (2013)</a> concluded that FSHD1 and FSHD2 share a common pathophysiologic pathway converging on transcriptional derepression of DUX4 in skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24075187" 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="#20" class="mim-tip-reference" title="Strafella, C., Caputo, V., Galota, R. M., Campoli, G., Bax, C., Colantoni, L., Minozzi, G., Orsini, C., Politano, L., Tasca, G., Novelli, G., Ricci, E., Giardina, E., Cascella, R. <strong>The variability of SMCHD1 gene in FSHD patients: evidence of new mutations.</strong> Hum. Molec. Genet. 28: 3912-3920, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31600781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31600781</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31600781[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/ddz239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31600781">Strafella et al. (2019)</a> performed next-generation sequencing of the SMCHD1 gene in a cohort of patients with FSHD and identified 7 heterozygous pathogenic/likely pathogenic variants (see, e.g., <a href="#0016">614982.0016</a>-<a href="#0019">614982.0019</a>) in 7 patients; 5 of the patients had a borderline D4Z4 fragment size (8-10 repeats) and 2 had a normal D4Z4 fragment size (more than 11 repeats). All 7 mutations were predicted to affect protein structure and conformation, resulting in loss of the GHKL-ATPase domain and/or the SMC hinge domain. <a href="#20" class="mim-tip-reference" title="Strafella, C., Caputo, V., Galota, R. M., Campoli, G., Bax, C., Colantoni, L., Minozzi, G., Orsini, C., Politano, L., Tasca, G., Novelli, G., Ricci, E., Giardina, E., Cascella, R. <strong>The variability of SMCHD1 gene in FSHD patients: evidence of new mutations.</strong> Hum. Molec. Genet. 28: 3912-3920, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31600781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31600781</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31600781[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/ddz239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31600781">Strafella et al. (2019)</a> concluded that borderline D4Z4 size may be a risk factor or pathogenic modifier in patients with SMCHD1 mutations. <a href="#20" class="mim-tip-reference" title="Strafella, C., Caputo, V., Galota, R. M., Campoli, G., Bax, C., Colantoni, L., Minozzi, G., Orsini, C., Politano, L., Tasca, G., Novelli, G., Ricci, E., Giardina, E., Cascella, R. <strong>The variability of SMCHD1 gene in FSHD patients: evidence of new mutations.</strong> Hum. Molec. Genet. 28: 3912-3920, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31600781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31600781</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31600781[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/ddz239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31600781">Strafella et al. (2019)</a> also identified 5 variants in the 3-prime UTR of the SMCHD1 gene, which were predicted to disrupt an existing miRNA binding site or to create a novel binding site for different miRNAs, suggesting a potential miRNA-dependent regulatory effect on associated pathways associated with FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31600781" 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>Bosma Arhinia Microphthalmia Syndrome</em></strong></p><p>
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By whole-genome, whole-exome, and targeted sequencing in 38 probands with Bosma arhinia microphthalmia syndrome (BAMS; <a href="/entry/603457">603457</a>), <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a> identified heterozygous missense mutations in the SMCHD1 gene in 32 (84%) of the probands (see, e.g., <a href="#0007">614982.0007</a>-<a href="#0015">614982.0015</a>). The mutations all occurred within exons 3 to 13, spanning a GHKL-type ATPase domain. Experiments in zebrafish embryos suggested that the likely mode of action of the arhinia-associated alleles is loss of function. The authors observed largely identical methylation patterning at D4Z4 in arhinia and FSHD2 patients, and concluded that 2 completely distinct phenotypes can arise from deleterious changes in the same gene and even the same alleles. Noting the marked intrafamilial and interfamilial phenotypic variability in SMCHD1-mutated BAMS families, <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a> suggested that BAMS-associated SMCHD1 variants are not fully penetrant and that such variants alone may not be sufficient to cause arhinia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28067909" 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>Simultaneously and independently, <a href="#9" class="mim-tip-reference" title="Gordon, C. T., Xue, S., Yigit, G., Filali, H., Chen, K., Rosin, N., Yoshiura, K., Oufadem, M., Beck, T. J., McGowan, R., Magee, A. C., Altmuller, J., and 39 others. <strong>De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.</strong> Nature Genet. 49: 249-255, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067911</a>] [<a href="https://doi.org/10.1038/ng.3765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067911">Gordon et al. (2017)</a> performed whole-exome and/or Sanger sequencing in 14 probands with arhinia, 6 of whom were also studied by <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a>. They identified mutations in the SMCHD1 gene in all 14 probands (see, e.g., <a href="#0008">614982.0008</a>, <a href="#0013">614982.0013</a>, and <a href="#0014">614982.0014</a>). The mutations were shown to have occurred de novo in the 11 families for which DNA was available from the parents; all of the mutations occurred at highly conserved residues within the ATPase domain, and none was found in public variant databases. <a href="#9" class="mim-tip-reference" title="Gordon, C. T., Xue, S., Yigit, G., Filali, H., Chen, K., Rosin, N., Yoshiura, K., Oufadem, M., Beck, T. J., McGowan, R., Magee, A. C., Altmuller, J., and 39 others. <strong>De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.</strong> Nature Genet. 49: 249-255, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067911</a>] [<a href="https://doi.org/10.1038/ng.3765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067911">Gordon et al. (2017)</a> noted that 6 of the 14 patients had mutations involving 3 adjacent amino acids (A134, S135, and E136; see, e.g., <a href="#0013">614982.0013</a>-<a href="#0015">614982.0015</a>), and that 2 other mutations, H348R (<a href="#0008">614982.0008</a>) and D420V were identified in 3 and 2 probands each, suggesting possible mutation hotspots. Analysis of patient methylation status showed a trend for hypomethylation compared to controls or unaffected family members; however, some patients with BAMS were normally methylated. In contrast to FSHD2-associated loss-of-function mutations (see <a href="#0006">614982.0006</a>), functional analysis of ATPase activity showed increased protein hydrolysis of ATP by 3 of the BAMS-associated mutants tested compared to wildtype SMCHD1 (see <a href="#0013">614982.0013</a>), and 1 BAMS variant showed unchanged ATPase activity. In addition, overexpression of BAMS-associated mutant SMCHD1 in Xenopus embryos resulted in tadpoles with noticeable craniofacial anomalies, including microphthalmia or anophthalmia, and eye diameters at 4 days postfertilization were significantly smaller in those embryos than in embryos with overexpression of wildtype SMCHD1 or an FSHD2-associated mutant. <a href="#9" class="mim-tip-reference" title="Gordon, C. T., Xue, S., Yigit, G., Filali, H., Chen, K., Rosin, N., Yoshiura, K., Oufadem, M., Beck, T. J., McGowan, R., Magee, A. C., Altmuller, J., and 39 others. <strong>De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.</strong> Nature Genet. 49: 249-255, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067911</a>] [<a href="https://doi.org/10.1038/ng.3765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067911">Gordon et al. (2017)</a> concluded that BAMS-associated missense mutations might exhibit gain-of-function or neomorphic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28067909+28067911" 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 an N-ethyl-N-nitrosourea mutagenesis screen, <a href="#2" class="mim-tip-reference" title="Blewitt, M. E., Gendrel, A.-V., Pang, Z., Sparrow, D. B., Whitelaw, N., Craig, J. M., Apedaile, A., Hilton, D. J., Dunwoodie, S. L., Brockdorff, N., Kay, G. F., Whitelaw, E. <strong>SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation.</strong> Nature Genet. 40: 663-669, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18425126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18425126</a>] [<a href="https://doi.org/10.1038/ng.142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18425126">Blewitt et al. (2008)</a> identified the modifier of murine metastable epialleles (MommeD1) mutation. Homozygosity for MommeD1 resulted in female-specific midgestation lethality and hypomethylation of the X-linked Hprt1 gene (<a href="/entry/308000">308000</a>) CpG island, suggesting a defect in X inactivation. <a href="#2" class="mim-tip-reference" title="Blewitt, M. E., Gendrel, A.-V., Pang, Z., Sparrow, D. B., Whitelaw, N., Craig, J. M., Apedaile, A., Hilton, D. J., Dunwoodie, S. L., Brockdorff, N., Kay, G. F., Whitelaw, E. <strong>SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation.</strong> Nature Genet. 40: 663-669, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18425126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18425126</a>] [<a href="https://doi.org/10.1038/ng.142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18425126">Blewitt et al. (2008)</a> found that the MommeD1 mutation resulted in a nonsense codon in exon 23 of the 48-exon Smchd1 gene. Homozygous mutant female embryos, but not male embryos, showed placental defects, with smaller trophoblast giant cell layer and smaller trophoblast giant cell nuclei. MommeD1 heterozygous female embryos showed delayed methylation at CpG islands, with normal methylation levels achieved by embryonic day 10.5. Smchd1 was not required for initial Xist expression, but it was required for subsequent DNA methylation and gene silencing on Xi. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18425126" 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 facial cartilage patterning in zebrafish as a surrogate structure homologous to the human nose, <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a> generated Smchd1-knockdown morphant zebrafish models and observed that all morphants exhibited narrowing of the ethmoid plate and an increase in the ceratohyal arch angle, both of which were dose-dependent phenomena, as well as delayed or absent development of ceratobranchial arches and microphthalmia. Ventral imaging revealed that morphant olfactory bulbs and hypothalami were intact, but the average projection length of the terminal nerve, where GnRH3 neurons reside, was reduced by 45% compared to controls. The cartilage, eye, and GnRH phenotypes were rescued by wildtype human SMCHD1 mRNA. CRISPR/Cas9-mediated genome editing recapitulated the craniofacial, ocular, and GnRH defects observed in the morphant models. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28067909" 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=614982[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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<p>In a woman with facioscapulohumeral muscular dystrophy-2 (FSHD2; <a href="/entry/158901">158901</a>), <a href="#13" class="mim-tip-reference" title="Lemmers, R. J. L. F., Tawil, R., Petek, L. M., Balog, J., Block, G. J., Santen, G. W. E., Amell, A. M., van der Vliet, P. J., Almomani, R., Straasheijm, K. R., Krom, Y. D., Klooster, R., and 18 others. <strong>Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.</strong> Nature Genet. 44: 1370-1374, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23143600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23143600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23143600[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/ng.2454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23143600">Lemmers et al. (2012)</a> identified a heterozygous 5-bp deletion in exon 10 of the SMCHD1 gene (1302_1306del), resulting in a frameshift and premature termination (Y434X). The patient was also heterozygous for a permissive D4Z4 (see <a href="/entry/606009">606009</a>) haplotype; D4Z4 methylation was decreased to 25% (normal is about 50%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23143600" 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 patient with FSHD2 (<a href="/entry/158901">158901</a>), <a href="#13" class="mim-tip-reference" title="Lemmers, R. J. L. F., Tawil, R., Petek, L. M., Balog, J., Block, G. J., Santen, G. W. E., Amell, A. M., van der Vliet, P. J., Almomani, R., Straasheijm, K. R., Krom, Y. D., Klooster, R., and 18 others. <strong>Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.