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Entry
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- #158901 - FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC; FSHD2
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- OMIM
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<p>
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<span class="h4">#158901</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/158901"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS158900"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</h4>
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<div style="display: table-cell;">Clinical Resources</div>
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</a>
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<div><a href="https://clinicaltrials.gov/search?cond=FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=62&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1443/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/facioscapulohumeral-muscular-dystrophy" 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=158901[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=269" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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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/disease/DOID:0111193" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/158901" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<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>ORPHA:</strong> 269<br />
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<strong>DO:</strong> 0111193<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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158901
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</span>
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</span>
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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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FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC; FSHD2
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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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FSHD2, DIGENIC<br />
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MUSCULAR DYSTROPHY, FACIOSCAPULOHUMERAL, TYPE 2<br />
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MUSCULAR DYSTROPHY, FACIOSCAPULOHUMERAL, TYPE 1B; FSHD1B
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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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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
|
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</th>
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<th>
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Phenotype <br /> mapping key
|
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/18/24?start=-3&limit=10&highlight=24">
|
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18p11.32
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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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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</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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</td>
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<td>
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<span class="mim-font">
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SMCHD1
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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/614982"> 614982 </a>
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/158901" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
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|
|
<div class="btn-group">
|
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|
|
<a href="/phenotypicSeries/PS158900" class="btn btn-info" role="button"> Phenotypic Series </a>
|
|
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
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|
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|
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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/158901" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/158901" 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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<div>
|
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<p />
|
|
</div>
|
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|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Digenic, dominant <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5232824&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5232824</a>]</span><br />
|
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</span>
|
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</div>
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</div>
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|
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</div>
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
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|
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<em> Face </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Facial muscle weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95666008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95666008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R29.810" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R29.810</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.83</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/781.94" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.94</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0427055&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427055</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007209" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007209</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0030319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030319</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030319</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Ears </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hearing loss <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/103276001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">103276001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/343087000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">343087000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15188001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15188001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H91.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H91.