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Entry
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- #158900 - FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 1; FSHD1
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- OMIM
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<p>
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<span class="h4">#158900</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="/clinicalSynopsis/158900"><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="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#history">History</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</a>
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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" 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://www.diseaseinfosearch.org/x/2704" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=158900[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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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/be4fbe5a-034a-4082-8609-e5ce9a255ce4/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:158900" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 399091004<br />
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<strong>ICD10CM:</strong> G71.02<br />
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<strong>ORPHA:</strong> 269<br />
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<strong>DO:</strong> 0111192<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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158900
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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 1; FSHD1
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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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MUSCULAR DYSTROPHY, FACIOSCAPULOHUMERAL, TYPE 1<br />
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FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY; FSHD; FMD<br />
|
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MUSCULAR DYSTROPHY, FACIOSCAPULOHUMERAL, TYPE 1A; FSHD1A<br />
|
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LANDOUZY-DEJERINE MUSCULAR DYSTROPHY
|
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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="includedTitles" 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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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY, INFANTILE, INCLUDED
|
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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FACIOSCAPULOHUMERAL DYSTROPHY WITH SENSORINEURAL HEARING LOSS AND TORTUOSITY OF RETINAL ARTERIOLES, INCLUDED
|
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/4/698?start=-3&limit=10&highlight=698">4q35</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr4:182300001-190214555&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">4:182,300,001-190,214,555</a> </span>
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</em>
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</strong>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/4/698?start=-3&limit=10&highlight=698">
|
|
4q35
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Facioscapulohumeral muscular dystrophy 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/158900"> 158900 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="4 - A contiguous gene duplication or deletion syndrome in which multiple genes are involved">4</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
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|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/158900" 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>
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
|
|
<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>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<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/158900" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/158900" 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>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Face </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Facial muscle weakness and atrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674994&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674994</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Ears </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Hearing loss, sensorineural (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/60700002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">60700002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H90.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H90.5</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.10</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018784&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018784</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000407" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000407</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000407" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000407</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Retinal vasculopathy (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674995&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674995</a>]</span><br /> -
|
|
Peripheral retinal telangiectasia, capillary closure, leakage, and microaneurysm formation (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674996&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674996</a>]</span><br /> -
|
|
Exudative retinal detachment (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/38599001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">38599001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H33.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H33.2</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H33.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H33.20</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/361.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">361.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0154822&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0154822</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012231" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012231</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012231" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012231</a>]</span><br /> -
|
|
Macular exudates (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/423084001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">423084001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1827223&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1827223</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030496" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030496</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0030496" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0030496</a>]</span><br /> -
|
|
Macular hemorrhages (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2187053&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2187053</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0025574" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0025574</a>]</span><br /> -
|
|
External ophthalmoplegia (uncommon) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/19373007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">19373007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H49.88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H49.88</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/378.55" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">378.55</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0162292&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0162292</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000544" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000544</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000544" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000544</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Mouth </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Tongue atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/50805004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">50805004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K14.8" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K14.8</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241423&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241423</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012473" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012473</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012473" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012473</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> RESPIRATORY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Lung </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Restrictive pulmonary dysfunction (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2675006&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2675006</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CHEST </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Ribs Sternum Clavicles & Scapulae </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Scapular winging <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/17211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">17211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0240953&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0240953</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003691" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003691</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003691" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003691</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
|
|
|