</strong> Nature Genet. 44: 1370-1374, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23143600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23143600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23143600[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/ng.2454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23143600">Lemmers et al. (2012)</a> identified a heterozygous 2068C-T transition in exon 16 of the SMCHD1 gene, resulting in a pro690-to-ser (P690S) substitution. The patient was also heterozygous for a permissive D4Z4 (see <a href="/entry/606009">606009</a>) haplotype; D4Z4 methylation was decreased to 7%. The P690S mutation was inherited from the unaffected mother, who also had hypomethylation of D4Z4 (10%), but did not carry a permissive D4Z4 haplotype. The D4Z4 permissive haplotype was inherited from the unaffected father, who had normal D4Z4 methylation at 43%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23143600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 affected members of a 3-generation family with FSHD2 (<a href="/entry/158901">158901</a>), <a href="#13" class="mim-tip-reference" title="Lemmers, R. J. L. F., Tawil, R., Petek, L. M., Balog, J., Block, G. J., Santen, G. W. E., Amell, A. M., van der Vliet, P. J., Almomani, R., Straasheijm, K. R., Krom, Y. D., Klooster, R., and 18 others. <strong>Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.</strong> Nature Genet. 44: 1370-1374, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23143600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23143600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23143600[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/ng.2454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23143600">Lemmers et al. (2012)</a> identified a heterozygous 1-bp deletion in exon 12 of the SMCHD1 gene, resulting in a frameshift and premature termination (Asp537IleIfsTer10). One affected individual was heterozygous for a permissive D4Z4 (see <a href="/entry/606009">606009</a>) haplotype, whereas the other was homozygous for a D4Z4 permissive haplotype; D4Z4 methylation was decreased to 18 to 20% in the patients. The SMCHD1 mutation segregated with hypomethylation of D4Z4 in the family, and the D4Z4 permissive haplotype segregated independently. However, there were 4 apparently unaffected individuals with the SMCHD1 mutation, hypomethylation (11%), and a D4Z4 permissive haplotype, indicating incomplete penetrance. Western blot analysis of fibroblasts from 1 patient and 1 carrier showed decreased SMCHD1 levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23143600" 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 affected members of 2 families with FSHD2 (<a href="/entry/158901">158901</a>), <a href="#13" class="mim-tip-reference" title="Lemmers, R. J. L. F., Tawil, R., Petek, L. M., Balog, J., Block, G. J., Santen, G. W. E., Amell, A. M., van der Vliet, P. J., Almomani, R., Straasheijm, K. R., Krom, Y. D., Klooster, R., and 18 others. <strong>Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.</strong> Nature Genet. 44: 1370-1374, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23143600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23143600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23143600[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/ng.2454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23143600">Lemmers et al. (2012)</a> identified a heterozygous G-to-A transition in intron 29 of the SMCHD1 gene (3801+1G-A), resulting in a splice site mutation. All patients were also either homozygous or heterozygous for a permissive D4Z4 (see <a href="/entry/606009">606009</a>) haplotype. D4Z4 methylation in all patients was decreased to 5 to 16%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23143600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC</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">rs1598416221 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1598416221;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=rs1598416221" 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=rs1598416221" 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=RCV000033086 OR RCV003137554" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033086, RCV003137554" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033086...</a>
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<p>In 4 affected members of 2 families with FSHD2 (<a href="/entry/158901">158901</a>), <a href="#13" class="mim-tip-reference" title="Lemmers, R. J. L. F., Tawil, R., Petek, L. M., Balog, J., Block, G. J., Santen, G. W. E., Amell, A. M., van der Vliet, P. J., Almomani, R., Straasheijm, K. R., Krom, Y. D., Klooster, R., and 18 others. <strong>Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.</strong> Nature Genet. 44: 1370-1374, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23143600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23143600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23143600[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/ng.2454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23143600">Lemmers et al. (2012)</a> identified a heterozygous 4566G-A transition in exon 36 of the SMCHD1 gene, predicted to result in a synonymous thr1522-to-thr (T1522T) substitution. However, the mutation was demonstrated to cause aberrant splicing with the skipping of exon 36. Three affected individuals were also homozygous for a permissive D4Z4 (see <a href="/entry/606009">606009</a>) haplotype; the fourth was heterozygous for a permissive D4Z4 haplotype. D4Z4 methylation in all patients was decreased to 13 to 23%. Western blot analysis of fibroblasts from 2 patients showed decreased SMCHD1 levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23143600" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC</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">rs397518422 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397518422;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=rs397518422" 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=rs397518422" 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=RCV000074384" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074384" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074384</a>
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<p>In a 3-generation family with FSHD2 (<a href="/entry/158901">158901</a>), <a href="#18" class="mim-tip-reference" title="Sacconi, S., Lemmers, R. J. L. F., Balog, J., van der Vliet, P. J., Lahaut, P., van Nieuwenhuizen, M. P., Straasheijm, K. R., Debipersad, R. D., Vos-Versteeg, M., Salviati, L., Casarin, A., Pegoraro, E., Tawil, R., Bakker, E., Tapscott, S. J., Desnuelle, C., van der Maarel, S. M. <strong>The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1.</strong> Am. J. Hum. Genet. 93: 744-751, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24075187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24075187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24075187[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.08.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24075187">Sacconi et al. (2013)</a> identified a heterozygous c.1580C-T transition in exon 12 of the SMCHD1 gene, resulting in a thr527-to-met (T527M) substitution at a highly conserved residue. The mutation was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in in-house databases. The grandmother, who had a relatively mild phenotype, carried the T527M mutation on a normal-sized 4A D4Z4 allele (see <a href="/entry/609009">609009</a>). Her son and grandson, who had earlier onset and a more severe phenotype, each carried both the T527M mutation as well as a contracted 9-unit D4Z4 allele on a permissive 4A haplotype, consistent with a diagnosis of both FSHD2 and FSHD1 (<a href="/entry/158900">158900</a>). The findings indicated that a SMCHD1 mutation and a D4Z4 contraction can act synergistically to cause additional derepression of the DUX4 gene and a more severe phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24075187" 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="#9" class="mim-tip-reference" title="Gordon, C. T., Xue, S., Yigit, G., Filali, H., Chen, K., Rosin, N., Yoshiura, K., Oufadem, M., Beck, T. J., McGowan, R., Magee, A. C., Altmuller, J., and 39 others. <strong>De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.</strong> Nature Genet. 49: 249-255, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067911</a>] [<a href="https://doi.org/10.1038/ng.3765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067911">Gordon et al. (2017)</a> analyzed the effects on ATPase activity of SMCHD1 variants and observed slightly decreased protein hydrolysis of ATP by the T527M mutant compared to wildtype SMCHD1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28067911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 BOSMA ARHINIA MICROPHTHALMIA SYNDROME</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">rs1057519639 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519639;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=rs1057519639" 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=rs1057519639" 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=RCV000417316 OR RCV000497013 OR RCV002521501" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000417316, RCV000497013, RCV002521501" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000417316...</a>
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<p>In 2 sisters from a 3-generation German family (family O) with Bosma arhinia microphthalmia syndrome (BAMS; <a href="/entry/603457">603457</a>), originally reported by <a href="#21" class="mim-tip-reference" title="Thiele, H., Musil, A., Nagel, F., Majewski, F. <strong>Familial arhinia, choanal atresia, and microphthalmia</strong> Am. J. Med. Genet. 63: 310-313, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8723126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8723126</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19960503)63:1<310::AID-AJMG51>3.0.CO;2-N" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8723126">Thiele et al. (1996)</a>, <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a> identified heterozygosity for a c.1034A-G transition (c.1034A-G, ENST00000320876.10) in exon 8 of the SMCHD1 gene, resulting in a gln345-to-arg (Q345R) substitution at a conserved residue within the GHKL-type ATPase domain. Their mother, who exhibited abnormal dentition, asymmetric nares, and anosmia, was also heterozygous for the mutation, as was their maternal grandmother, who showed only abnormal dentition and asymmetric nares. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8723126+28067909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 BOSMA ARHINIA MICROPHTHALMIA SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1057519640 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519640;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1057519640?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1057519640" 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=rs1057519640" 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=RCV000417236" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000417236" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000417236</a>