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011053&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011053</a>, <a href="https://bioportal.bioontology.org/search?q=C0018772&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018772</a>, <a href="https://bioportal.bioontology.org/search?q=C1384666&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1384666</a>, <a href="https://bioportal.bioontology.org/search?q=C3887873&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887873</a>, <a href="https://bioportal.bioontology.org/search?q=C2029884&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2029884</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000365" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000365</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> External Features </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Abdominal wall muscle weakness (positive Beevor sign) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5542198&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5542198</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009023" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009023</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MUSCLE, SOFT TISSUES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Shoulder girdle muscle weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249940002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249940002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0427063&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427063</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003547" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003547</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003547" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003547</a>]</span><br /> -
|
|
Facial muscle weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95666008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95666008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R29.810" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R29.810</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/438.83" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">438.83</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/781.94" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">781.94</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0427055&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427055</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007209" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007209</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0030319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030319</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030319</a>]</span><br /> -
|
|
Hip girdle weakness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249941003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249941003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0427064&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0427064</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003749" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003749</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003749" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003749</a>]</span><br /> -
|
|
Foot dorsiflexor weakness <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866141&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866141</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009027</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009027" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009027</a>]</span><br /> -
|
|
Abdominal wall muscle weakness (positive Beevor sign) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5542198&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5542198</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0009023" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0009023</a>]</span><br /> -
|
|
Dystrophic changes, mild, seen on muscle biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3552703&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3552703</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Normal to elevated CPK <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5542199&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5542199</a>]</span><br /> -
|
|
Marked hypomethylation at the D4Z4 4q and 10q loci <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5542200&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5542200</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Average age of onset: 26 years (range 0-60 years)<br /> -
|
|
Wheelchair dependency in minority of patients<br /> -
|
|
Facial and upper extremity weakness at presentation<br /> -
|
|
Progression to upper and lower extremity involvement<br /> -
|
|
Asymmetric muscle weakness may occur <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5562920&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5562920</a>]</span><br /> -
|
|
Majority of cases are sporadic<br /> -
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Reduced penetrance <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836598&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836598</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003829</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003829</a>]</span><br />
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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the structural maintenance of chromosomes flexible hinge domain-containing protein 1 gene (SMCHD1, <a href="/entry/614982#0001">614982.0001</a>) and a haplotype on chromosome 4 that is permissive for DUX4 (<a href="/entry/606009">606009</a>) expression<br />
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<h5>
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Facioscapulohumeral muscular dystrophy
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- <a href="/phenotypicSeries/PS158900">PS158900</a>
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- 4 Entries
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<strong>Location</strong>
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<strong>Phenotype</strong>
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<strong>Inheritance</strong>
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<strong>Phenotype<br />mapping key</strong>
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<strong>Phenotype<br />MIM number</strong>
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<strong>Gene/Locus<br />MIM number</strong>
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<span class="mim-font">
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<a href="/geneMap/1/904?start=-3&limit=10&highlight=904"> 1p13.3 </a>
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<span class="mim-font">
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<a href="/entry/619477"> ?Facioscapulohumeral muscular dystrophy 3, digenic </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Digenic recessive">DR</abbr>
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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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<a href="/entry/619477"> 619477 </a>
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<a href="/entry/615354"> LRIF1 </a>
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<span class="mim-font">
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<a href="/entry/615354"> 615354 </a>
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<a href="/geneMap/4/698?start=-3&limit=10&highlight=698"> 4q35 </a>
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<span class="mim-font">