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|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Dysphagia (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/288939007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">288939007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40739000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40739000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R13.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R13.10</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/787.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/787.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">787.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0011168&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0011168</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002015" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002015</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
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|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<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 and atrophy, progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3805753&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3805753</a>]</span><br /> -
|
|
Facial muscle weakness and atrophy, progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2675000&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2675000</a>]</span><br /> -
|
|
Upper arm and pelvic muscle weakness and atrophy (later onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2675001&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2675001</a>]</span><br /> -
|
|
Asymmetric muscle weakness <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 /> -
|
|
Abdominal wall muscle weakness (later onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2675002&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2675002</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 /> -
|
|
Foot extensor muscle weakness (later onset) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2675003&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2675003</a>]</span><br /> -
|
|
Calf hypertrophy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1843057&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1843057</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008981" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008981</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008981" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008981</a>]</span><br /> -
|
|
Wheelchair dependency in 20% of patients by age 40 <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2675004&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2675004</a>]</span><br /> -
|
|
Dystrophic changes seein on skeletal muscle biopsy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5562921&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5562921</a>]</span><br /> -
|
|
Abnormal changes in the organization of the sarcolemma and the subsarcolemmal membrane cytoskeleton <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2675005&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2675005</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Impaired intellectual development (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747273&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747273</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
|
|
Seizures (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Increased serum creatine kinase <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241005&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241005</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003236" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003236</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003236" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003236</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">
|
|
|
|
- Slowly progressive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1854494&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1854494</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003677</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003677" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003677</a>]</span><br /> -
|
|
Onset range childhood to adulthood<br /> -
|
|
Clinical variability<br /> -
|
|
Incomplete 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 /> -
|
|
Incidence 1 in 20,000<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by contraction of a D4Z4 repeat array at chromosome 4q35<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Facioscapulohumeral muscular dystrophy
|
|
- <a href="/phenotypicSeries/PS158900">PS158900</a>
|
|
- 4 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/904?start=-3&limit=10&highlight=904"> 1p13.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619477"> ?Facioscapulohumeral muscular dystrophy 3, digenic </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Digenic recessive">DR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/619477"> 619477 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615354"> LRIF1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615354"> 615354 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/4/698?start=-3&limit=10&highlight=698"> 4q35 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/158900"> Facioscapulohumeral muscular dystrophy 1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="4 - A contiguous gene duplication or deletion syndrome in which multiple genes are involved"> 4 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/158900"> 158900 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/158900"> FSHD1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/158900"> 158900 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/18/24?start=-3&limit=10&highlight=24"> 18p11.32 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/158901"> Facioscapulohumeral muscular dystrophy 2, digenic </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
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<span class="mim-font">
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<p>A number sign (#) is used with this entry because facioscapulohumeral muscular dystrophy-1 (FSHD1) is associated with contraction of the D4Z4 macrosatellite repeat (see <a href="/entry/606009">606009</a>) in the subtelomeric region of chromosome 4q35.</p><p>In unaffected individuals, the D4Z4 array consists of 11 to 150 repeat units (corresponding to EcoRI fragments of 41 to 350 kb), whereas FSHD patients have contraction of the repeat units from 1 to 10 (corresponding to EcoRI fragments of 10 to 35 kb). Borderline fragment sizes (35 to 40 kb) must be interpreted with caution (summary by <a href="#57" class="mim-tip-reference" title="Mostacciuolo, M. L., Pastorello, E., Vazza, G., Miorin, M., Angelini, C., Tomelleri, G., Galluzzi, G., Trevisan, C. P. <strong>Facioscapulohumeral muscular dystrophy: epidemiological and molecular study in a north-east Italian population sample.</strong> Clin. Genet. 75: 550-555, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19320656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19320656</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01158.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19320656">Mostacciuolo et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19320656" 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>Facioscapulohumeral muscular dystrophy (FSHD) is a progressive skeletal muscle disorder with a highly variable phenotype. Most patients present as adults, although about 10% show symptoms before the age of 5 years, including from infancy in some cases. In general, the disease initially involves the upper body, including the face and the scapulae, followed by weakness at the foot dorsiflexors and hip girdles. Typical features are striking asymmetry of muscle involvement from side to side and sparing of bulbar extraocular and respiratory muscles. There is significant clinical variability, even within families, as well as incomplete penetrance. FSHD1 accounts for about 95% of patients. Facioscapulohumeral muscular dystrophy is the third most common hereditary disease of muscle after Duchenne (DMD; <a href="/entry/310200">310200</a>) and myotonic (<a href="/entry/160900">160900</a>) dystrophy (<a href="#82" class="mim-tip-reference" title="Tawil, R., Figlewicz, D. A., Griggs, R. C., Weiffenbach, B., FSH Consortium. <strong>Facioscapulohumeral dystrophy: a distinct regional myopathy with a novel molecular pathogenesis.</strong> Ann. Neurol. 43: 279-282, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9506542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9506542</a>] [<a href="https://doi.org/10.1002/ana.410430303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9506542">Tawil et al., 1998</a>; <a href="#95" class="mim-tip-reference" title="van den Boogaard, M. L., Lemmers, R. J. L. F., Balog, J., Wohlgemuth, M., Auranen, M., Mitsuhashi, S., van der Vliet, P. J., Straasheijm, K. R., van den Akker, R. F. P., Kriek, M., Laurense-Bik, M. E. Y., Raz, V., and 11 others. <strong>Mutations in DNMT3B modify epigenetic repression of the D4Z4 repeat and the penetrance of facioscapulohumeral dystrophy.</strong> Am. J. Hum. Genet. 98: 1020-1029, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27153398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27153398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27153398[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.2016.03.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27153398">van den Boogaard et al., 2016</a>; <a href="#31" class="mim-tip-reference" title="Johnson, N. E., Ankala, A. <strong>Evolving genetic heterogeneity of facioscapulohumeral muscular dystrophy</strong> Neurology 94: 1011-1012, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32467132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32467132</a>] [<a href="https://doi.org/10.1212/WNL.0000000000009580" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32467132">Johnson and Ankala, 2020</a>; <a href="#73" class="mim-tip-reference" title="Schatzl, T., Kaiser, L., Deigner, H.-P. <strong>Facioscapulohumeral muscular dystrophy: genetics, gene activation and downstream signalling with regard to recent therapeutic approaches: an update.</strong> Orphanet. J. Rare Dis. 16: 129, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33712050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33712050</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33712050[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13023-021-01760-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33712050">Schatzl et al., 2021</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=32467132+27153398+9506542+33712050" 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="#66" class="mim-tip-reference" title="Richards, M., Coppee, F., Thomas, N., Belayew, A., Upadhyaya, M. <strong>Facioscapulohumeral muscular dystrophy (FSHD): an enigma unravelled?