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<p>In 7 sporadic patients with Bosma arhinia microphthalmia syndrome (BAMS; <a href="/entry/603457">603457</a>), including a Norwegian girl (patient L1) originally reported by <a href="#16" class="mim-tip-reference" title="Olsen, O. E., Gjelland, K., Reigstad, H., Rosendahl, K. <strong>Congenital absence of the nose: a case report and literature review.</strong> Pediat. Radiol. 31: 225-232, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11321738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11321738</a>] [<a href="https://doi.org/10.1007/s002470000419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11321738">Olsen et al. (2001)</a>, a Caucasian man (patient F1) previously reported by <a href="#10" class="mim-tip-reference" title="Graham, J. M., Jr., Lee, J. <strong>Bosma arhinia microphthalmia syndrome.</strong> Am. J. Med. Genet. 140A: 189-193, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16353241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16353241</a>] [<a href="https://doi.org/10.1002/ajmg.a.31039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16353241">Graham and Lee (2006)</a> as 'patient 1,' and a Mexican boy (patient Z1) described by <a href="#1" class="mim-tip-reference" title="Becerra-Solano, L. E., Chacon, L., Morales-Mata, D., Zenteno, J. C., Ramirez-Duenas, M. L., Garcia-Ortiz, J. E. <strong>Bosma arrhinia microphthalmia syndrome in a Mexican patient with a molecular analysis of PAX6.</strong> Clin. Dysmorph. 25: 12-15, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26440771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26440771</a>] [<a href="https://doi.org/10.1097/MCD.0000000000000101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26440771">Becerra-Solano et al. (2016)</a>, <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a> identified heterozygosity for a c.1043A-G transition (c.1043A-G, ENST00000320876.10) in exon 9 of the SMCHD1 gene, resulting in a his348-to-arg (H348R) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation segregated with disease in the 4 families for which DNA was available from other family members, and it was shown to have arisen de novo in the probands from 3 of those families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28067909+16353241+26440771+11321738" 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="#9" class="mim-tip-reference" title="Gordon, C. T., Xue, S., Yigit, G., Filali, H., Chen, K., Rosin, N., Yoshiura, K., Oufadem, M., Beck, T. J., McGowan, R., Magee, A. C., Altmuller, J., and 39 others. <strong>De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.</strong> Nature Genet. 49: 249-255, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067911</a>] [<a href="https://doi.org/10.1038/ng.3765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067911">Gordon et al. (2017)</a> independently studied 2 of the patients reported by <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a>, the Norwegian girl (patient L1) and a Chinese boy (patient N1), as well as an affected Ukrainian girl, and identified the H348R mutation in all 3 patients; analysis of parental DNA in the Chinese family demonstrated that the mutation arose de novo in the proband. <a href="#9" class="mim-tip-reference" title="Gordon, C. T., Xue, S., Yigit, G., Filali, H., Chen, K., Rosin, N., Yoshiura, K., Oufadem, M., Beck, T. J., McGowan, R., Magee, A. C., Altmuller, J., and 39 others. <strong>De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.</strong> Nature Genet. 49: 249-255, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067911</a>] [<a href="https://doi.org/10.1038/ng.3765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067911">Gordon et al. (2017)</a> noted that the H348R variant was not found in the ExAC, Exome Variant Server, or dbSNP (build 144) databases. Overexpression of the H348R mutant in Xenopus embryos resulted in significantly smaller eye diameter than overexpression of wildtype SMCHD1 or an FSHD2-associated mutant. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28067909+28067911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1057519641 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519641;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1057519641?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1057519641" 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=rs1057519641" 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=RCV000417278" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000417278" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000417278</a>
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<p>In 4 unrelated probands with Bosma arhinia microphthalmia syndrome (BAMS; <a href="/entry/603457">603457</a>), including a patient (patient E1) originally reported by <a href="#8" class="mim-tip-reference" title="Gifford, G. H., Jr., Swanson, L., MacCollum, D. W. <strong>Congenital absence of the nose and anterior nasopharynx: report of two cases.</strong> Plast. Reconst. Surg. 50: 5-12, 1972.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5032329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5032329</a>] [<a href="https://doi.org/10.1097/00006534-197207000-00002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5032329">Gifford et al. (1972)</a> and also studied by <a href="#3" class="mim-tip-reference" title="Bosma, J. F., Henkin, R. I., Christiansen, R. L., Herdt, J. R. <strong>Hypoplasia of the nose and eyes, hyposmia, hypogeusia, and hypogonadotropic hypogonadism in two males.</strong> J. Craniofac. Genet. Dev. Biol. 1: 153-184, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6802865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6802865</a>]" pmid="6802865">Bosma et al. (1981)</a>, and another patient (patient C1) previously described by <a href="#22" class="mim-tip-reference" title="Tryggestad, J. B., Li, S., Chernausek, S. D. <strong>Hypogonadotropic hypogonadism presenting with arhinia: a case report.</strong> J. Med. Case Rep. 7: 52, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23432817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23432817</a>] [<a href="https://doi.org/10.1186/1752-1947-7-52" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23432817">Tryggestad et al. (2013)</a>, <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a> identified heterozygosity for a c.423G-C transversion (c.423G-C, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a leu141-to-phe (L141F) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation segregated with disease in the 2 families for which DNA was available from other family members, and was shown to have arisen de novo in a Swiss boy (patient V1). The authors noted that 1 of the patients (C1) did not exhibit the complete 'Bosma triad,' since he had arhinia and hypogonadism, but not microphthalmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5032329+6802865+28067909+23432817" 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">rs1057519642 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519642;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=rs1057519642" 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=rs1057519642" 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=RCV000417324 OR RCV000497004 OR RCV000497016" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000417324, RCV000497004, RCV000497016" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000417324...</a>
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<p>In an 11-year-old Caucasian Hispanic girl (patient AH1) with Bosma arhinia microphthalmia syndrome (BAMS; <a href="/entry/603457">603457</a>), <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a> identified heterozygosity for a c.1199A-T transversion (c.1199A-T, ENST00000320876.10) in exon 10 of the SMCHD1 gene, resulting in a gln400-to-leu (Q400L) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation was also present in the proband's half sister, who had a hypoplastic nose, and in their father, who exhibited only anosmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28067909" 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">rs1057519643 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519643;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=rs1057519643" 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=rs1057519643" 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=RCV000417233 OR RCV000497012" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000417233, RCV000497012" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000417233...</a>
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<p>In a 46-year-old Caucasian man (patient T1) with Bosma arhinia microphthalmia syndrome (BAMS; <a href="/entry/603457">603457</a>), originally reported by <a href="#4" class="mim-tip-reference" title="Brasseur, B., Martin, C. M., Cayci, Z., Burmeister, L., Schimmenti, L. A. <strong>Bosma arhinia microphthalmia syndrome: clinical report and review of the literature.</strong> Am. J. Med. Genet. 170A: 1302-1307, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26842768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26842768</a>] [<a href="https://doi.org/10.1002/ajmg.a.37572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26842768">Brasseur et al. (2016)</a>, <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a> identified heterozygosity for a c.408A-C transversion (c.408A-C, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a glu136-to-asp (E136D) substitution at a highly conserved residue within the GHKL-type ATPase domain. The proband's father, who had been diagnosed with limb/girdle muscular dystrophy but exhibited no apparent facial dysmorphism and had no history of vision abnormalities or anosmia, was also heterozygous for the mutation, which was not found in the proband's unaffected mother. DNA was unavailable for the paternal grandmother and great-aunt, who were reported to have colobomata, or a paternal great-uncle, who was born blind. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26842768+28067909" 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 BOSMA ARHINIA MICROPHTHALMIA SYNDROME</strong>
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FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC, INCLUDED
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000417296 OR RCV000417337" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000417296, RCV000417337" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000417296...</a>
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<p>In a 17-year-old African American girl (patient AG1) with Bosma arhinia microphthalmia syndrome (BAMS; <a href="/entry/603457">603457</a>), <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a> identified heterozygosity for a c.410G-A transition (c.410G-A, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a gly137-to-glu (G137E) substitution at a highly conserved residue within the GHKL-type ATPase domain. <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a> noted that the G137E mutation had previously been reported in a patient with facioscapulohumeral muscular dystrophy-2 (FSHD2; <a href="/entry/158901">158901</a>) by <a href="#13" class="mim-tip-reference" title="Lemmers, R. J. L. F., Tawil, R., Petek, L. M., Balog, J., Block, G. J., Santen, G. W. E., Amell, A. M., van der Vliet, P. J., Almomani, R., Straasheijm, K. R., Krom, Y. D., Klooster, R., and 18 others. <strong>Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.</strong> Nature Genet. 44: 1370-1374, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23143600/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23143600</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23143600[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/ng.2454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23143600">Lemmers et al. (2012)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28067909+23143600" 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">rs1057519645 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519645;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=rs1057519645" 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=rs1057519645" 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 28-year-old German woman (patient M1) and a 3-year-old Irish girl (patient AF1) with Bosma arhinia microphthalmia syndrome (BAMS; <a href="/entry/603457">603457</a>), originally reported by <a href="#14" class="mim-tip-reference" title="Muhlbauer, W., Schmidt, A., Fairley, J. <strong>Simultaneous construction of an internal and external nose in an infant with arhinia.</strong> Plast. Reconstr. Surg. 91: 720-725, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8446727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8446727</a>] [<a href="https://doi.org/10.1097/00006534-199304000-00027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8446727">Muhlbauer et al. (1993)</a> and <a href="#6" class="mim-tip-reference" title="Courtney, J., Mccabe, J., Craig, S. <strong>Congenital arhinia.</strong> Arch. Dis. Child. Fetal Neonatal Ed. 99: F75 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23852095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23852095</a>] [<a href="https://doi.org/10.1136/archdischild-2013-304412" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23852095">Courtney et al. (2014)</a>, respectively, <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a> and <a href="#9" class="mim-tip-reference" title="Gordon, C. T., Xue, S., Yigit, G., Filali, H., Chen, K., Rosin, N., Yoshiura, K., Oufadem, M., Beck, T. J., McGowan, R., Magee, A. C., Altmuller, J., and 39 others. <strong>De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.</strong> Nature Genet. 49: 249-255, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067911</a>] [<a href="https://doi.org/10.1038/ng.3765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067911">Gordon et al. (2017)</a> independently identified heterozygosity for a c.403A-T transversion (c.403A-T, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a ser135-to-cys (S135C) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation was not found in the unaffected parents from either family, indicating that it arose de novo in both probands; <a href="#9" class="mim-tip-reference" title="Gordon, C. T., Xue, S., Yigit, G., Filali, H., Chen, K., Rosin, N., Yoshiura, K., Oufadem, M., Beck, T. J., McGowan, R., Magee, A. C., Altmuller, J., and 39 others. <strong>De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.</strong> Nature Genet. 49: 249-255, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067911</a>] [<a href="https://doi.org/10.1038/ng.3765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067911">Gordon et al. (2017)</a> stated that the variant was not found in the ExAC, Exome Variant Server, or dbSNP (build 144) databases. Fibroblasts from patient M1 showed no defects in the DNA damage response or impaired nonhomologous end joining. ATPase assays demonstrated increased protein hydrolysis of ATP with the S135C mutant compared to wildtype. <a href="#9" class="mim-tip-reference" title="Gordon, C. T., Xue, S., Yigit, G., Filali, H., Chen, K., Rosin, N., Yoshiura, K., Oufadem, M., Beck, T. J., McGowan, R., Magee, A. C., Altmuller, J., and 39 others. <strong>De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.</strong> Nature Genet. 49: 249-255, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067911</a>] [<a href="https://doi.org/10.1038/ng.3765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067911">Gordon et al. (2017)</a> concluded that S135C represents a gain-of-function variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28067909+23852095+28067911+8446727" 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">rs1057519646 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519646;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=rs1057519646" 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=rs1057519646" 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=RCV000417284 OR RCV003932541" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000417284, RCV003932541" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000417284...</a>