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<a href="/entry/158900"> Facioscapulohumeral muscular dystrophy 1 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="4 - A contiguous gene duplication or deletion syndrome in which multiple genes are involved"> 4 </abbr>
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<span class="mim-font">
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<a href="/entry/158900"> 158900 </a>
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<span class="mim-font">
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<a href="/entry/158900"> FSHD1 </a>
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<span class="mim-font">
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<a href="/entry/158900"> 158900 </a>
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<a href="/geneMap/18/24?start=-3&limit=10&highlight=24"> 18p11.32 </a>
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<span class="mim-font">
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<a href="/entry/158901"> Facioscapulohumeral muscular dystrophy 2, digenic </a>
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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 class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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<a href="/entry/158901"> 158901 </a>
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<span class="mim-font">
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<a href="/entry/614982"> SMCHD1 </a>
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<span class="mim-font">
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<a href="/entry/614982"> 614982 </a>
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<a href="/geneMap/20/203?start=-3&limit=10&highlight=203"> 20q11.21 </a>
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<span class="mim-font">
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<a href="/entry/619478"> Facioscapulohumeral muscular dystrophy 4, digenic </a>
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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 class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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<a href="/entry/619478"> 619478 </a>
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<a href="/entry/602900"> DNMT3B </a>
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<span class="mim-font">
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<a href="/entry/602900"> 602900 </a>
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that facioscapulohumeral muscular dystrophy-2 (FSHD2) is caused by the combination of a heterozygous mutation in the SMCHD1 gene (<a href="/entry/614982">614982</a>) on chromosome 18p11 and the presence of a haplotype on chromosome 4 that is permissive for DUX4 (<a href="/entry/606009">606009</a>) expression.</p>
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<p>Facioscapulohumeral muscular dystrophy-2 (FSHD2) is a form of muscular dystrophy characterized by muscle weakness that first affects the facial muscles and upper extremities, later progressing to involve the lower extremities. The pattern of weakness is usually asymmetric (summary by <a href="#3" 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/?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>For a discussion of genetic heterogeneity of FSHD, see FSHD1 (<a href="/entry/158900">158900</a>), which is associated with physical contraction of D4Z4 macrosatellite repeats (see <a href="/entry/606009">606009</a>) in the subtelomeric region of chromosome 4q35. The pathogenesis of FSHD1 and FSHD2 converge at the level of D4Z4 chromatin relaxation and inappropriate expression of DUX4 in skeletal muscle (summary by <a href="#3" 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/?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>Clinical Features</strong>
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<p><a href="#1" class="mim-tip-reference" title="de Greef, J. C., Lemmers, R. J. L. F., Camano, P., Day, J. W., Sacconi, S., Dunand, M., van Engelen, B. G. M., Kiuru-Enari, S., Padberg, G. W., Rosa, A. L., Desnuelle, C., Spuler, S., Tarnopolsky, M., Venance, S. L., Frants, R. R., van der Maarel, S. M., Tawil, R. <strong>Clinical features of facioscapulohumeral muscular dystrophy 2.</strong> Neurology 75: 1548-1554, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20975055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20975055</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20975055[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/10.1212/WNL.0b013e3181f96175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20975055">De Greef et al. (2010)</a> examined 33 patients with FSHD2, defined as having no D4Z4 repeat less than 11 units on the permissive 4A161 haplotype, low D4Z4 methylation levels on chromosomes 4q and 10q, and a clinical phenotype consistent with FSHD. The average age at onset was 26 years (range 0 to 60), almost 10 years later than in FSHD1. The most common initial symptom was scapular weakness (61%), followed by foot dorsiflexor weakness (27%), facial weakness (10%), and hip girdle weakness (3%). On examination, all had scapular weakness, 79% had foot dorsiflexor weakness, and all but 2 patients had facial weakness. Positive Beevor sign, indicating abdominal muscle weakness, was found in 67% tested. The clinical severity score on average was similar to that reported in FSHD1. Less common findings included lack of ambulation (9%) and hearing loss (18%). Evaluation of the retinal vessels was not performed, but 2 patients examined showed no retinal vasculopathy. The majority of cases (20/33) were sporadic, 11 were familial, and the inheritance pattern was uncertain in 2, suggesting a different inheritance pattern from that in FSHD1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20975055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Sacconi, S., Camano, P., de Greef, J. C., Lemmers, R. J. L. F., Salviati, L., Boileau, P., Lopez de Munain Arregui, A., van der Maarel, S. M., Desnuelle, C. <strong>Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity.</strong> J. Med. Genet. 49: 41-46, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21984748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21984748</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21984748">Sacconi et al. (2012)</a> reported 6 patients with sporadic occurrence of FSHD2, including 1 reported by <a href="#1" class="mim-tip-reference" title="de Greef, J. C., Lemmers, R. J. L. F., Camano, P., Day, J. W., Sacconi, S., Dunand, M., van Engelen, B. G. M., Kiuru-Enari, S., Padberg, G. W., Rosa, A. L., Desnuelle, C., Spuler, S., Tarnopolsky, M., Venance, S. L., Frants, R. R., van der Maarel, S. M., Tawil, R. <strong>Clinical features of facioscapulohumeral muscular dystrophy 2.