</strong> Hum. Genet. 131: 325-340, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21984394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21984394</a>] [<a href="https://doi.org/10.1007/s00439-011-1100-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21984394">Richards et al. (2012)</a> and <a href="#73" class="mim-tip-reference" title="Schatzl, T., Kaiser, L., Deigner, H.-P. <strong>Facioscapulohumeral muscular dystrophy: genetics, gene activation and downstream signalling with regard to recent therapeutic approaches: an update.</strong> Orphanet. J. Rare Dis. 16: 129, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33712050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33712050</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33712050[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13023-021-01760-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33712050">Schatzl et al. (2021)</a> provided detailed reviews of FSHD, including clinical features, genetics, diagnosis, pathogenesis, and potential therapeutic avenues. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21984394+33712050" 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>Genetic Heterogeneity of FSHD</em></strong></p><p>
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Several other genetic forms of FSHD that are clinically indistinguishable from FSHD1, but not associated with physical contraction of the D4Z4 microsatellite repeat, have been identified. Historically, these forms have collectively been called 'FSHD2.' Tissue from patients with 'FSHD2' shows D4Z4 hypomethylation on chromosomes 4 and 10, suggesting the presence of unique transactivating factors, some of which have been identified. Genetic forms of FSHD other than FSHD1 account for about 5% of patients overall (summary by <a href="#26" class="mim-tip-reference" title="Hamanaka, K., Sikrova, D., Mitsuhashi, S., Masuda, H., Sekiguchi, Y., Sugiyama, A., Shibuya, K., Lemmers, R. J. L. F., Goossens, R., Ogawa, M., Nagao, K., Obuse, C., Noguchi, S, Hayashi, Y. K., Kuwabara, S., Balog, J., Nishino, I., van der Maarel, S. M. <strong>Homozygous nonsense variant in LRIF1 associated with facioscapulohumeral muscular dystrophy.</strong> Neurology 94: e2441-e2447, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32467133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32467133</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32467133[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.0000000000009617" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32467133">Hamanaka et al., 2020</a>; <a href="#31" class="mim-tip-reference" title="Johnson, N. E., Ankala, A. <strong>Evolving genetic heterogeneity of facioscapulohumeral muscular dystrophy</strong> Neurology 94: 1011-1012, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32467132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32467132</a>] [<a href="https://doi.org/10.1212/WNL.0000000000009580" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32467132">Johnson and Ankala, 2020</a>; review by <a href="#73" class="mim-tip-reference" title="Schatzl, T., Kaiser, L., Deigner, H.-P. <strong>Facioscapulohumeral muscular dystrophy: genetics, gene activation and downstream signalling with regard to recent therapeutic approaches: an update.</strong> Orphanet. J. Rare Dis. 16: 129, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33712050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33712050</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33712050[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13023-021-01760-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33712050">Schatzl et al., 2021</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=32467132+32467133+33712050" 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>FSHD2 (<a href="/entry/158901">158901</a>) is caused by mutation in the SMCHD1 gene (<a href="/entry/614982">614982</a>) on chromosome 18p11; FSHD3 (<a href="/entry/619477">619477</a>) by mutation in the LRIF1 gene (<a href="/entry/615354">615354</a>) on chromosome 1p13; and FSHD4 (<a href="/entry/619478">619478</a>) by mutation in the DMNT3B gene (<a href="/entry/602900">602900</a>) on chromosome 20q11. Patients with FSHD2, FSHD3, and FSHD4 also carry a 'permissive haplotype' on chromosome 4 (4qA) that promotes DUX4 (<a href="/entry/606009">606009</a>) expression. There is significant clinical variability and incomplete penetrance.</p>
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<p><a href="#32" class="mim-tip-reference" title="Justin-Besancon, L., Pequignot, H., Contamin, F., Delavierre, P., Rolland, P. <strong>Myopathie du type Landouzy-Dejerine. Rapport d'une observation historique.</strong> Sem. Hop. Paris 40: 2990-2999, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14257214/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14257214</a>]" pmid="14257214">Justin-Besancon et al. (1964)</a> added 3 affected generations to the 4 described by <a href="#34" class="mim-tip-reference" title="Landouzy, L., Dejerine, J. <strong>De la myopathie atrophique progressive.</strong> Rev. Med. Franc. 5: 81, 1885."None>Landouzy and Dejerine (1885)</a> and gave autopsy findings in 1 of the original patients who died at age 86 years. Some cases show congenital absence of part or all of certain muscles such as a pectoral muscle. The relationship of the congenital defect of muscle to the dystrophy is unclear. <a href="#90" class="mim-tip-reference" title="Tyler, F. H., Stephens, F. E. <strong>Studies in disorders of muscle. II. Clinical manifestations and inheritance of facioscapulohumeral dystrophy in a large family.</strong> Ann. Intern. Med. 32: 640-660, 1950.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15411118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15411118</a>] [<a href="https://doi.org/10.7326/0003-4819-32-4-640" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15411118">Tyler and Stephens (1950)</a> and <a href="#91" class="mim-tip-reference" title="Tyler, F. H. <strong>The inheritance of neuromuscular disorders.</strong> Res. Publ. Assoc. Res. Nerv. Ment. Dis. 33: 283-292, 1954.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13246083/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13246083</a>]" pmid="13246083">Tyler (1954)</a> reported 17 families. In 1 kindred 150 members were affected over 6 generations. A girl, whose face alone was affected at age 9 when examined by <a href="#34" class="mim-tip-reference" title="Landouzy, L., Dejerine, J. <strong>De la myopathie atrophique progressive.</strong> Rev. Med. Franc. 5: 81, 1885."None>Landouzy and Dejerine (1885)</a>, did not develop weakness of the arms until age 60 and of the legs until age 70, and survived to age 85 years. In her family, affected members were distributed through 8 generations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13246083+14257214+15411118" 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="#52" class="mim-tip-reference" title="Meyerson, M. D., Lewis, E., Ill, K. <strong>Facioscapulohumeral muscular dystrophy and accompanying hearing loss.</strong> Arch. Otolaryng. 110: 261-266, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6704043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6704043</a>] [<a href="https://doi.org/10.1001/archotol.1984.00800300053012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6704043">Meyerson et al. (1984)</a> reported sensorineural hearing loss in 2 sibs with FSH muscular dystrophy which affected other members of the family in typical manner. The studies of <a href="#8" class="mim-tip-reference" title="Brouwer, O. F., Padberg, G. W., Ruys, C. J. M., Brand, R., de Laat, J. A. P. M., Grote, J. J. <strong>Hearing loss in facioscapulohumeral muscular dystrophy.</strong> Neurology 41: 1878-1881, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1745341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1745341</a>] [<a href="https://doi.org/10.1212/wnl.41.12.1878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1745341">Brouwer et al. (1991)</a> suggest that a 'change of hearing function is part of the disease and may lead to severe hearing loss in some patients.' Deafness and abnormalities of retinal vessels (see later) are probably integral parts of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1745341+6704043" 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="#72" class="mim-tip-reference" title="Sayli, B. S., Yaltkaya, K., Cin, S. <strong>Facioscapulohumeral muscular dystrophy concentrated in the village Cullar, Nevsehir, Turkey.</strong> Hum. Genet. 67: 201-208, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6745940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6745940</a>] [<a href="https://doi.org/10.1007/BF00273001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6745940">Sayli et al. (1984)</a> found at least 53 affected persons in a Turkish kindred originating in the village of Cullar. Initial signs and symptoms seemed to appear early in infancy in many. The disorder progressed slowly without interfering significantly with survival and reproduction. Symptoms first involved the face, upper arms, and shoulder muscles. Creatine kinase levels were 1.5 to 2 times normal. Many of the affected persons were identified on examination; only 13 reported complaints and their mean age was 40.1 years. After the kindred reported by <a href="#90" class="mim-tip-reference" title="Tyler, F. H., Stephens, F. E. <strong>Studies in disorders of muscle. II. Clinical manifestations and inheritance of facioscapulohumeral dystrophy in a large family.</strong> Ann. Intern. Med. 32: 640-660, 1950.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15411118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15411118</a>] [<a href="https://doi.org/10.7326/0003-4819-32-4-640" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15411118">Tyler and Stephens (1950)</a>, this is the most extensively affected family studied to date. <a href="#1" class="mim-tip-reference" title="Awerbuch, G. I., Nigro, M. A., Wishnow, R. <strong>Beevor's sign and facioscapulohumeral dystrophy.