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<p>In a German woman (patient R1) with Bosma arhinia microphthalmia syndrome (BAMS; <a href="/entry/603457">603457</a>), who was 1 of 2 affected sisters originally reported by <a href="#17" class="mim-tip-reference" title="Ruprecht, K. W., Majewski, F. <strong>Familiaeire Arhinie mit Petersscher Anomalie und Kiefermissbildungen, ein neues Fehlbildungssyndrom?</strong> Klin. Monatsbl. Augenheilkd. 172: 708-715, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/672092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">672092</a>]" pmid="672092">Ruprecht and Majewski (1978)</a>, and in an unrelated affected Caucasian man (patient I1), <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a> identified heterozygosity for a c.404G-A transition (c.404G-A, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a ser135-to-asn (S135N) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation was shown to have arisen de novo in the male proband, as it was not found in his unaffected parents; it was also not found in his 2 unaffected sisters. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28067909+672092" 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="#9" class="mim-tip-reference" title="Gordon, C. T., Xue, S., Yigit, G., Filali, H., Chen, K., Rosin, N., Yoshiura, K., Oufadem, M., Beck, T. J., McGowan, R., Magee, A. C., Altmuller, J., and 39 others. <strong>De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development.</strong> Nature Genet. 49: 249-255, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067911/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067911</a>] [<a href="https://doi.org/10.1038/ng.3765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067911">Gordon et al. (2017)</a> independently identified the S135N mutation in a 4-year-old North African boy with BAMS, in whom it arose de novo; they stated that the variant was not found in the ExAC, Exome Variant Server, or dbSNP (build 144) databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28067911" 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=RCV000417347 OR RCV004797810" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000417347, RCV004797810" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000417347...</a>
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<p>In a 4-year-old boy (patient AK1) with Bosma arhinia microphthalmia syndrome (BAMS; <a href="/entry/603457">603457</a>), <a href="#19" class="mim-tip-reference" title="Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others. <strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong> Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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/ng.3743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28067909">Shaw et al. (2017)</a> identified heterozygosity for a de novo c.404G-T transversion (c.404G-T, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a ser135-to-ile (S135I) substitution at a highly conserved residue within the GHKL-type ATPase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28067909" 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">rs2073052786 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2073052786;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=rs2073052786" 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=rs2073052786" 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 28-year-old patient (patient I) with facioscapulohumeral muscular dystrophy-2 (FSHD2; <a href="/entry/158901">158901</a>), <a href="#20" class="mim-tip-reference" title="Strafella, C., Caputo, V., Galota, R. M., Campoli, G., Bax, C., Colantoni, L., Minozzi, G., Orsini, C., Politano, L., Tasca, G., Novelli, G., Ricci, E., Giardina, E., Cascella, R. <strong>The variability of SMCHD1 gene in FSHD patients: evidence of new mutations.</strong> Hum. Molec. Genet. 28: 3912-3920, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31600781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31600781</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31600781[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/ddz239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31600781">Strafella et al. (2019)</a> identified heterozygosity for a 2-bp duplication (c.182_183dupGT, NM_015295.2) in exon 1 of the SMCHD1 gene, predicted to result in a frameshift and premature termination (Gln62ValfsTer48). The mutation, which was identified by next-generation sequencing and direct sequencing of the SMCHD1 gene, was not present in the ExAC, gnomAD, and 1000 Genomes Project databases. The mutation was predicted to result in nonsense-mediated mRNA decay, a truncated protein lacking the essential functional GHKL-ATPase and SMC hinge domains, and/or disruption of normal splicing. The patient was also heterozygous for a D4Z4 (<a href="/entry/606009">606009</a>) repeat size of 10 repeated units. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31600781" 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">rs2075308386 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2075308386;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=rs2075308386" 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=rs2075308386" 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 52-year-old patient (patient III) with facioscapulohumeral muscular dystrophy-2 (FSHD2; <a href="/entry/158901">158901</a>), <a href="#20" class="mim-tip-reference" title="Strafella, C., Caputo, V., Galota, R. M., Campoli, G., Bax, C., Colantoni, L., Minozzi, G., Orsini, C., Politano, L., Tasca, G., Novelli, G., Ricci, E., Giardina, E., Cascella, R. <strong>The variability of SMCHD1 gene in FSHD patients: evidence of new mutations.</strong> Hum. Molec. Genet. 28: 3912-3920, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31600781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31600781</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31600781[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/ddz239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31600781">Strafella et al. (2019)</a> identified heterozygosity for a c.3469G-T transversion (c.3469G-T, NM_015295.2) in exon 27 of the SMCHD1 gene, predicted to result in a gly1157-to-ter (G1157X) substitution. The mutation, which was identified by next-generation sequencing and direct sequencing of the SMCHD1 gene, was not present in the 1000 Genomes Project, ExAC, and gnomAD databases. The mutation was predicted to result in nonsense-mediated mRNA decay or a truncated protein lacking the C-terminal SMC hinge domain and consequent disruption of protein secondary structure. The patient was also heterozygous for a D4Z4 (<a href="/entry/606009">606009</a>) repeat size of 8 units. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31600781" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0018 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC</strong>
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<p>In a 62-year-old patient (patient V) with facioscapulohumeral muscular dystrophy-2 (FSHD2; <a href="/entry/158901">158901</a>), <a href="#20" class="mim-tip-reference" title="Strafella, C., Caputo, V., Galota, R. M., Campoli, G., Bax, C., Colantoni, L., Minozzi, G., Orsini, C., Politano, L., Tasca, G., Novelli, G., Ricci, E., Giardina, E., Cascella, R. <strong>The variability of SMCHD1 gene in FSHD patients: evidence of new mutations.</strong> Hum. Molec. Genet. 28: 3912-3920, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31600781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31600781</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31600781[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/ddz239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31600781">Strafella et al. (2019)</a> identified heterozygosity for a 2-bp deletion (c.5150_5051delAA, NM_015295.2) in exon 41 of the SMCHD1 gene, predicted to result in a frameshift and premature termination (Lys1717ArgfsTer16). The mutation was identified by next-generation sequencing and direct sequencing of the SMCHD1 gene. The mutation was predicted to result in nonsense-mediated mRNA decay or a truncated protein lacking the C-terminal SMC hinge domain. The patient was found to have a normal D4Z4 (<a href="/entry/606009">606009</a>) repeat size of more than 11 repeated units. Functional studies were not performed. This patient was previously reported by <a href="#5" class="mim-tip-reference" title="Cascella, R., Strafella, C., Caputo, V., Galota, R. M., Errichiello, V., Scutifero, M., Petillo, R., Marella, G. L., Arcangeli, M., Colantoni, L., Zampatti, S., Ricci, E., Deidda, G., Politano, L., Giardina, E. <strong>Digenic inheritance of shortened repeat units of the D4Z4 region and a loss of function variant in SMCHD1 in a family with FSHD.</strong> Front. Neurol. 9: 1027, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30546343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30546343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30546343[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/10.3389/fneur.2018.01027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30546343">Cascella et al. (2018)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30546343+31600781" 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">rs2074549354 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2074549354;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=rs2074549354" 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=rs2074549354" 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 73-year-old patient (patient II) with facioscapulohumeral muscular dystrophy-2 (FSHD2; <a href="/entry/158901">158901</a>), <a href="#20" class="mim-tip-reference" title="Strafella, C., Caputo, V., Galota, R. M., Campoli, G., Bax, C., Colantoni, L., Minozzi, G., Orsini, C., Politano, L., Tasca, G., Novelli, G., Ricci, E., Giardina, E., Cascella, R. <strong>The variability of SMCHD1 gene in FSHD patients: evidence of new mutations.</strong> Hum. Molec. Genet. 28: 3912-3920, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31600781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31600781</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31600781[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/ddz239" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31600781">Strafella et al. (2019)</a> identified heterozygosity for a 1-bp duplication (c.2129dupC, NM_015295.2) in exon 16 of the SMCHD1 gene, predicted to result in a frameshift and a premature termination codon (Ala711CysfsTer11). The mutation, which was identified by next-generation sequencing and direct sequencing of the SMCHD1 gene, was not present in the 1000 Genomes Project, ExAC, and gnomAD databases. The mutation was predicted to result in nonsense-mediated mRNA decay or a truncated protein lacking the C-terminal hinge domain. The patient was also heterozygous for a D4Z4 (<a href="/entry/606009">606009</a>) repeat size of 9 repeated units. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31600781" 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>Bosma arrhinia microphthalmia syndrome in a Mexican patient with a molecular analysis of PAX6.</strong>
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Clin. Dysmorph. 25: 12-15, 2016.