</strong> Neurology 75: 1548-1554, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20975055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20975055</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20975055[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/10.1212/WNL.0b013e3181f96175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20975055">de Greef et al. (2010)</a>. All had facial muscle and scapular weakness, and 5 had humeral, abdominal, and anterior foreleg weakness in an asymmetric pattern. Three had pelvic girdle weakness. Most of them experienced pain and fatigue, and 1 had sensorineural hearing loss. Creatine kinase levels were normal to 2-fold increased, muscle biopsies showed only mild dystrophic changes, and all had a myopathic pattern on EMG. All patients carried a 45- to 95-kb 4A161 allele and showed marked hypomethylation of the D4Z4 locus, typical of FSHD2. Study of family members showed that 3 unaffected mothers and 1 unaffected father carried the same 4A161 allele as their affected offspring, but they were not hypomethylated. One patient's unaffected daughter had significant hypomethylation, but the D4Z4 repeats were on a nonpermissive chromosome 4 background, suggesting that the hypomethylation determinant segregates independently from D4Z4 at 4q35. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21984748+20975055" 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>FSHD2 shows digenic inheritance, requiring the inheritance of 2 independent genetic variations: autosomal dominant inheritance of a mutation in the SMCHD1 gene and an FSHD-permissive DUX4 allele (<a href="#3" 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/?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><a href="#2" class="mim-tip-reference" title="Gilbert, J. R., Stajich, J. M., Wall, S., Carter, S. C., Qiu, H., Vance, J. M., Stewart, C. S., Speer, M. C., Pufky, J., Yamaoka, L. H., Rozear, M., Samson, F., Fardeau, M., Roses, A. D., Pericak-Vance, M. A. <strong>Evidence for heterogeneity in facioscapulohumeral muscular dystrophy (FSHD).</strong> Am. J. Hum. Genet. 53: 401-408, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8328457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8328457</a>]" pmid="8328457">Gilbert et al. (1993)</a> found evidence for heterogeneity in FSHD. In linkage studies, 5 of 7 families gave a posterior probability of more than 95% of being of the linked type, while 2 families appeared unlinked to that region of distal 4q. Affected members of the 2 unlinked families met the clinical criteria for the diagnosis of FSHD, including facial weakness, clavicular flattening, scapula winging, proximal muscle weakness, and myopathic changes on muscle biopsy without inflammatory or mitochondrial pathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8328457" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In FSHD1A on 4q35-qter, the disease is associated with deletion of 3.3-kb repeats from a tandem repeat located near the gene. This repeat cross-hybridizes with a telomeric region on 10q, making this cross-hybridizing region a plausible candidate gene for FSHD1B. <a href="#6" class="mim-tip-reference" title="Speer, M. C., Pericak-Vance, M. A., Stajich, J. M., Sarrica, J., Jordan, M., Roses, A. D., Vance, J. M., Gilbert, J. R. <strong>Further exclusion of FSHD1B from the telomeric region of 10q.</strong> Neurogenetics 1: 151-152, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10732819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10732819</a>] [<a href="https://doi.org/10.1007/s100480050023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10732819">Speer et al. (1997)</a> tested the most telomeric marker on 10q (sAVA4) and excluded approximately 17 cM on either side of this marker as harboring the FSHD1B gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10732819" 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>Among 33 patients with FSHD2, <a href="#1" class="mim-tip-reference" title="de Greef, J. C., Lemmers, R. J. L. F., Camano, P., Day, J. W., Sacconi, S., Dunand, M., van Engelen, B. G. M., Kiuru-Enari, S., Padberg, G. W., Rosa, A. L., Desnuelle, C., Spuler, S., Tarnopolsky, M., Venance, S. L., Frants, R. R., van der Maarel, S. M., Tawil, R. <strong>Clinical features of facioscapulohumeral muscular dystrophy 2.</strong> Neurology 75: 1548-1554, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20975055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20975055</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20975055[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/10.1212/WNL.0b013e3181f96175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20975055">de Greef et al. (2010)</a> found that all carried at least 1 D4Z4 repeat at chromosome 4q on the permissive haplotype 4A161. The shortest repeat on average was 16, which is shorter than the average of 28 observed in controls. Patients with FSHD2 showed significantly decreased methylation at D4Z4 on chromosomes 4q and 10q compared to controls, whereas those with FSHD1 had decreased methylation only at 4q. Moreover, the degree of decreased methylation in FSHD2 was significantly more than that observed in FSHD1; however, this was not associated with increased severity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20975055" 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="#8" class="mim-tip-reference" title="van Overveld, P. G. M., Lemmers, R. J. F. L., Sandkuijl, L. A., Enthoven, L., Winokur, S. T., Bakels, F., Padberg, G. W., van Ommen, G.-J. B., Frants, R. R., van der Maarel, S. M. <strong>Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy.</strong> Nature Genet. 35: 315-317, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14634647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14634647</a>] [<a href="https://doi.org/10.1038/ng1262" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14634647">Van Overveld et al. (2003)</a> showed that contraction of the D4Z4 repeat array in cases of FSHD1A causes marked hypomethylation of the contracted D4Z4 allele. Individuals with FSHD clinically identical to other cases but with an unaltered D4Z4 also have hypomethylation of D4Z4. These results strongly suggested that hypomethylation of D4Z4 is a key event in the cascade of epigenetic events causing FSHD1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14634647" 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 chromatin immunoprecipitation (ChIP) in HeLa cells, <a href="#9" class="mim-tip-reference" title="Zeng, W., de Greef, J. C., Chen, Y.-Y., Chien, R., Kong, X., Gregson, H. C., Winokur, S. T., Pyle, A., Robertson, K. D., Schmiesing, J. A., Kimonis, V. E., Balog, J., Frants, R. R., Ball, A. R., Jr., Lock, L. F., Donovan, P. J., van der Maarel, S. M., Yokomori, K. <strong>Specific loss of histone H3 lysine 9 trimethylation and HP1-gamma/cohesin binding at D4Z4 repeats is associated with facioscapulohumeral dystrophy (FSHD).</strong> PLoS Genet. 