</strong> Arch. Neurol. 47: 1208-1209, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2146943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2146943</a>] [<a href="https://doi.org/10.1001/archneur.1990.00530110066018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2146943">Awerbuch et al. (1990)</a> found that the Beevor sign was present in 27 of 30 patients with FSHD but absent in all 40 patients with other neuromuscular disorders. They concluded that it is a common finding in FSHD patients even before functional weakness of abdominal wall muscles is apparent. Because of weakness of the lower rectus abdominis muscles, the umbilicus moves upward when the subject in the supine position raises his or her head, producing the Beevor sign. (This sign was originally proposed by English neurologist Charles E. Beevor as an indication of the level of involvement in spinal cord lesions.) <a href="#6" class="mim-tip-reference" title="Bodensteiner, J. B., Schochet, S. S. <strong>Facioscapulohumeral muscular dystrophy: the choice of a biopsy site.</strong> Muscle Nerve 9: 544-547, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3736585/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3736585</a>] [<a href="https://doi.org/10.1002/mus.880090611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3736585">Bodensteiner and Schochet (1986)</a> suggested the supraspinatus muscle as the site of choice for biopsy in this disorder. <a href="#64" class="mim-tip-reference" title="Reardon, W., Temple, I. K., Harwood, G., Baraitser, M. <strong>Atypical facio-scapulo-humeral muscular dystrophy--a counselling dilemma.</strong> Clin. Genet. 39: 172-177, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2036737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2036737</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1991.tb03007.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2036737">Reardon et al. (1991)</a> pointed out the difficulties in some cases in distinguishing FSHD from the Becker type of muscular dystrophy (<a href="/entry/300376">300376</a>). Calf hypertrophy, although rare, has been reported in FSHD. <a href="#29" class="mim-tip-reference" title="Jardine, P., Jones, M., Tyfield, L., Upadhyaya, M., Lunt, P. <strong>De novo DNA rearrangement in atypical facioscapulohumeral muscular dystrophy. (Letter)</strong> Clin. Genet. 44: 167, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8275579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8275579</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1993.tb03872.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8275579">Jardine et al. (1993)</a> reexamined the 3 affected members in the family reported by <a href="#64" class="mim-tip-reference" title="Reardon, W., Temple, I. K., Harwood, G., Baraitser, M. <strong>Atypical facio-scapulo-humeral muscular dystrophy--a counselling dilemma.</strong> Clin. Genet. 39: 172-177, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2036737/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2036737</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1991.tb03007.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2036737">Reardon et al. (1991)</a> and demonstrated that they had a rearrangement in the region of the FSHD gene as indicated by studies with probe p13E-11. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15411118+8275579+3736585+2036737+6745940+2146943" 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="#76" class="mim-tip-reference" title="Shen, E. N., Madsen, T. <strong>Facioscapulohumeral muscular dystrophy and recurrent pacemaker lead dislodgment.</strong> Am. Heart J. 122: 1167-1169, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1927871/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1927871</a>] [<a href="https://doi.org/10.1016/0002-8703(91)90491-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1927871">Shen and Madsen (1991)</a> described symptomatic atrial tachycardia, for which an antitachycardic pacing device was implanted, in a 44-year-old woman. Her severe scapular and shoulder weakness led to recurrent dislodgment of the atrial pacemaker lead. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1927871" 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>According to <a href="#2" class="mim-tip-reference" title="Bailey, R. O., Marzulo, D. C., Hans, M. B. <strong>Infantile facioscapulohumeral muscular dystrophy: new observations.</strong> Acta Neurol. Scand. 74: 51-58, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3766116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3766116</a>] [<a href="https://doi.org/10.1111/j.1600-0404.1986.tb04625.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3766116">Bailey et al. (1986)</a>, infantile facioscapulohumeral muscular dystrophy was recognized by <a href="#15" class="mim-tip-reference" title="Duchenne, G.-B. <strong>Album de photographies pathologiques complementaire de liver initule de l'electrisation localisee.</strong> Paris: J.-B. Bailliere (pub.) 1862."None>Duchenne (1862)</a> and differentiated from pseudohypertrophic muscular dystrophy over 20 years before the description of the usual form of facioscapulohumeral muscular dystrophy by <a href="#34" class="mim-tip-reference" title="Landouzy, L., Dejerine, J. <strong>De la myopathie atrophique progressive.</strong> Rev. Med. Franc. 5: 81, 1885."None>Landouzy and Dejerine (1885)</a>. Whereas FSHD is generally a benign, slowly progressive myopathy that begins in late childhood or adolescence and leads to disability only late in its course, occasional families contain individuals with a severe infantile form of the disorder who have 1 asymptomatic or minimally affected parent. <a href="#2" class="mim-tip-reference" title="Bailey, R. O., Marzulo, D. C., Hans, M. B. <strong>Infantile facioscapulohumeral muscular dystrophy: new observations.</strong> Acta Neurol. Scand. 74: 51-58, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3766116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3766116</a>] [<a href="https://doi.org/10.1111/j.1600-0404.1986.tb04625.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3766116">Bailey et al. (1986)</a> reported a family in which the severe infantile presentation predominated. They suggested 'that the gene coding for this disorder may be different from that responsible for conventional facioscapulohumeral muscular dystrophy.' The genes for the 2 forms of the disease may, of course, be allelic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3766116" 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 56 of 75 persons with clinical or genetic evidence of FSH muscular dystrophy, <a href="#18" class="mim-tip-reference" title="Fitzsimons, R. B., Gurwin, E. B., Bird, A. C. <strong>Retinal vascular abnormalities in facioscapulohumeral muscular dystrophy: a general association with genetic and therapeutic implications.</strong> Brain 110: 631-648, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3580827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3580827</a>] [<a href="https://doi.org/10.1093/brain/110.3.631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3580827">Fitzsimons et al. (1987)</a> found peripheral retinal capillary abnormalities including telangiectasia, closure, leakage, and microaneurysm formation. They were prompted to do this study by the occasional reports of exudative retinal detachment and deafness with this disorder. The study included 1 FSH family in which the proband was treated for exudative retinopathy and 13 other members had retinal telangiectasia. There were 8 cases, including 3 parents of apparently 'sporadic' FSH cases, in which fluorescein angiography 'confirmed the abnormal genotype, even though clinical examination of skeletal muscle revealed no clear abnormality.' <a href="#18" class="mim-tip-reference" title="Fitzsimons, R. B., Gurwin, E. B., Bird, A. C. <strong>Retinal vascular abnormalities in facioscapulohumeral muscular dystrophy: a general association with genetic and therapeutic implications.</strong> Brain 110: 631-648, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3580827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3580827</a>] [<a href="https://doi.org/10.1093/brain/110.3.631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3580827">Fitzsimons et al. (1987)</a> concluded that retinal capillary abnormalities are an integral part of FSH muscular dystrophy and raised the question as to whether analogous capillary abnormalities may be implicated in the pathogenesis of the muscle disease. <a href="#61" class="mim-tip-reference" title="Padberg, G. W., Brouwer, O. F., de Keizer, R. J. W., Gruter, A. M., Wijmenga, C., Grote, J. J., Frants, R. R. <strong>Retinal vascular disease and sensorineural deafness are part of facioscapulohumeral muscular dystrophy. (Abstract)</strong> Am. J. Hum. Genet. 51 (suppl.): A104, 1992."None>Padberg et al. (1992)</a> came to similar conclusions on the basis of studies using fluorescein retinal angiography in 32 patients from 19 families. In 16 of the 32, representing 11 families, retinal capillary changes were found consisting of telangiectasia, microaneurysms, vessel occlusions, and small exudates and hemorrhages in the macular as well as in the peripheral retina. In addition, tone audiometry was performed, with the finding that 20 sibs from 14 families had some degree of high-tone deafness. Similar findings were observed in 8 sporadic cases: 4 had retinal vasculopathy and 5 had high-tone deafness. Combined with linkage data, these observations demonstrated that retinal vasculopathy and high-tone sensorineural deafness are part of the clinical picture of FSHD and are no grounds for assuming genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3580827" 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="#80" class="mim-tip-reference" title="Small, R. G. <strong>Coats' disease and muscular dystrophy.</strong> Trans. Am. Acad. Ophthal. Otolaryng. 72: 225-231, 1968.