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Sacconi, S., Lemmers, R. J. L. F., Balog, J., van der Vliet, P. J., Lahaut, P., van Nieuwenhuizen, M. P., Straasheijm, K. R., Debipersad, R. D., Vos-Versteeg, M., Salviati, L., Casarin, A., Pegoraro, E., Tawil, R., Bakker, E., Tapscott, S. J., Desnuelle, C., van der Maarel, S. M.
|
|
<strong>The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1.</strong>
|
|
Am. J. Hum. Genet. 93: 744-751, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24075187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24075187</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24075187[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=24075187" 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.ajhg.2013.08.004" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Shaw2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shaw, N. D., Brand, H., Kupchinsky, Z. A., Bengani, H., Plummer, L., Jones, T. I., Erdin, S., Williamson, K. A., Rainger, J., Stortchevoi, A., Samocha, K., Currall, B. B., and 66 others.
|
|
<strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong>
|
|
Nature Genet. 49: 238-248, 2017. Note: Erratum: Nature Genet. 49: 969 only, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28067909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28067909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28067909[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=28067909" 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/ng.3743" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Strafella2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Strafella, C., Caputo, V., Galota, R. M., Campoli, G., Bax, C., Colantoni, L., Minozzi, G., Orsini, C., Politano, L., Tasca, G., Novelli, G., Ricci, E., Giardina, E., Cascella, R.
|
|
<strong>The variability of SMCHD1 gene in FSHD patients: evidence of new mutations.</strong>
|
|
Hum. Molec. Genet. 28: 3912-3920, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31600781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31600781</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31600781[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=31600781" 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/ddz239" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Thiele1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thiele, H., Musil, A., Nagel, F., Majewski, F.
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<strong>Familial arhinia, choanal atresia, and microphthalmia</strong>
|
|
Am. J. Med. Genet. 63: 310-313, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8723126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8723126</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8723126" 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/(SICI)1096-8628(19960503)63:1<310::AID-AJMG51>3.0.CO;2-N" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Tryggestad2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tryggestad, J. B., Li, S., Chernausek, S. D.
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<strong>Hypogonadotropic hypogonadism presenting with arhinia: a case report.</strong>
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|
J. Med. Case Rep. 7: 52, 2013. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23432817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23432817</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23432817" 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/10.1186/1752-1947-7-52" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Wang2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, C.-Y., Jegu, T., Chu, H.-P., Oh, H. J., Lee, J. T.
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<strong>SMCHD1 merges chromosome compartments and assists formation of super-structures on the inactive X.</strong>
|
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Cell 174: 406-421, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29887375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29887375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29887375[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=29887375" 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.cell.2018.05.007" target="_blank">Full Text</a>]
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</p>
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</div>
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</ol>
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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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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 03/05/2021
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</span>
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</div>
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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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Bao Lige - updated : 10/12/2018<br>Marla J. F. O'Neill - updated : 02/27/2017<br>Cassandra L. Kniffin - updated : 11/4/2013<br>Cassandra L. Kniffin - updated : 12/17/2012
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz : 12/14/2012
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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="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 04/30/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/03/2021<br>carol : 03/05/2021<br>mgross : 10/12/2018<br>alopez : 06/20/2017<br>carol : 02/27/2017<br>carol : 08/11/2016<br>carol : 11/06/2013<br>ckniffin : 11/4/2013<br>carol : 8/29/2013<br>carol : 4/22/2013<br>carol : 12/18/2012<br>ckniffin : 12/17/2012<br>mgross : 12/14/2012
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 614982
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
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STRUCTURAL MAINTENANCE OF CHROMOSOMES FLEXIBLE HINGE DOMAIN-CONTAINING PROTEIN 1; SMCHD1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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SMC HINGE DOMAIN-CONTAINING PROTEIN 1<br />
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KIAA0650
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SMCHD1</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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 720511000;
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</span>
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</p>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 18p11.32
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Genomic coordinates <span class="small">(GRCh38)</span> : 18:2,655,726-2,805,017 </span>
|
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</em>
|
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</strong>
|
|
<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">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
|
18p11.32
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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Bosma arhinia microphthalmia syndrome
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
603457
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal dominant
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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|
3
|
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Facioscapulohumeral muscular dystrophy 2, digenic
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
158901
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
Digenic dominant
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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3
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<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>TEXT</strong>
|
|
</span>
|
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</h4>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
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<p>Proteins that contain a structural maintenance of chromosomes (SMC) hinge domain, such as SMCHD1, are typically involved in DNA management. SMCHD1 plays an essential role in X chromosome inactivation (Blewitt et al., 2008). </p>
|
|
</span>
|
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<div>
|
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>By sequencing clones obtained from a size-fractionated human brain cDNA library, Ishikawa et al. (1998) obtained a partial SMCHD1 clone, which they designated KIAA0650. RT-PCR analysis detected variable SMCHD1 expression in all tissues examined, with highest expression in testis, ovary, and lung. </p><p>Blewitt et al. (2008) cloned mouse Smchd1. The deduced 2,007-amino acid protein has an N-terminal ATPase domain and a C-terminal SMC hinge domain. Database analysis revealed orthologs in amphibians, birds, and eutherian and metatherian mammals. In female mouse embryonic fibroblasts, Smchd1 localized to the inactive X chromosome (Xi). </p><p>By histochemical staining of mouse embryos, Gordon et al. (2017) detected Smchd1 expression in the nasal placodes and optic vesicles at embryonic day (E) 9.5 and in the nasal epithelium at E12.5. The authors noted that in situ hybridization data indicated regional expression of Smchd1 in the nasal cavity in E14.5 mice, and that transcriptional profiling of mouse postnatal olfactory epithelium had shown that Smchd1 is specifically expressed in immature olfactory sensory neurons (Nickell et al., 2012). </p>
|
|
</span>
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<div>
|
|
<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By radiation hybrid analysis, Ishikawa et al. (1998) mapped the SMCHD1 gene to chromosome 18. Hartz (2012) mapped the SMCHD1 gene to chromosome 18p11.32 based on an alignment of the SMCHD1 sequence (GenBank AB014550) with the genomic sequence (GRCh37). </p><p>Blewitt et al. (2008) mapped the mouse Smchd1 gene to chromosome 17. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Gendrel et al. (2012) identified 3 major classes of CpG islands on Xi that showed rapid, intermediate, or slow methylation kinetics during X inactivation in mouse cells. A fourth class consisted of CpG islands on Xi for which methylation dynamics could not be assigned to any of the other classes. CpG islands with slow methylation kinetics were most common. CpG islands showing rapid or intermediate methylation kinetics had higher CpG density and GC content than those with slow methylation kinetics. Fast-methylating CpG islands were associated with fewer genes than slow-methylating CpG islands, and these genes were only weakly expressed in embryonic stem cells. Slow-methylating CpG islands were associated with low CpG density and higher levels of gene expression in embryonic stem cells than fast-methylating CpG islands. CpG islands with intermediate kinetics were located closer to the Xist locus relative to other classes. Use of knockout mouse embryonic fibroblasts revealed that Dnmt3b (602900), but not Dnmt3a (602769) or Dnmt3l (606588), was required for methylation of CpG islands of all classes. Smchd1 was required only for methylation of CpG islands with slow methylation kinetics. Smchd1 was not detected on Xi early during X inactivation, but was highly expressed throughout Xi late during X inactivation. Dnmt3b did not appear to be actively targeted to Xi. </p><p>Using CRISPR-Cas technology, Wang et al. (2018) generated Smchd1 -/- clones from a mouse hybrid cell line carrying 1 M. musculus X chromosome and 1 M. castaneus X chromosome. Loss of Smchd1 in mouse cells resulted in failure to silence a large subset of genes, termed 'Smchd1-sensitive genes' by the authors, on Xi. Analysis by