5: e1000559, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19593370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19593370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19593370[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/10.1371/journal.pgen.1000559" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19593370">Zeng et al. (2009)</a> found SUV39H1 (<a href="/entry/300254">300254</a>)-mediated trimethylation of histone H3 (see <a href="/entry/602810">602810</a>) at lysine-9 (H3K9), as well as trimethylation at H3 at lysine-27 (H3K27), both at D4Z4, representing transcriptionally repressive heterochromatin. There was also H3K4 dimethylation and H3 acetylation at proximal D4Z4 repeat regions, marking transcriptionally permissive euchromatin. The methylation signal at H3K9, at both the 4q and the 10q locus, was significantly decreased in cell lines derived from patients with FSHD1 (myoblasts and fibroblasts) and FSHD2 (fibroblasts) compared to controls. Contraction of D4Z4 at 1 allele showed a dominant effect on methylation of H3K9 at the other allele, as well as at the 10q locus, suggesting a spreading effect of histone modification. DNA hypomethylation was not observed in FSHD cells, and the decrease in H3K9 methylation was not observed in cells from patients with other forms of muscular dystrophy. Immunoprecipitation studies showed that loss of methylation at H3K9 interrupted binding of CBX3 (<a href="/entry/604477">604477</a>) and the cohesin complex (see, e.g., SCC1, <a href="/entry/606462">606462</a>) at this region. <a href="#9" class="mim-tip-reference" title="Zeng, W., de Greef, J. C., Chen, Y.-Y., Chien, R., Kong, X., Gregson, H. C., Winokur, S. T., Pyle, A., Robertson, K. D., Schmiesing, J. A., Kimonis, V. E., Balog, J., Frants, R. R., Ball, A. R., Jr., Lock, L. F., Donovan, P. J., van der Maarel, S. M., Yokomori, K. <strong>Specific loss of histone H3 lysine 9 trimethylation and HP1-gamma/cohesin binding at D4Z4 repeats is associated with facioscapulohumeral dystrophy (FSHD).</strong> PLoS Genet. 5: e1000559, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19593370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19593370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19593370[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/10.1371/journal.pgen.1000559" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19593370">Zeng et al. (2009)</a> hypothesized that loss of H3K9 methylation, and thus loss of CBX3 and cohesion, results in the disruption of chromatin regulation, thereby causing abnormal derepression of distant target genes that leads to the dystrophic phenotype specific to muscle tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19593370" 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>Mutation in the SMCHD1 Gene</em></strong></p><p>
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In affected members of 15 (79%) of 19 families with facioscapulohumeral muscular dystrophy 1B, <a href="#3" 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="/entry/614982#0001">614982.0001</a>-<a href="/entry/614982#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 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-permissive D4Z4 haplotype that contains a polyadenylation signal to stabilize DUX4 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 FSMD2 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="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="#7" 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 FSHD2 and identified 7 different pathogenic/likely pathogenic heterozygous mutations (see, e.g., <a href="/entry/614982#0016">614982.0016</a>-<a href="/entry/614982#0019">614982.0019</a>) in 7 patients. All of the mutations were predicted to strongly affect protein structure. Five of the patients had a borderline D4Z4 fragment size (8-10 repeats) and the other 2 had a normal D4Z4 fragment size (more than 11 repeats). <a href="#7" 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="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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<p><a href="#5" 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="/entry/614982#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="#5" 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>
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[<a href="https://doi.org/10.1212/WNL.0b013e3181f96175" target="_blank">Full Text</a>]
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Gilbert, J. R., Stajich, J. M., Wall, S., Carter, S. C., Qiu, H., Vance, J. M., Stewart, C. S., Speer, M. C., Pufky, J., Yamaoka, L. H., Rozear, M., Samson, F., Fardeau, M., Roses, A. D., Pericak-Vance, M. A.
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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.
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<strong>Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.</strong>
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[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://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'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.2454" target="_blank">Full Text</a>]
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Sacconi, S., Camano, P., de Greef, J. C., Lemmers, R. J. L. F., Salviati, L., Boileau, P., Lopez de Munain Arregui, A., van der Maarel, S. M., Desnuelle, C.
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<strong>Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity.</strong>
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J. Med. Genet. 49: 41-46, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21984748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21984748</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21984748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2011-100101" target="_blank">Full Text</a>]
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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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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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Speer, M. C., Pericak-Vance, M. A., Stajich, J. M., Sarrica, J., Jordan, M., Roses, A. D., Vance, J. M., Gilbert, J. R.
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Neurogenetics 1: 151-152, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10732819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10732819</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10732819" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s100480050023" target="_blank">Full Text</a>]
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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.
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<strong>The variability of SMCHD1 gene in FSHD patients: evidence of new mutations.</strong>
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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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van Overveld, P. G. M., Lemmers, R. J. F. L., Sandkuijl, L. A., Enthoven, L., Winokur, S. T., Bakels, F., Padberg, G. W., van Ommen, G.-J. B., Frants, R. R., van der Maarel, S. M.
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<strong>Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy.</strong>
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Nature Genet. 35: 315-317, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14634647/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14634647</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14634647" 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/ng1262" target="_blank">Full Text</a>]
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Zeng, W., de Greef, J. C., Chen, Y.-Y., Chien, R., Kong, X., Gregson, H. C., Winokur, S. T., Pyle, A., Robertson, K. D., Schmiesing, J. A., Kimonis, V. E., Balog, J., Frants, R. R., Ball, A. R., Jr., Lock, L. F., Donovan, P. J., van der Maarel, S. M., Yokomori, K.