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5659903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5659903</a>]" pmid="5659903">Small (1968)</a> described 4 sibs with facioscapulohumeral dystrophy and bilateral retinal exudative telangiectasia, labeled Coats disease (see <a href="/entry/300216">300216</a>). Neurosensory deafness and mental retardation were present in all 4. <a href="#86" class="mim-tip-reference" title="Taylor, D. A., Carroll, J. E., Smith, M. E., Johnson, M. O., Johnston, G. P., Brooke, M. H. <strong>Facioscapulohumeral dystrophy associated with hearing loss and Coats syndrome.</strong> Ann. Neurol. 12: 395-398, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7149664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7149664</a>] [<a href="https://doi.org/10.1002/ana.410120414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7149664">Taylor et al. (1982)</a> and <a href="#106" class="mim-tip-reference" title="Voit, T., Lamprecht, A., Lenard, H. G., Goebel, H. H. <strong>Hearing loss in facioscapulohumeral dystrophy.</strong> Europ. J. Pediat. 145: 280-285, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3769995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3769995</a>] [<a href="https://doi.org/10.1007/BF00439401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3769995">Voit et al. (1986)</a> described the same association. <a href="#120" class="mim-tip-reference" title="Yasukohchi, S., Yagi, Y., Akabane, T., Terauchi, A., Tamagawa, K., Mizuno, Y. <strong>Facioscapulohumeral dystrophy associated with sensorineural hearing loss, tortuosity of retinal arterioles, and an early onset and rapid progression of respiratory failure.</strong> Brain Dev. 10: 319-324, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3239698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3239698</a>] [<a href="https://doi.org/10.1016/s0387-7604(88)80063-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3239698">Yasukohchi et al. (1988)</a> described a brother and sister with facioscapulohumeral dystrophy. The brother, aged 13 years, also had sensorineural hearing loss, marked tortuosity of retinal arterioles, early onset and progression of severe restrictive pulmonary dysfunction, and cor pulmonale. The 8-year-old sister had only muscle manifestations. Bilateral sensorineural hearing loss in the high frequency range was described in the above patients. In some, the hearing loss was clearly progressive and with time tended to involve lower frequencies (<a href="#106" class="mim-tip-reference" title="Voit, T., Lamprecht, A., Lenard, H. G., Goebel, H. H. <strong>Hearing loss in facioscapulohumeral dystrophy.</strong> Europ. J. Pediat. 145: 280-285, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3769995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3769995</a>] [<a href="https://doi.org/10.1007/BF00439401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3769995">Voit et al., 1986</a>). As noted from the cases cited, autosomal dominant inheritance was not always clear; recessive inheritance was possible and might point to this being an entity separate from FSHD. <a href="#8" class="mim-tip-reference" title="Brouwer, O. F., Padberg, G. W., Ruys, C. J. M., Brand, R., de Laat, J. A. P. M., Grote, J. J. <strong>Hearing loss in facioscapulohumeral muscular dystrophy.</strong> Neurology 41: 1878-1881, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1745341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1745341</a>] [<a href="https://doi.org/10.1212/wnl.41.12.1878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1745341">Brouwer et al. (1991)</a> performed screening audiometry in 56 patients with autosomal dominant FSHD and in 72 healthy family members, and found that the difference in hearing levels between 4,000 Hz and 6,000 Hz was significantly greater in FSHD patients than in their unaffected relatives. This led them to conclude that a change in hearing function is part of the disease and may lead to severe hearing loss in some patients. <a href="#21" class="mim-tip-reference" title="Gieron, M. A., Korthals, J. K., Kousseff, B. G. <strong>Facioscapulohumeral dystrophy with cochlear hearing loss and tortuosity of retinal vessels.</strong> Am. J. Med. Genet. 22: 143-147, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4050849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4050849</a>] [<a href="https://doi.org/10.1002/ajmg.1320220116" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4050849">Gieron et al. (1985)</a> described a mother and 3 children with FSHD, sensorineural hearing loss, and marked tortuosity of retinal vessels. The deafness, which varied from mild to moderate, was bilateral and early in onset. Audiologic studies indicated the cochlea as the site of the abnormality. <a href="#51" class="mim-tip-reference" title="Matsuzaka, T., Sakuragawa, N., Terasawa, K., Kuwabara, H. <strong>Facioscapulohumeral dystrophy associated with mental retardation, hearing loss, and tortuosity of retinal arterioles.</strong> J. Child Neurol. 1: 218-223, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3598127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3598127</a>] [<a href="https://doi.org/10.1177/088307388600100308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3598127">Matsuzaka et al. (1986)</a> reported a sporadic case of this constellation of manifestations plus mental retardation and suggested that these cases constitute a nosologically specific form of FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5659903+3769995+4050849+3239698+1745341+3598127+7149664" 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="#77" class="mim-tip-reference" title="Shields, C. L., Zahler, J., Falk, N., Furuta, M., Eagle, R. C., Jr., Espinosa, L. E. B., Fischer, P. R., Shields, J. A. <strong>Neovascular glaucoma from advanced Coats disease as the initial manifestation of facioscapulohumeral dystrophy in a 2-year-old child.</strong> Arch. Ophthal. 125: 840-842, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17563001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17563001</a>] [<a href="https://doi.org/10.1001/archopht.125.6.840" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17563001">Shields et al. (2007)</a> noted that retinal telangiectasia compatible with Coats disease (<a href="/entry/300216">300216</a>) can be an extramuscular manifestation of FSHD but that most affected patients have asymptomatic retinal telangiectasia found at ocular screening after diagnosis of FSHD. They described a young child who had advanced eye findings of unilateral neovascular glaucoma from bilateral retinal telangiectasia 3 years before FSHD became apparent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17563001" 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="#55" class="mim-tip-reference" title="Miura, K., Kumagai, T., Matsumoto, A., Iriyama, E., Watanabe, K., Goto, K., Arahata, K. <strong>Two cases of chromosome 4q35-linked early onset facioscapulohumeral muscular dystrophy with mental retardation and epilepsy.</strong> Neuropediatrics 29: 239-241, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9810558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9810558</a>] [<a href="https://doi.org/10.1055/s-2007-973568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9810558">Miura et al. (1998)</a> reported 2 sporadic cases of early-onset scapulohumeral muscular dystrophy with mental retardation and epilepsy in unrelated, severely affected females. In both cases, Southern blot analysis of the EcoRI-digested genomic DNA, using 2 probes, detected 10-kb EcoRI fragments, the shortest reported to that time. Patient 1 showed infantile spasms at the age of 4 months and localization-related epilepsy at the age of 2.5 years. Muscular atrophy in the face, shoulder girdle, and upper arms was observed from the age of 4 years. In patient 2, lack of facial expression was noticed since the age of 1 year, and at 4 years she was noted to have loss of upward gaze bilaterally. She developed localization-related epilepsy at the age of 9 years. From the age of 10 years, weakness of the lower limbs progressed and she became wheelchair-bound at the age of 14 years. She had moderate sensorineural hearing loss, a loss of upward gaze bilaterally, and tongue atrophy. Their IQs were 33 and 45, respectively. <a href="#55" class="mim-tip-reference" title="Miura, K., Kumagai, T., Matsumoto, A., Iriyama, E., Watanabe, K., Goto, K., Arahata, K. <strong>Two cases of chromosome 4q35-linked early onset facioscapulohumeral muscular dystrophy with mental retardation and epilepsy.</strong> Neuropediatrics 29: 239-241, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9810558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9810558</a>] [<a href="https://doi.org/10.1055/s-2007-973568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9810558">Miura et al. (1998)</a> suggested that mental retardation and epilepsy may be part of the clinical spectrum of FSHD, especially in very early-onset patients with large deletions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9810558" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 151 Japanese patients with FSHD, <a href="#119" class="mim-tip-reference" title="Yamanaka, G., Goto, K., Matsumura, T., Funakoshi, M., Komori, T., Hayashi, Y. K., Arahata, K. <strong>Tongue atrophy in facioscapulohumeral muscular dystrophy.</strong> Neurology 57: 733-735, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11524495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11524495</a>] [<a href="https://doi.org/10.1212/wnl.57.4.733" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11524495">Yamanaka et al. (2001)</a> reported 7 patients with tongue atrophy with abnormal tongue MRI findings (disorganized architecture) and typical myogenic patterns of electromyography. All patients were classified as having early-onset FSHD with large gene deletions within the 4q35 gene region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11524495" 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="#33" class="mim-tip-reference" title="Krasnianski, M., Eger, K., Neudecker, S., Jakubiczka, S., Zierz, S. <strong>Atypical phenotypes in patients with facioscapulohumeral muscular dystrophy 4q35 deletion.</strong> Arch. Neurol. 