allele-specific chromatin immunoprecipitation sequencing (ChIP-seq) showed that failure to silence Smchd1-sensitive genes correlated with an erosion of heterochromatin, indicating that Smchd1 regulates spreading of Xi heterochromatin. Loss of Smchd1 also resulted in regional defects in Xist RNA spreading. In situ high-throughput chromosome conformation capture revealed that the Xi in Smchd1 -/- cells contained unique new compartments, termed S1 and S2 compartments, that were different from the A and B compartments found on the active X chromosome (Xa). Characterization of these new compartments confirmed that Smchd1 played a critical role in organizing Xi structures by merging chromatin compartments. Xi in wildtype mouse cells contained weak but clearly discernible topologically associated domains (TADs) across the entire Xi. Depletion of Smchd1 led to Xi-specific strengthening of TADs, showing that Smchd1 controls TAD strength in an Xi-specific manner. Allele-specific ChIP-seq further demonstrated that Smchd1 suppressed binding of architectural factors to the Xi on a pan-Xi scale, as Ctcf (604167) and Rad21 (606462) exhibited increased binding to the Xi in Smchd1 -/- cells. Examination of Smchd1 genomic binding sites showed that Smchd1 was enriched in both gene-rich and gene-poor regions on Xi and bridged the S1 and S2 compartments. Further investigation demonstrated that S1 and S2 compartments occurred naturally, but only transiently, during de novo inactivation of the X chromosome before Smchd1 bound and facilitated Xist spreading in wildtype mouse cells. Upon recruitment of Smchd1, S1 and S2 compartments were merged by Smchd1 to create a compartmentless Xi, explaining why deletion of Smchd1 in mouse cells resulted in persistent S1 and S2 compartments. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Facioscapulohumeral Muscular Dystrophy 2</em></strong></p><p>
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In affected members of 15 (79%) of 19 families with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901), Lemmers et al. (2012) identified heterozygous loss-of-function mutations in the SMCHD1 gene (see, e.g., 614982.0001-614982.0005). The mutations in 7 families were initially identified by exome sequencing and confirmed by Sanger sequencing. The mutational spectrum included small deletions, splice site mutations, and missense mutations, resulting in haploinsufficiency. Patients showed D4Z4 (see 606009) hypomethylation to levels less than 25% (normal being about 50%), and protein blot analysis in several patients showed decreased SMCHD1 protein in fibroblasts. Affected individuals were also heterozygous or homozygous for an FSHD1 (158900)-permissive D4Z4 haplotype that contains a polyadenylation signal to stabilize DUX4 (606009) mRNA in skeletal muscle. Primary myotubes from a normal individual with a normal-sized and methylated D4Z4 array on a permissive haplotype showed no DUX4 mRNA. However, decreasing SMCHD1 expression to about 50% using RNA interference resulted in transcriptional activation of DUX4 and a variegated pattern of DUX4 protein expression in the myotubes. The pattern of variegated DUX4 expression that resulted was similar to that observed in FSHD1 and FSHD2 myotube cultures. The findings indicated that SMCHD1 activity is necessary for D4Z4 hypermethylation and somatic repression of DUX4, and that reduction of SMCHD1 results in D4Z4 arrays that express DUX4 when a permissive haplotype is present. The SMCHD1 mutation and the permissive D4Z4 haplotype segregated independently in the families, indicating digenic inheritance. Of the 26 individuals with hypomethylation at D4Z4, a SMCHD1 mutation, and a permissive D4Z4 haplotype, 5 (19%) were asymptomatic, indicating incomplete penetrance. Lemmers et al. (2012) suggested that SMCHD1 mutations may modify the epigenetic repression of other genomic regions and the penetrance of other human diseases. </p><p>Sacconi et al. (2013) found that mutation in the SMCHD1 gene is a modifier of disease severity in families affected by FSHD1. Three unrelated families with intrafamilial clinical variability of the disorder were studied. In 1 family, a mildly affected man with FSHD1 carried a 9-unit D4Z4 repeat on a 4A allele with no SMCHD1 mutations, whereas his mildly affected wife carried a SMCHD1 mutation (T527M; 614982.0006) on a normal-sized 4A allele, consistent with FSHD2. Their more severely affected son and grandson each carried the 9-unit D4Z4 repeat on a 4A allele as well as the T527M SMCHD1 mutation, consistent with having both FSHD1 and FSHD2. In a second family, a man with a severe early-onset phenotype had both a 9-unit D4Z4 repeat on a 4A permissive allele and a mutation in the SMCHD1 gene. Each of his children, who had milder symptoms, inherited 1 of the genetic defects. In a third family, a man with a severe phenotype was also found to carry a 9-unit D4Z4 repeat on a 4A permissive allele with a SMCHD1 mutation. No information from his parents was available. Transduction of SMCHD1 shRNA into FSHD1 myotubes caused increased levels of DUX4 mRNA as well as transcriptional activation of known DUX4 target genes. These findings were consistent with further chromatin relaxation of the contracted FSHD1 repeat upon knockdown of SMCHD1. Sacconi et al. (2013) concluded that FSHD1 and FSHD2 share a common pathophysiologic pathway converging on transcriptional derepression of DUX4 in skeletal muscle. </p><p>Strafella et al. (2019) performed next-generation sequencing of the SMCHD1 gene in a cohort of patients with FSHD and identified 7 heterozygous pathogenic/likely pathogenic variants (see, e.g., 614982.0016-614982.0019) in 7 patients; 5 of the patients had a borderline D4Z4 fragment size (8-10 repeats) and 2 had a normal D4Z4 fragment size (more than 11 repeats). All 7 mutations were predicted to affect protein structure and conformation, resulting in loss of the GHKL-ATPase domain and/or the SMC hinge domain. Strafella et al. (2019) concluded that borderline D4Z4 size may be a risk factor or pathogenic modifier in patients with SMCHD1 mutations. Strafella et al. (2019) also identified 5 variants in the 3-prime UTR of the SMCHD1 gene, which were predicted to disrupt an existing miRNA binding site or to create a novel binding site for different miRNAs, suggesting a potential miRNA-dependent regulatory effect on associated pathways associated with FSHD. </p><p><strong><em>Bosma Arhinia Microphthalmia Syndrome</em></strong></p><p>
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By whole-genome, whole-exome, and targeted sequencing in 38 probands with Bosma arhinia microphthalmia syndrome (BAMS; 603457), Shaw et al. (2017) identified heterozygous missense mutations in the SMCHD1 gene in 32 (84%) of the probands (see, e.g., 614982.0007-614982.0015). The mutations all occurred within exons 3 to 13, spanning a GHKL-type ATPase domain. Experiments in zebrafish embryos suggested that the likely mode of action of the arhinia-associated alleles is loss of function. The authors observed largely identical methylation patterning at D4Z4 in arhinia and FSHD2 patients, and concluded that 2 completely distinct phenotypes can arise from deleterious changes in the same gene and even the same alleles. Noting the marked intrafamilial and interfamilial phenotypic variability in SMCHD1-mutated BAMS families, Shaw et al. (2017) suggested that BAMS-associated SMCHD1 variants are not fully penetrant and that such variants alone may not be sufficient to cause arhinia. </p><p>Simultaneously and independently, Gordon et al. (2017) performed whole-exome and/or Sanger sequencing in 14 probands with arhinia, 6 of whom were also studied by Shaw et al. (2017). They identified mutations in the SMCHD1 gene in all 14 probands (see, e.g., 614982.0008, 614982.0013, and 614982.0014). The mutations were shown to have occurred de novo in the 11 families for which DNA was available from the parents; all of the mutations occurred at highly conserved residues within the ATPase domain, and none was found in public variant databases. Gordon et al. (2017) noted that 6 of the 14 patients had mutations involving 3 adjacent amino acids (A134, S135, and E136; see, e.g., 614982.0013-614982.0015), and that 2 other mutations, H348R (614982.0008) and D420V were identified in 3 and 2 probands each, suggesting possible mutation hotspots. Analysis of patient methylation status showed a trend for hypomethylation compared to controls or unaffected family members; however, some patients with BAMS were normally methylated. In contrast to FSHD2-associated loss-of-function mutations (see 614982.0006), functional analysis of ATPase activity showed increased protein hydrolysis of ATP by 3 of the BAMS-associated mutants tested compared to wildtype SMCHD1 (see 614982.0013), and 1 BAMS variant showed unchanged ATPase activity. In addition, overexpression of BAMS-associated mutant SMCHD1 in Xenopus embryos resulted in tadpoles with noticeable craniofacial anomalies, including microphthalmia or anophthalmia, and eye diameters at 4 days postfertilization were significantly smaller in those embryos than in embryos with overexpression of wildtype SMCHD1 or an FSHD2-associated mutant. Gordon et al. (2017) concluded that BAMS-associated missense mutations might exhibit gain-of-function or neomorphic activity. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In an N-ethyl-N-nitrosourea mutagenesis screen, Blewitt et al. (2008) identified the modifier of murine metastable epialleles (MommeD1) mutation. Homozygosity for MommeD1 resulted in female-specific midgestation lethality and hypomethylation of the X-linked Hprt1 gene (308000) CpG island, suggesting a defect in X inactivation. Blewitt et al. (2008) found that the MommeD1 mutation resulted in a nonsense codon in exon 23 of the 48-exon Smchd1 gene. Homozygous mutant female embryos, but not male embryos, showed placental defects, with smaller trophoblast giant cell layer and smaller trophoblast giant cell nuclei. MommeD1 heterozygous female embryos showed delayed methylation at CpG islands, with normal methylation levels achieved by embryonic day 10.5. Smchd1 was not required for initial Xist expression, but it was required for subsequent DNA methylation and gene silencing on Xi. </p><p>Using facial cartilage patterning in zebrafish as a surrogate structure homologous to the human nose, Shaw et al. (2017) generated Smchd1-knockdown morphant zebrafish models and observed that all morphants exhibited narrowing of the ethmoid plate and an increase in the ceratohyal arch angle, both of which were dose-dependent phenomena, as well as delayed or absent development of ceratobranchial arches and microphthalmia. Ventral imaging revealed that morphant olfactory bulbs and hypothalami were intact, but the average projection length of the terminal nerve, where GnRH3 neurons reside, was reduced by 45% compared to controls. The cartilage, eye, and GnRH phenotypes were rescued by wildtype human SMCHD1 mRNA. CRISPR/Cas9-mediated genome editing recapitulated the craniofacial, ocular, and GnRH defects observed in the morphant models. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>19 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMCHD1, 5-BP DEL, NT1302
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<br />
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SNP: rs387907319,
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ClinVar: RCV000033082