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<strong>Specific loss of histone H3 lysine 9 trimethylation and HP1-gamma/cohesin binding at D4Z4 repeats is associated with facioscapulohumeral dystrophy (FSHD).</strong>
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PLoS Genet. 5: e1000559, 2009. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19593370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19593370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19593370[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=19593370" 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/10.1371/journal.pgen.1000559" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 03/05/2021
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Cassandra L. Kniffin - updated : 11/4/2013<br>Cassandra L. Kniffin - updated : 12/17/2012<br>Cassandra L. Kniffin - updated : 4/25/2012<br>Cassandra L. Kniffin - updated : 11/21/2011<br>Victor A. McKusick - updated : 5/5/1998
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Victor A. McKusick : 4/13/1994
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alopez : 05/01/2023
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carol : 10/08/2021<br>carol : 08/16/2021<br>ckniffin : 08/12/2021<br>carol : 03/05/2021<br>joanna : 02/08/2021<br>carol : 11/06/2013<br>ckniffin : 11/4/2013<br>mgross : 2/4/2013<br>carol : 12/18/2012<br>ckniffin : 12/17/2012<br>carol : 4/26/2012<br>ckniffin : 4/25/2012<br>carol : 11/23/2011<br>ckniffin : 11/21/2011<br>carol : 9/16/2011<br>joanna : 3/18/2004<br>carol : 5/12/1998<br>terry : 5/5/1998<br>alopez : 6/2/1997<br>carol : 4/13/1994
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<strong>#</strong> 158901
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FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 2, DIGENIC; FSHD2
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FSHD2, DIGENIC<br />
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MUSCULAR DYSTROPHY, FACIOSCAPULOHUMERAL, TYPE 2<br />
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MUSCULAR DYSTROPHY, FACIOSCAPULOHUMERAL, TYPE 1B; FSHD1B
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<strong>ORPHA:</strong> 269;
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<strong>DO:</strong> 0111193;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus <br /> MIM number
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18p11.32
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Facioscapulohumeral muscular dystrophy 2, digenic
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158901
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Digenic dominant
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SMCHD1
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614982
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<p>A number sign (#) is used with this entry because of evidence that facioscapulohumeral muscular dystrophy-2 (FSHD2) is caused by the combination of a heterozygous mutation in the SMCHD1 gene (614982) on chromosome 18p11 and the presence of a haplotype on chromosome 4 that is permissive for DUX4 (606009) expression.</p>
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<strong>Description</strong>
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<p>Facioscapulohumeral muscular dystrophy-2 (FSHD2) is a form of muscular dystrophy characterized by muscle weakness that first affects the facial muscles and upper extremities, later progressing to involve the lower extremities. The pattern of weakness is usually asymmetric (summary by Lemmers et al., 2012). </p><p>For a discussion of genetic heterogeneity of FSHD, see FSHD1 (158900), which is associated with physical contraction of D4Z4 macrosatellite repeats (see 606009) in the subtelomeric region of chromosome 4q35. The pathogenesis of FSHD1 and FSHD2 converge at the level of D4Z4 chromatin relaxation and inappropriate expression of DUX4 in skeletal muscle (summary by Lemmers et al., 2012). </p>
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<p>De Greef et al. (2010) examined 33 patients with FSHD2, defined as having no D4Z4 repeat less than 11 units on the permissive 4A161 haplotype, low D4Z4 methylation levels on chromosomes 4q and 10q, and a clinical phenotype consistent with FSHD. The average age at onset was 26 years (range 0 to 60), almost 10 years later than in FSHD1. The most common initial symptom was scapular weakness (61%), followed by foot dorsiflexor weakness (27%), facial weakness (10%), and hip girdle weakness (3%). On examination, all had scapular weakness, 79% had foot dorsiflexor weakness, and all but 2 patients had facial weakness. Positive Beevor sign, indicating abdominal muscle weakness, was found in 67% tested. The clinical severity score on average was similar to that reported in FSHD1. Less common findings included lack of ambulation (9%) and hearing loss (18%). Evaluation of the retinal vessels was not performed, but 2 patients examined showed no retinal vasculopathy. The majority of cases (20/33) were sporadic, 11 were familial, and the inheritance pattern was uncertain in 2, suggesting a different inheritance pattern from that in FSHD1. </p><p>Sacconi et al. (2012) reported 6 patients with sporadic occurrence of FSHD2, including 1 reported by de Greef et al. (2010). All had facial muscle and scapular weakness, and 5 had humeral, abdominal, and anterior foreleg weakness in an asymmetric pattern. Three had pelvic girdle weakness. Most of them experienced pain and fatigue, and 1 had sensorineural hearing loss. Creatine kinase levels were normal to 2-fold increased, muscle biopsies showed only mild dystrophic changes, and all had a myopathic pattern on EMG. All patients carried a 45- to 95-kb 4A161 allele and showed marked hypomethylation of the D4Z4 locus, typical of FSHD2. Study of family members showed that 3 unaffected mothers and 1 unaffected father carried the same 4A161 allele as their affected offspring, but they were not hypomethylated. One patient's unaffected daughter had significant hypomethylation, but the D4Z4 repeats were on a nonpermissive chromosome 4 background, suggesting that the hypomethylation determinant segregates independently from D4Z4 at 4q35. </p>