60: 1421-1425, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14568813/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14568813</a>] [<a href="https://doi.org/10.1001/archneur.60.10.1421" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14568813">Krasnianski et al. (2003)</a> described atypical features in 6 of 41 patients with FSHD and the 4q35 deletion. Three patients from 1 family showed the typical phenotype with the additional feature of chronic progressive external ophthalmoplegia. Three patients, 2 from 1 family, showed sparing of the facial muscles, and 2 of these patients had severe, diffuse myalgia. There was no correlation between the atypical features and the DNA fragment size due to the deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14568813" 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="#117" class="mim-tip-reference" title="Wohlgemuth, M., de Swart, B. J. M., Kalf, J. G., Joosten, F. B. M., Van der Vliet, A. M., Padberg, G. W. <strong>Dysphagia in facioscapulohumeral muscular dystrophy.</strong> Neurology 66: 1926-1928, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16801662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16801662</a>] [<a href="https://doi.org/10.1212/01.wnl.0000219760.76441.f8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16801662">Wohlgemuth et al. (2006)</a> found that 10 of 87 individuals with FSHD had signs of weakness in the jaw, lips, or tongue. Oropharyngeal evaluation in 8 of these patients detected mild to moderate swallowing abnormalities in 7 patients and tongue atrophy in 6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16801662" 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>See <a href="/entry/182970">182970</a> for a form of spinal muscular atrophy simulating FSH muscular dystrophy.</p><p><strong><em>Pathologic Features</em></strong></p><p>
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In a 20-year-old woman who had inherited FSHD from her father and who also had an affected brother, <a href="#79" class="mim-tip-reference" title="Slipetz, D. M., Aprille, J. R., Goodyer, P. R., Rozen, R. <strong>Deficiency of complex III of the mitochondrial respiratory chain in a patient with facioscapulohumeral disease.</strong> Am. J. Hum. Genet. 48: 502-510, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1847791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1847791</a>]" pmid="1847791">Slipetz et al. (1991)</a> found that muscle biopsy showed fiber atrophy with patchy staining for oxidative enzymes; that electron microscopy of liver showed many enlarged mitochondria with paracrystalline inclusions; and that skin fibroblasts showed decreased oxidation of the respiratory substrates alanine and succinate, suggesting deficiency of complex III of the electron-transport chain. Cytochrome c oxidase activity (complex IV) was normal. Biochemical analysis of liver supported the fibroblast data, since succinate oxidase activity (electron-transport activity through complexes II-IV) was reduced and complex IV activity was normal. Cytochrome b, a component of complex III, was undetectable in liver, although typical peaks were found for other cytochromes. Southern blot analysis of fibroblast mtDNA showed no major deletions or rearrangements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1847791" 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 confocal microscopy, <a href="#65" class="mim-tip-reference" title="Reed, P., Porter, N. C., Strong, J., Pumplin, D. W., Corse, A. M., Luther, P. W., Flanigan, K. M., Bloch, R. J. <strong>Sarcolemmal reorganization in facioscapulohumeral muscular dystrophy.</strong> Ann. Neurol. 59: 289-297, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16437580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16437580</a>] [<a href="https://doi.org/10.1002/ana.20750" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16437580">Reed et al. (2006)</a> found that some of the structures at the sarcolemma in FSHD skeletal muscle biopsies were misaligned with respect to the underlying contractile apparatus. Electron microscopy showed a significant increase in the distance between the sarcolemma and the nearest myofibrils, from less than 100 nm in controls to 550 nm in FSHD. <a href="#65" class="mim-tip-reference" title="Reed, P., Porter, N. C., Strong, J., Pumplin, D. W., Corse, A. M., Luther, P. W., Flanigan, K. M., Bloch, R. J. <strong>Sarcolemmal reorganization in facioscapulohumeral muscular dystrophy.</strong> Ann. Neurol. 59: 289-297, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16437580/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16437580</a>] [<a href="https://doi.org/10.1002/ana.20750" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16437580">Reed et al. (2006)</a> concluded that the pathophysiology of FSHD includes novel changes in the organization of the sarcolemma and the subsarcolemmal membrane cytoskeleton. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16437580" 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="#60" class="mim-tip-reference" title="Padberg, G., Eriksson, A. W., Volkers, W. S., Bernini, L., van Loghem, E., Meera Khan, P., Nijenhuis, L. E., Pronk, J. C., Schreuder, G. M. T. <strong>Linkage studies in autosomal dominant facioscapulohumeral muscular dystrophy.</strong> J. Neurol. Sci. 65: 261-268, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6593433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6593433</a>] [<a href="https://doi.org/10.1016/0022-510x(84)90090-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6593433">Padberg et al. (1984)</a> found possible linkage to Gm (<a href="/entry/147100">147100</a>) (maximum lod score = 1.428 at theta = 0.2). <a href="#62" class="mim-tip-reference" title="Padberg, G. W., Klasen, E. C., Volkers, W. S., de Lange, G. G., Wintzen, A. R. <strong>Linkage studies in facioscapulohumeral muscular dystrophy.</strong> Muscle Nerve 11: 833-835, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3140007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3140007</a>] [<a href="https://doi.org/10.1002/mus.880110806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3140007">Padberg et al. (1988)</a> followed up on this observation by testing linkage with D14S1 (<a href="/entry/107750">107750</a>). They excluded linkage, thus suggesting that the FSH muscular dystrophy locus is not situated on the distal part of the long arm of chromosome 14. <a href="#70" class="mim-tip-reference" title="Sarfarazi, M., Upadhyaya, M., Padberg, G., Pericak-Vance, M., Siddique, T., Lucotte, G., Lunt, P. <strong>An exclusion map for facioscapulohumeral (Landouzy-Dejerine) disease.</strong> J. Med. Genet. 26: 481-484, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2769720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2769720</a>] [<a href="https://doi.org/10.1136/jmg.26.8.481" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2769720">Sarfarazi et al. (1989)</a> presented exclusion data, resulting from an international collaboration, showing that more than 85% of the human genome has been excluded as a likely location for the FSHD gene. Chromosomes 3, 5, 10, 11, 15, and 19 remained largely unexcluded. <a href="#43" class="mim-tip-reference" title="Lucotte, G., Berriche, S., Fardeau, M. <strong>Linkage analysis of French families with facioscapulohumeral muscular dystrophy.</strong> J. Med. Genet. 26: 485-486, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2769721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2769721</a>] [<a href="https://doi.org/10.1136/jmg.26.8.485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2769721">Lucotte et al. (1989)</a> excluded 3 chromosomal regions, including proximal 19q. <a href="#47" class="mim-tip-reference" title="Lunt, P. W., Upadhyaya, M., Sarfarazi, M., Broadhead, W., Harper, P. S. <strong>Linkage studies in facioscapulohumeral disease. (Abstract)</strong> Cytogenet. Cell Genet. 51: 1036, 1989."None>Lunt et al. (1989)</a> presented linkage data for 22 different DNA markers in 24 families with FSHD. They achieved a maximum lod score of 1.87 at a theta of 0.15 with anonymous marker D18S3, which has been localized to 18p11.3. In a clinically homogeneous group of families, <a href="#28" class="mim-tip-reference" title="Jacobsen, S. J., Diala, E. S., Dorsey, B. V., Rising, M. B., Graveline, R., Falls, K., Schultz, P., Hogan, C., Rediker, K., D'Amico, C., Weiffenbach, B. <strong>A clinically homogeneous group of families with facioscapulohumeral (Landouzy-Dejerine) muscular dystrophy: linkage analysis of six autosomes.</strong> Am. J. Hum. Genet. 47: 376-388, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1975474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1975474</a>]" pmid="1975474">Jacobsen et al. (1990)</a> excluded chromosomes 1, 2, 5, 7, 10, and 16 as the site of the FMD mutation. They estimated that 23% of the human genome was excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2769720+3140007+6593433+2769721+1975474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 10 Dutch families, <a href="#111" class="mim-tip-reference" title="Wijmenga, C., Frants, R. R., Brouwer, O. F., Moerer, P., Weber, J. L., Padberg, G. W. <strong>Location of facioscapulohumeral muscular dystrophy gene on chromosome 4.</strong> Lancet 336: 651-653, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1975852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1975852</a>] [<a href="https://doi.org/10.1016/0140-6736(90)92148-b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1975852">Wijmenga et al. (1990)</a> found linkage of FSH muscular dystrophy to a microsatellite marker Mfd22 (D4S171) on chromosome 4; maximum lod score = 6.34 at theta = 0.13. Only 1 family was uninformative for this marker. No evidence of heterogeneity was found. From the map location of the marker, it appeared that the FSHD gene was located near the distal end of 4q. <a href="#78" class="mim-tip-reference" title="Siddique, T., Roper, H., Pericak-Vance, M. A., Shaw, J., Warner, K. L., Hung, W.-Y., Phillips, K. L., Lunt, P., Cumming, W. J. K., Roses, A. D. <strong>Linkage analysis in the spinal muscular atrophy type of facioscapulohumeral disease.</strong> J. Med. Genet. 26: 487-489, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2570155/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2570155</a>] [<a href="https://doi.org/10.1136/jmg.26.8.487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2570155">Siddique et al. (1989)</a> studied 2 multigeneration families with the neurogenic form of facioscapulohumeral disease considered to be a form of spinal muscular atrophy. Possible linkage to MNS on 4q was found. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1975852+2570155" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a linkage study of FSHD families, <a href="#94" class="mim-tip-reference" title="Upadhyaya, M., Lunt, P. W., Sarfarazi, M., Broadhead, W., Daniels, J., Owen, M., Harper, P. S. <strong>A closely linked DNA marker for facioscapulohumeral disease on chromosome 4q.</strong> J. Med. Genet. 28: 665-671, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1941963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1941963</a>] [<a href="https://doi.org/10.1136/jmg.28.10.665" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1941963">Upadhyaya et al. (1991)</a> found 3 recombinants in a total of 140 meioses for linkage with a hypervariable DNA probe on 4q (pH30, locus D4S139), giving a maximum lod score of 36.77 at a recombination fraction of 0.02. <a href="#113" class="mim-tip-reference" title="Wijmenga, C., Padberg, G. W., Moerer, P., Wiegant, J., Liem, L., Brouwer, O. F., Milner, E. C. B., Weber, J. L., van Ommen, G. B., Sandkuyl, L. A., Frants, R. R. <strong>Mapping of facioscapulohumeral muscular dystrophy gene to chromosome 4q35-qter by multipoint linkage analysis and in situ hybridization.</strong> Genomics 9: 570-575, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2037288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2037288</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90348-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2037288">Wijmenga et al. (1991)</a> found a VNTR locus, D4S139, to be much more closely linked to FSHD than to D4S171. This marker was mapped to 4q35-qter by in situ hybridization. One small family yielded a negative lod score for D4S139, but otherwise there was no evidence of genetic heterogeneity. In 9 informative families, they found a maximum lod score of 17.28 at theta = 0.027. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1941963+2037288" 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="#50" class="mim-tip-reference" title="Mathews, K. D., Mills, K. A., Leysens, N. J., Xu, Y., Bodrug, S., Buetow, K. H., Murray, J. C. <strong>Characterization of the facioscapulohumeral dystrophy locus on 4q35. (Abstract)</strong> Am. J. Hum. Genet. 49 (suppl.): 350, 1991."None>Mathews et al. (1991)</a> defined the location of FSHD as 4q35. They used a probe derived from the breakpoint of an X;4 translocation with a breakpoint at 4q35. The patient had facial weakness at age 4 years. A peak lod score of 8.23 at theta = 0.00 was found with a 4q35 probe, D4S139. Reporting for a consortium, <a href="#71" class="mim-tip-reference" title="Sarfarazi, M., Wijmenga, C., Upadhyaya, M., Weiffenbach, B., Hyser, C., Mathews, K., Murray, J., Gilbert, J., Pericak-Vance, M., Lunt, P., Frants, R. R., Jacobsen, S., Harper, P. S., Padberg, G. W. <strong>Regional mapping of facioscapulohumeral muscular dystrophy gene on 4q35: combined analysis of an international consortium.</strong> Am. J. Hum. Genet. 51: 396-403, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1642237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1642237</a>]" pmid="1642237">Sarfarazi et al. (1992)</a> defined the relationship of the FSHD locus to markers in the 4q35 region in 65 families containing a total of 504 affected persons. No evidence of heterogeneity was found in the initial study; however, after completion of the analysis, 1 large family that might show heterogeneity was identified. In view of this and the fact that all of the linked markers were on the centromeric side of the FSHD locus, <a href="#71" class="mim-tip-reference" title="Sarfarazi, M., Wijmenga, C., Upadhyaya, M., Weiffenbach, B., Hyser, C., Mathews, K., Murray, J., Gilbert, J., Pericak-Vance, M., Lunt, P., Frants, R. R., Jacobsen, S., Harper, P. S., Padberg, G. W. <strong>Regional mapping of facioscapulohumeral muscular dystrophy gene on 4q35: combined analysis of an international consortium.</strong> Am. J. Hum. Genet. 51: 396-403, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1642237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1642237</a>]" pmid="1642237">Sarfarazi et al. (1992)</a> recommended that these markers not yet be used in clinical applications. <a href="#92" class="mim-tip-reference" title="Upadhyaya, M., Lunt, P., Sarfarazi, M., Broadhead, W., Farnham, J., Harper, P. S. <strong>The mapping of chromosome 4q markers in relation to facioscapulohumeral muscular dystrophy (FSHD).</strong> Am. J. Hum. Genet. 51: 404-410, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1642238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1642238</a>]" pmid="1642238">Upadhyaya et al. (1992)</a> found that FSHD was situated telomeric to all 4 DNA markers that they used in a series of 23 families. However, <a href="#114" class="mim-tip-reference" title="Wijmenga, C., Sandkuijl, L. A., Moerer, P., van der Boorn, N., Bodrug, S. E., Ray, P. N., Brouwer, O. F., Murray, J. C., van Ommen, G. J. B., Padberg, G. W., Frants, R. R. <strong>Genetic linkage map of facioscapulohumeral muscular dystrophy and five polymorphic loci on chromosome 4q35-qter.</strong> Am. J. Hum. Genet. 51: 411-415, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1642239/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1642239</a>]" pmid="1642239">Wijmenga et al. (1992)</a> found at least one recombination event which suggested that 1 of the 4 markers, D4S139, might lie distal to FSHD. In a study of 4 families with FSHD, <a href="#49" class="mim-tip-reference" title="Mathews, K. D., Mills, K. A., Bosch, E. P., Ionasescu, V. V., Wiles, K. R., Buetow, K. H., Murray, J. C. <strong>Linkage localization of facioscapulohumeral muscular dystrophy (FSHD) in 4q35.</strong> Am. J. Hum. Genet. 51: 428-431, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1642242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1642242</a>]" pmid="1642242">Mathews et al. (1992)</a> found close linkage to three 4q35 probes, D4S163, D4S139, and D4S171. Two of their families included males with a rapidly progressive muscle disease that had been diagnosed, on the basis of clinical features, as Duchenne muscular dystrophy. One of these males was available for linkage study and shared the haplotype of his FSHD-affected cousin and aunt. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1642242+1642238+1642237+1642239" 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="#53" class="mim-tip-reference" title="Mills, K. A., Buetow, K. H., Xu, Y., Ritty, T. M., Mathews, K. D., Bodrug, S. E., Wijmenga, C., Balazs, I., Murray, J. C. <strong>Genetic and physical mapping on chromosome 4 narrows the localization of the gene for facioscapulohumeral muscular dystrophy (FSHD).</strong> Am. J. Hum. Genet. 51: 432-439, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1642243/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1642243</a>]" pmid="1642243">Mills et al. (1992)</a> generated a fine-structured genetic map of the distal long arm of chromosome 4 by a combination of classical RFLPs and PCR-based polymorphisms including CA repeats and single-strand conformation polymorphisms (SSCP). <a href="#22" class="mim-tip-reference" title="Gilbert, J. R., Stajich, J. M., Speer, M. C., Vance, J. M., Stewart, C. S., Yamaoka, L. H., Samson, F., Fardeau, M., Potter, T. G., Roses, A. D., Pericak-Vance, M. A. <strong>Linkage studies in facioscapulohumeral muscular dystrophy (FSHD).</strong> Am. J. Hum. Genet. 51: 424-427, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1642241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1642241</a>]" pmid="1642241">Gilbert et al. (1992)</a> and <a href="#109" class="mim-tip-reference" title="Weiffenbach, B., Bagley, R., Falls, K., Hyser, C., Storvick, D., Jacobsen, S. J., Schultz, P., Mendell, J., van Dijk, K. W., Milner, E. C. B., Griggs, R. <strong>Linkage analyses of five chromosome 4 markers localizes the facioscapulohumeral muscular dystrophy (FSHD) gene to distal 4q35.</strong> Am. J. Hum. Genet. 51: 416-423, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1642240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1642240</a>]" pmid="1642240">Weiffenbach et al. (1992)</a> demonstrated that both D4S139 and D4S163 are closely linked to FSHD, with D4S139 being the closest proximal marker to FSHD. No telomeric marker to FSHD had been demonstrated. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1642240+1642243+1642241" 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="#23" 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. See <a href="/entry/158901">158901</a>. <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>
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<p>All patients with a confirmed diagnosis of FSHD and for whom detailed molecular studies have been performed carry a chromosomal rearrangement within the subtelomeric region of 4q (4q35). This subtelomeric region is composed mainly of a polymorphic repeat structure consisting of 3.3-kb repeated elements, designated D4Z4 (see <a href="/entry/606009">606009</a>). The number of repeat units varies from 10 to more than 100 in the population, and, in FSHD patients, an allele of 1 to 10 residual units is observed because of the deletion of an integral number of these units (<a href="#112" class="mim-tip-reference" title="Wijmenga, C., Hewitt, J. E., Sandkuijl, L. A., Clark, L. N., Wright, T. J., Dauwerse, H. G., Gruter, A.-M., Hofker, M. H., Moerer, P., Williamson, R., van Ommen, G.-J. B., Padberg, G. W., Frants, R. R. <strong>Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy.</strong> Nature Genet. 2: 26-30, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1363881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1363881</a>] [<a href="https://doi.org/10.1038/ng0992-26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1363881">Wijmenga et al., 1992</a>; <a href="#27" class="mim-tip-reference" title="Hewitt, J. E., Lyle, R., Clark, L. N., Valleley, E. M., Wright, T. J., Wijmenga, C., van Deutekom, J. C. T., Francis, F., Sharpe, P. T., Hofker, M., Frants, R. R., Williamson, R. <strong>Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy.</strong> Hum. Molec. Genet. 