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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 woman with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901), Lemmers et al. (2012) identified a heterozygous 5-bp deletion in exon 10 of the SMCHD1 gene (1302_1306del), resulting in a frameshift and premature termination (Y434X). The patient was also heterozygous for a permissive D4Z4 (see 606009) haplotype; D4Z4 methylation was decreased to 25% (normal is about 50%). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMCHD1, PRO690SER
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<br />
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SNP: rs397514623,
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ClinVar: RCV000033083
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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 patient with FSHD2 (158901), Lemmers et al. (2012) identified a heterozygous 2068C-T transition in exon 16 of the SMCHD1 gene, resulting in a pro690-to-ser (P690S) substitution. The patient was also heterozygous for a permissive D4Z4 (see 606009) haplotype; D4Z4 methylation was decreased to 7%. The P690S mutation was inherited from the unaffected mother, who also had hypomethylation of D4Z4 (10%), but did not carry a permissive D4Z4 haplotype. The D4Z4 permissive haplotype was inherited from the unaffected father, who had normal D4Z4 methylation at 43%. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMCHD1, 1-BP DEL, NT1608
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<br />
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SNP: rs1057519614,
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ClinVar: RCV000033084
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 affected members of a 3-generation family with FSHD2 (158901), Lemmers et al. (2012) identified a heterozygous 1-bp deletion in exon 12 of the SMCHD1 gene, resulting in a frameshift and premature termination (Asp537IleIfsTer10). One affected individual was heterozygous for a permissive D4Z4 (see 606009) haplotype, whereas the other was homozygous for a D4Z4 permissive haplotype; D4Z4 methylation was decreased to 18 to 20% in the patients. The SMCHD1 mutation segregated with hypomethylation of D4Z4 in the family, and the D4Z4 permissive haplotype segregated independently. However, there were 4 apparently unaffected individuals with the SMCHD1 mutation, hypomethylation (11%), and a D4Z4 permissive haplotype, indicating incomplete penetrance. Western blot analysis of fibroblasts from 1 patient and 1 carrier showed decreased SMCHD1 levels. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMCHD1, IVS29DS, G-A, +1
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<br />
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SNP: rs886042417,
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ClinVar: RCV000033085, RCV000356100
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of 2 families with FSHD2 (158901), Lemmers et al. (2012) identified a heterozygous G-to-A transition in intron 29 of the SMCHD1 gene (3801+1G-A), resulting in a splice site mutation. All patients were also either homozygous or heterozygous for a permissive D4Z4 (see 606009) haplotype. D4Z4 methylation in all patients was decreased to 5 to 16%. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMCHD1, THR1522THR
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<br />
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SNP: rs1598416221,
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ClinVar: RCV000033086, RCV003137554
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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 4 affected members of 2 families with FSHD2 (158901), Lemmers et al. (2012) identified a heterozygous 4566G-A transition in exon 36 of the SMCHD1 gene, predicted to result in a synonymous thr1522-to-thr (T1522T) substitution. However, the mutation was demonstrated to cause aberrant splicing with the skipping of exon 36. Three affected individuals were also homozygous for a permissive D4Z4 (see 606009) haplotype; the fourth was heterozygous for a permissive D4Z4 haplotype. D4Z4 methylation in all patients was decreased to 13 to 23%. Western blot analysis of fibroblasts from 2 patients showed decreased SMCHD1 levels. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMCHD1, THR527MET
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<br />
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SNP: rs397518422,
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ClinVar: RCV000074384
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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 3-generation family with FSHD2 (158901), Sacconi et al. (2013) identified a heterozygous c.1580C-T transition in exon 12 of the SMCHD1 gene, resulting in a thr527-to-met (T527M) substitution at a highly conserved residue. The mutation was not present in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in in-house databases. The grandmother, who had a relatively mild phenotype, carried the T527M mutation on a normal-sized 4A D4Z4 allele (see 609009). Her son and grandson, who had earlier onset and a more severe phenotype, each carried both the T527M mutation as well as a contracted 9-unit D4Z4 allele on a permissive 4A haplotype, consistent with a diagnosis of both FSHD2 and FSHD1 (158900). The findings indicated that a SMCHD1 mutation and a D4Z4 contraction can act synergistically to cause additional derepression of the DUX4 gene and a more severe phenotype. </p><p>Gordon et al. (2017) analyzed the effects on ATPase activity of SMCHD1 variants and observed slightly decreased protein hydrolysis of ATP by the T527M mutant compared to wildtype SMCHD1. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0007 BOSMA ARHINIA MICROPHTHALMIA SYNDROME</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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SMCHD1, GLN345ARG
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<br />
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SNP: rs1057519639,
|
|
|
|
|
|
|
|
ClinVar: RCV000417316, RCV000497013, RCV002521501
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 sisters from a 3-generation German family (family O) with Bosma arhinia microphthalmia syndrome (BAMS; 603457), originally reported by Thiele et al. (1996), Shaw et al. (2017) identified heterozygosity for a c.1034A-G transition (c.1034A-G, ENST00000320876.10) in exon 8 of the SMCHD1 gene, resulting in a gln345-to-arg (Q345R) substitution at a conserved residue within the GHKL-type ATPase domain. Their mother, who exhibited abnormal dentition, asymmetric nares, and anosmia, was also heterozygous for the mutation, as was their maternal grandmother, who showed only abnormal dentition and asymmetric nares. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
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|
</div>
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|
</div>
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|
<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 BOSMA ARHINIA MICROPHTHALMIA SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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SMCHD1, HIS348ARG
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<br />
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SNP: rs1057519640,
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gnomAD: rs1057519640,
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|
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ClinVar: RCV000417236
|
|
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|
|
</span>
|
|
</div>
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|
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<div>
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<span class="mim-text-font">
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|
<p>In 7 sporadic patients with Bosma arhinia microphthalmia syndrome (BAMS; 603457), including a Norwegian girl (patient L1) originally reported by Olsen et al. (2001), a Caucasian man (patient F1) previously reported by Graham and Lee (2006) as 'patient 1,' and a Mexican boy (patient Z1) described by Becerra-Solano et al. (2016), Shaw et al. (2017) identified heterozygosity for a c.1043A-G transition (c.1043A-G, ENST00000320876.10) in exon 9 of the SMCHD1 gene, resulting in a his348-to-arg (H348R) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation segregated with disease in the 4 families for which DNA was available from other family members, and it was shown to have arisen de novo in the probands from 3 of those families. </p><p>Gordon et al. (2017) independently studied 2 of the patients reported by Shaw et al. (2017), the Norwegian girl (patient L1) and a Chinese boy (patient N1), as well as an affected Ukrainian girl, and identified the H348R mutation in all 3 patients; analysis of parental DNA in the Chinese family demonstrated that the mutation arose de novo in the proband. Gordon et al. (2017) noted that the H348R variant was not found in the ExAC, Exome Variant Server, or dbSNP (build 144) databases. Overexpression of the H348R mutant in Xenopus embryos resulted in significantly smaller eye diameter than overexpression of wildtype SMCHD1 or an FSHD2-associated mutant. </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>.0009 BOSMA ARHINIA MICROPHTHALMIA SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMCHD1, LEU141PHE
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|
|
<br />
|
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|
|
SNP: rs1057519641,
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|
|
|
gnomAD: rs1057519641,
|
|
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|
|
|
ClinVar: RCV000417278
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 unrelated probands with Bosma arhinia microphthalmia syndrome (BAMS; 603457), including a patient (patient E1) originally reported by Gifford et al. (1972) and also studied by Bosma et al. (1981), and another patient (patient C1) previously described by Tryggestad et al. (2013), Shaw et al. (2017) identified heterozygosity for a c.423G-C transversion (c.423G-C, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a leu141-to-phe (L141F) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation segregated with disease in the 2 families for which DNA was available from other family members, and was shown to have arisen de novo in a Swiss boy (patient V1). The authors noted that 1 of the patients (C1) did not exhibit the complete 'Bosma triad,' since he had arhinia and hypogonadism, but not microphthalmia. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 BOSMA ARHINIA MICROPHTHALMIA SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMCHD1, GLN400LEU
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|
|
<br />
|
|
|
|
SNP: rs1057519642,
|
|
|
|
|
|
|
|
ClinVar: RCV000417324, RCV000497004, RCV000497016
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 11-year-old Caucasian Hispanic girl (patient AH1) with Bosma arhinia microphthalmia syndrome (BAMS; 603457), Shaw et al. (2017) identified heterozygosity for a c.1199A-T transversion (c.1199A-T, ENST00000320876.10) in exon 10 of the SMCHD1 gene, resulting in a gln400-to-leu (Q400L) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation was also present in the proband's half sister, who had a hypoplastic nose, and in their father, who exhibited only anosmia. </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
|
|
<br />
|
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</div>
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|
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</div>
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|
|
|
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|