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<strong>Inheritance</strong>
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<p>FSHD2 shows digenic inheritance, requiring the inheritance of 2 independent genetic variations: autosomal dominant inheritance of a mutation in the SMCHD1 gene and an FSHD-permissive DUX4 allele (Lemmers et al., 2012). </p>
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<strong>Mapping</strong>
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<p>Gilbert et al. (1993) found evidence for heterogeneity in FSHD. In linkage studies, 5 of 7 families gave a posterior probability of more than 95% of being of the linked type, while 2 families appeared unlinked to that region of distal 4q. Affected members of the 2 unlinked families met the clinical criteria for the diagnosis of FSHD, including facial weakness, clavicular flattening, scapula winging, proximal muscle weakness, and myopathic changes on muscle biopsy without inflammatory or mitochondrial pathology. </p><p>In FSHD1A on 4q35-qter, the disease is associated with deletion of 3.3-kb repeats from a tandem repeat located near the gene. This repeat cross-hybridizes with a telomeric region on 10q, making this cross-hybridizing region a plausible candidate gene for FSHD1B. Speer et al. (1997) tested the most telomeric marker on 10q (sAVA4) and excluded approximately 17 cM on either side of this marker as harboring the FSHD1B gene. </p>
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<strong>Molecular Genetics</strong>
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<p>Among 33 patients with FSHD2, de Greef et al. (2010) found that all carried at least 1 D4Z4 repeat at chromosome 4q on the permissive haplotype 4A161. The shortest repeat on average was 16, which is shorter than the average of 28 observed in controls. Patients with FSHD2 showed significantly decreased methylation at D4Z4 on chromosomes 4q and 10q compared to controls, whereas those with FSHD1 had decreased methylation only at 4q. Moreover, the degree of decreased methylation in FSHD2 was significantly more than that observed in FSHD1; however, this was not associated with increased severity. </p><p>Van Overveld et al. (2003) showed that contraction of the D4Z4 repeat array in cases of FSHD1A causes marked hypomethylation of the contracted D4Z4 allele. Individuals with FSHD clinically identical to other cases but with an unaltered D4Z4 also have hypomethylation of D4Z4. These results strongly suggested that hypomethylation of D4Z4 is a key event in the cascade of epigenetic events causing FSHD1. </p><p>Using chromatin immunoprecipitation (ChIP) in HeLa cells, Zeng et al. (2009) found SUV39H1 (300254)-mediated trimethylation of histone H3 (see 602810) at lysine-9 (H3K9), as well as trimethylation at H3 at lysine-27 (H3K27), both at D4Z4, representing transcriptionally repressive heterochromatin. There was also H3K4 dimethylation and H3 acetylation at proximal D4Z4 repeat regions, marking transcriptionally permissive euchromatin. The methylation signal at H3K9, at both the 4q and the 10q locus, was significantly decreased in cell lines derived from patients with FSHD1 (myoblasts and fibroblasts) and FSHD2 (fibroblasts) compared to controls. Contraction of D4Z4 at 1 allele showed a dominant effect on methylation of H3K9 at the other allele, as well as at the 10q locus, suggesting a spreading effect of histone modification. DNA hypomethylation was not observed in FSHD cells, and the decrease in H3K9 methylation was not observed in cells from patients with other forms of muscular dystrophy. Immunoprecipitation studies showed that loss of methylation at H3K9 interrupted binding of CBX3 (604477) and the cohesin complex (see, e.g., SCC1, 606462) at this region. Zeng et al. (2009) hypothesized that loss of H3K9 methylation, and thus loss of CBX3 and cohesion, results in the disruption of chromatin regulation, thereby causing abnormal derepression of distant target genes that leads to the dystrophic phenotype specific to muscle tissue. </p><p><strong><em>Mutation in the SMCHD1 Gene</em></strong></p><p>
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In affected members of 15 (79%) of 19 families with facioscapulohumeral muscular dystrophy 1B, 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 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-permissive D4Z4 haplotype that contains a polyadenylation signal to stabilize DUX4 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 FSMD2 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. </p><p>Strafella et al. (2019) performed next-generation sequencing of the SMCHD1 gene in a cohort of patients with FSHD2 and identified 7 different pathogenic/likely pathogenic heterozygous mutations (see, e.g., 614982.0016-614982.0019) in 7 patients. All of the mutations were predicted to strongly affect protein structure. Five of the patients had a borderline D4Z4 fragment size (8-10 repeats) and the other 2 had a normal D4Z4 fragment size (more than 11 repeats). Strafella et al. (2019) concluded that borderline D4Z4 size may be a risk factor or pathogenic modifier in patients with SMCHD1 mutations. </p>
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<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>
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<strong>REFERENCES</strong>
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de Greef, J. C., Lemmers, R. J. L. F., Camano, P., Day, J. W., Sacconi, S., Dunand, M., van Engelen, B. G. M., Kiuru-Enari, S., Padberg, G. W., Rosa, A. L., Desnuelle, C., Spuler, S., Tarnopolsky, M., Venance, S. L., Frants, R. R., van der Maarel, S. M., Tawil, R.
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<strong>Clinical features of facioscapulohumeral muscular dystrophy 2.</strong>
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Neurology 75: 1548-1554, 2010.
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[PubMed: 20975055]
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[Full Text: https://doi.org/10.1212/WNL.0b013e3181f96175]
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Gilbert, J. R., Stajich, J. M., Wall, S., Carter, S. C., Qiu, H., Vance, J. M., Stewart, C. S., Speer, M. C., Pufky, J., Yamaoka, L. H., Rozear, M., Samson, F., Fardeau, M., Roses, A. D., Pericak-Vance, M. A.
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<strong>Evidence for heterogeneity in facioscapulohumeral muscular dystrophy (FSHD).</strong>
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Am. J. Hum. Genet. 53: 401-408, 1993.
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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.
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<strong>Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.</strong>
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Sacconi, S., Camano, P., de Greef, J. C., Lemmers, R. J. L. F., Salviati, L., Boileau, P., Lopez de Munain Arregui, A., van der Maarel, S. M., Desnuelle, C.
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<strong>Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity.</strong>
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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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Speer, M. C., Pericak-Vance, M. A., Stajich, J. M., Sarrica, J., Jordan, M., Roses, A. D., Vance, J. M., Gilbert, J. R.
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<strong>Further exclusion of FSHD1B from the telomeric region of 10q.</strong>
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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.
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<strong>The variability of SMCHD1 gene in FSHD patients: evidence of new mutations.</strong>
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van Overveld, P. G. M., Lemmers, R. J. F. L., Sandkuijl, L. A., Enthoven, L., Winokur, S. T., Bakels, F., Padberg, G. W., van Ommen, G.-J. B., Frants, R. R., van der Maarel, S. M.
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<strong>Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy.</strong>
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Zeng, W., de Greef, J. C., Chen, Y.-Y., Chien, R., Kong, X., Gregson, H. C., Winokur, S. T., Pyle, A., Robertson, K. D., Schmiesing, J. A., Kimonis, V. E., Balog, J., Frants, R. R., Ball, A. R., Jr., Lock, L. F., Donovan, P. J., van der Maarel, S. M., Yokomori, K.
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<strong>Specific loss of histone H3 lysine 9 trimethylation and HP1-gamma/cohesin binding at D4Z4 repeats is associated with facioscapulohumeral dystrophy (FSHD).</strong>
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[PubMed: 19593370]
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Hilary J. Vernon - updated : 03/05/2021<br>Cassandra L. Kniffin - updated : 11/4/2013<br>Cassandra L. Kniffin - updated : 12/17/2012<br>Cassandra L. Kniffin - updated : 4/25/2012<br>Cassandra L. Kniffin - updated : 11/21/2011<br>Victor A. McKusick - updated : 5/5/1998
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Victor A. McKusick : 4/13/1994
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alopez : 05/01/2023<br>carol : 10/08/2021<br>carol : 08/16/2021<br>ckniffin : 08/12/2021<br>carol : 03/05/2021<br>joanna : 02/08/2021<br>carol : 11/06/2013<br>ckniffin : 11/4/2013<br>mgross : 2/4/2013<br>carol : 12/18/2012<br>ckniffin : 12/17/2012<br>carol : 4/26/2012<br>ckniffin : 4/25/2012<br>carol : 11/23/2011<br>ckniffin : 11/21/2011<br>carol : 9/16/2011<br>joanna : 3/18/2004<br>carol : 5/12/1998<br>terry : 5/5/1998<br>alopez : 6/2/1997<br>carol : 4/13/1994
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