<div>
|
|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 BOSMA ARHINIA MICROPHTHALMIA SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMCHD1, GLU136ASP
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs1057519643,
|
|
|
|
|
|
|
|
ClinVar: RCV000417233, RCV000497012
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 46-year-old Caucasian man (patient T1) with Bosma arhinia microphthalmia syndrome (BAMS; 603457), originally reported by Brasseur et al. (2016), Shaw et al. (2017) identified heterozygosity for a c.408A-C transversion (c.408A-C, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a glu136-to-asp (E136D) substitution at a highly conserved residue within the GHKL-type ATPase domain. The proband's father, who had been diagnosed with limb/girdle muscular dystrophy but exhibited no apparent facial dysmorphism and had no history of vision abnormalities or anosmia, was also heterozygous for the mutation, which was not found in the proband's unaffected mother. DNA was unavailable for the paternal grandmother and great-aunt, who were reported to have colobomata, or a paternal great-uncle, who was born blind. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
</div>
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|
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 BOSMA ARHINIA MICROPHTHALMIA SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMCHD1, GLY137GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057519644,
|
|
|
|
|
|
|
|
ClinVar: RCV000417296, RCV000417337
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 17-year-old African American girl (patient AG1) with Bosma arhinia microphthalmia syndrome (BAMS; 603457), Shaw et al. (2017) identified heterozygosity for a c.410G-A transition (c.410G-A, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a gly137-to-glu (G137E) substitution at a highly conserved residue within the GHKL-type ATPase domain. Shaw et al. (2017) noted that the G137E mutation had previously been reported in a patient with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901) by Lemmers et al. (2012). </p>
|
|
</span>
|
|
</div>
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 BOSMA ARHINIA MICROPHTHALMIA SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMCHD1, SER135CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057519645,
|
|
|
|
|
|
|
|
ClinVar: RCV000417256
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 28-year-old German woman (patient M1) and a 3-year-old Irish girl (patient AF1) with Bosma arhinia microphthalmia syndrome (BAMS; 603457), originally reported by Muhlbauer et al. (1993) and Courtney et al. (2014), respectively, Shaw et al. (2017) and Gordon et al. (2017) independently identified heterozygosity for a c.403A-T transversion (c.403A-T, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a ser135-to-cys (S135C) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation was not found in the unaffected parents from either family, indicating that it arose de novo in both probands; Gordon et al. (2017) stated that the variant was not found in the ExAC, Exome Variant Server, or dbSNP (build 144) databases. Fibroblasts from patient M1 showed no defects in the DNA damage response or impaired nonhomologous end joining. ATPase assays demonstrated increased protein hydrolysis of ATP with the S135C mutant compared to wildtype. Gordon et al. (2017) concluded that S135C represents a gain-of-function variant. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 BOSMA ARHINIA MICROPHTHALMIA SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMCHD1, SER135ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057519646,
|
|
|
|
|
|
|
|
ClinVar: RCV000417284, RCV003932541
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a German woman (patient R1) with Bosma arhinia microphthalmia syndrome (BAMS; 603457), who was 1 of 2 affected sisters originally reported by Ruprecht and Majewski (1978), and in an unrelated affected Caucasian man (patient I1), Shaw et al. (2017) identified heterozygosity for a c.404G-A transition (c.404G-A, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a ser135-to-asn (S135N) substitution at a highly conserved residue within the GHKL-type ATPase domain. The mutation was shown to have arisen de novo in the male proband, as it was not found in his unaffected parents; it was also not found in his 2 unaffected sisters. </p><p>Gordon et al. (2017) independently identified the S135N mutation in a 4-year-old North African boy with BAMS, in whom it arose de novo; they stated that the variant was not found in the ExAC, Exome Variant Server, or dbSNP (build 144) databases. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 BOSMA ARHINIA MICROPHTHALMIA SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMCHD1, SER135ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057519646,
|
|
|
|
|
|
|
|
ClinVar: RCV000417347, RCV004797810
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4-year-old boy (patient AK1) with Bosma arhinia microphthalmia syndrome (BAMS; 603457), Shaw et al. (2017) identified heterozygosity for a de novo c.404G-T transversion (c.404G-T, ENST00000320876.10) in exon 3 of the SMCHD1 gene, resulting in a ser135-to-ile (S135I) substitution at a highly conserved residue within the GHKL-type ATPase domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMCHD1, 2-BP DUP, 182GT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2073052786,
|
|
|
|
|
|
|
|
ClinVar: RCV001310238
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 28-year-old patient (patient I) with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901), Strafella et al. (2019) identified heterozygosity for a 2-bp duplication (c.182_183dupGT, NM_015295.2) in exon 1 of the SMCHD1 gene, predicted to result in a frameshift and premature termination (Gln62ValfsTer48). The mutation, which was identified by next-generation sequencing and direct sequencing of the SMCHD1 gene, was not present in the ExAC, gnomAD, and 1000 Genomes Project databases. The mutation was predicted to result in nonsense-mediated mRNA decay, a truncated protein lacking the essential functional GHKL-ATPase and SMC hinge domains, and/or disruption of normal splicing. The patient was also heterozygous for a D4Z4 (606009) repeat size of 10 repeated units. Functional studies were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMCHD1, GLY1157TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2075308386,
|
|
|
|
|
|
|
|
ClinVar: RCV001310239
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 52-year-old patient (patient III) with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901), Strafella et al. (2019) identified heterozygosity for a c.3469G-T transversion (c.3469G-T, NM_015295.2) in exon 27 of the SMCHD1 gene, predicted to result in a gly1157-to-ter (G1157X) substitution. The mutation, which was identified by next-generation sequencing and direct sequencing of the SMCHD1 gene, was not present in the 1000 Genomes Project, ExAC, and gnomAD databases. The mutation was predicted to result in nonsense-mediated mRNA decay or a truncated protein lacking the C-terminal SMC hinge domain and consequent disruption of protein secondary structure. The patient was also heterozygous for a D4Z4 (606009) repeat size of 8 units. Functional studies were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SMCHD1, 2-BP DEL, 5150AA
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV001310240
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 62-year-old patient (patient V) with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901), Strafella et al. (2019) identified heterozygosity for a 2-bp deletion (c.5150_5051delAA, NM_015295.2) in exon 41 of the SMCHD1 gene, predicted to result in a frameshift and premature termination (Lys1717ArgfsTer16). The mutation was identified by next-generation sequencing and direct sequencing of the SMCHD1 gene. The mutation was predicted to result in nonsense-mediated mRNA decay or a truncated protein lacking the C-terminal SMC hinge domain. The patient was found to have a normal D4Z4 (606009) repeat size of more than 11 repeated units. Functional studies were not performed. This patient was previously reported by Cascella et al. (2018). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
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<h4>
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<span class="mim-font">
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<strong>.0019 FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SMCHD1, 1-BP DUP, 2129C
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<br />
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SNP: rs2074549354,
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ClinVar: RCV001310241
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</span>
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<span class="mim-text-font">
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<p>In a 73-year-old patient (patient II) with facioscapulohumeral muscular dystrophy-2 (FSHD2; 158901), Strafella et al. (2019) identified heterozygosity for a 1-bp duplication (c.2129dupC, NM_015295.2) in exon 16 of the SMCHD1 gene, predicted to result in a frameshift and a premature termination codon (Ala711CysfsTer11). The mutation, which was identified by next-generation sequencing and direct sequencing of the SMCHD1 gene, was not present in the 1000 Genomes Project, ExAC, and gnomAD databases. The mutation was predicted to result in nonsense-mediated mRNA decay or a truncated protein lacking the C-terminal hinge domain. The patient was also heterozygous for a D4Z4 (606009) repeat size of 9 repeated units. Functional studies were not performed. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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Sacconi, S., Lemmers, R. J. L. F., Balog, J., van der Vliet, P. J., Lahaut, P., van Nieuwenhuizen, M. P., Straasheijm, K. R., Debipersad, R. D., Vos-Versteeg, M., Salviati, L., Casarin, A., Pegoraro, E., Tawil, R., Bakker, E., Tapscott, S. J., Desnuelle, C., van der Maarel, S. M.
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<strong>The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1.</strong>
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<strong>SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.</strong>
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<p class="mim-text-font">
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Wang, C.-Y., Jegu, T., Chu, H.-P., Oh, H. J., Lee, J. T.
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<strong>SMCHD1 merges chromosome compartments and assists formation of super-structures on the inactive X.</strong>
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[PubMed: 29887375]
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 03/05/2021<br>Bao Lige - updated : 10/12/2018<br>Marla J. F. O'Neill - updated : 02/27/2017<br>Cassandra L. Kniffin - updated : 11/4/2013<br>Cassandra L. Kniffin - updated : 12/17/2012
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Patricia A. Hartz : 12/14/2012
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carol : 04/30/2024<br>carol : 08/03/2021<br>carol : 03/05/2021<br>mgross : 10/12/2018<br>alopez : 06/20/2017<br>carol : 02/27/2017<br>carol : 08/11/2016<br>carol : 11/06/2013<br>ckniffin : 11/4/2013<br>carol : 8/29/2013<br>carol : 4/22/2013<br>carol : 12/18/2012<br>ckniffin : 12/17/2012<br>mgross : 12/14/2012
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OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
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