3: 1287-1295, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987304</a>] [<a href="https://doi.org/10.1093/hmg/3.8.1287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987304">Hewitt et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7987304+1363881" 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="#67" class="mim-tip-reference" title="Sacconi, S., Briand-Suleau, A., Gros, M., Baudoin, C., Lemmers, R. J. L. F., Rondeau, S., Lagha, N., Nigumann, P., Cambieri, C., Puma, A., Chapon, F., Stojkovic, T., and 14 others. <strong>FSHD1 and FSHD2 form a disease continuum.</strong> Neurology 92: e2273-e2285, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30979860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30979860</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30979860[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.0000000000007456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30979860">Sacconi et al. (2019)</a> examined the molecular genetics and epigenetic modifiers of 103 patients with FSHD, including 64 with FSHD1 and 20 with FSHD2. There was variation in the size of the D4Z4 repeat and in hypomethylation status. An inverse correlation between the size of the repeat and FSHD1 disease severity was observed: patients with 8-10 units had a milder disease compared to those with 4-7 repeats. There was also variability in the presence of the permissive 4q allele in patients with FSHD2. <a href="#67" class="mim-tip-reference" title="Sacconi, S., Briand-Suleau, A., Gros, M., Baudoin, C., Lemmers, R. J. L. F., Rondeau, S., Lagha, N., Nigumann, P., Cambieri, C., Puma, A., Chapon, F., Stojkovic, T., and 14 others. <strong>FSHD1 and FSHD2 form a disease continuum.</strong> Neurology 92: e2273-e2285, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30979860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30979860</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30979860[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.0000000000007456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30979860">Sacconi et al. (2019)</a> concluded that various genetic types of FSHD form a clinical and genetic disease continuum. They suggested that repeat size thresholds used in diagnosis may need to be reconsidered. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30979860" 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>D4Z4 Macrosatellite Repeat</em></strong></p><p>
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For a full discussion of the D4Z4 macrosatellite repeat, see <a href="/entry/606009">606009</a>.</p><p><a href="#41" class="mim-tip-reference" title="Lemmers, R. J. L. F., van Overveld, P. G. M., Sandkuijl, L. A., Vrieling, H., Padberg, G. W., Frants, R. R., van der Maarel, S. M. <strong>Mechanism and timing of mitotic rearrangements in the subtelomeric D4Z4 repeat involved in facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 75: 44-53, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15154112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15154112</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15154112[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/422175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15154112">Lemmers et al. (2004)</a> summarized the relationship of the D4Z4 repeat to FSHD. The polymorphic D4Z4 repeat is highly recombinogenic, since somatic mosaicism for rearrangement of D4Z4 is found in as much as 3% of the general population (<a href="#103" class="mim-tip-reference" title="van Overveld, P. G. M., Lemmers, R. J. F. L., Deidda, G., Sandkuijl, L., Padberg, G. W., Frants, R. R., van der Maarel, S. M. <strong>Interchromosomal repeat array interactions between chromosomes 4 and 10: a model for subtelomeric plasticity.</strong> Hum. Molec. Genet. 9: 2879-2884, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11092764/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11092764</a>] [<a href="https://doi.org/10.1093/hmg/9.19.2879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11092764">van Overveld et al., 2000</a>). The D4Z4 repeat consists of identical units defined by the restriction enzyme KpnI, each 3.3 kb, ordered in a head-to-tail fashion, and varying between 11 and 100 units on 'healthy' chromosomes (<a href="#100" class="mim-tip-reference" title="van Deutekom, J. C. T., Wijmenga, C., van Tienhoven, E. A. E., Gruter, A.-M., Hewitt, J. E., Padberg, G. W., van Ommen, G.-J., Hofker, M. H., Frants, R. R. <strong>FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit.</strong> Hum. Molec. Genet. 2: 2037-2042, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8111371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8111371</a>] [<a href="https://doi.org/10.1093/hmg/2.12.2037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8111371">van Deutekom et al., 1993</a>). Patients with FSHD carry a repeat of 1 to 10 units on one of their chromosomes 4 (<a href="#112" class="mim-tip-reference" title="Wijmenga, C., Hewitt, J. E., Sandkuijl, L. A., Clark, L. N., Wright, T. J., Dauwerse, H. G., Gruter, A.-M., Hofker, M. H., Moerer, P., Williamson, R., van Ommen, G.-J. B., Padberg, G. W., Frants, R. R. <strong>Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy.</strong> Nature Genet. 2: 26-30, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1363881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1363881</a>] [<a href="https://doi.org/10.1038/ng0992-26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1363881">Wijmenga et al., 1992</a>). A rough and inverse correlation has been observed between the severity and age at onset of the disease and the residual repeat unit number. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15154112+11092764+8111371+1363881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a review of genetic disorders associated with aberrant chromatin structure, <a href="#5" class="mim-tip-reference" title="Bickmore, W. A., van der Maarel, S. M. <strong>Perturbations of chromatin structure in human genetic disease: recent advances.</strong> Hum. Molec. Genet. 12: R207-R213, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915455</a>] [<a href="https://doi.org/10.1093/hmg/ddg260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915455">Bickmore and van der Maarel (2003)</a> noted that FSHD represents a potential example of gene activation through loss of repression complexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12915455" 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 review of the D4Z4 repeat-mediated pathogenesis of FSHD was provided by <a href="#98" class="mim-tip-reference" title="van der Maarel, S. M., Frants, R. R. <strong>The D4Z4 repeat-mediated pathogenesis of facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 76: 375-386, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15674778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15674778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15674778[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/428361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15674778">van der Maarel and Frants (2005)</a>. They pointed out that in contrast to most monogenic disorders, in which the genetic lesion typically affects the structure or function of a specific disease gene, evidence suggested that FSHD is caused by a complex epigenetic mechanism involving the contraction of a subtelomeric macrosatellite repeat. It is likely not the structure but rather the (spatiotemporal-restricted) transcriptional control of one or more disease genes that is perturbed in FSHD as a result of repeat-contraction-mediated chromatin alterations. Their review focused on the cause and consequence of the repeat-array contraction. <a href="#98" class="mim-tip-reference" title="van der Maarel, S. M., Frants, R. R. <strong>The D4Z4 repeat-mediated pathogenesis of facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 76: 375-386, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15674778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15674778</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15674778[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/428361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15674778">Van der Maarel and Frants (2005)</a> designated FSHD a macrosatellite repeat-contraction disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15674778" 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="#104" 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 causes marked hypomethylation of the contracted D4Z4 allele in individuals with FSHD1. Individuals with FSHD clinically identical to other cases but with an unaltered D4Z4 (FSHD2; <a href="/entry/158901">158901</a>) 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="#123" 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="#123" 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>DUX4 Expression</em></strong></p><p>
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<a href="#13" class="mim-tip-reference" title="Dmitriev, P., Lipinski, M., Vassetsky, Y. S. <strong>Pearls in the junk: dissecting the molecular pathogenesis of facioscapulohumeral muscular dystrophy.</strong> Neuromusc. Disord. 19: 17-20, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18974002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18974002</a>] [<a href="https://doi.org/10.1016/j.nmd.2008.09.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18974002">Dmitriev et al. (2008)</a> noted that the DUX4 gene (<a href="/entry/606009">606009</a>) found within the D4Z4 repeat was initially considered to be nonfunctional because it lacked introns and polyadenylation signals. Furthermore, expression of DUX4 could not be detected despite the efforts of several groups using various methods including screening of cDNA libraries, RT-PCR, microarray, and Pol II ChIP. Subsequently, work by <a href="#12" class="mim-tip-reference" title="Dixit, M., Ansseau, E., Tassin, A., Winokur, S., Shi, R., Qian, H., Sauvage, S., Matteotti, C., van Acker, A. M., Leo, O., Figlewicz, D., Barro, M., Laoudj-Chenivesse, D., Belayew, A., Coppee, F., Chen, Y.-W. <strong>DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.</strong> Proc. Nat. Acad. Sci. 104: 18157-18162, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984056</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17984056[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/10.1073/pnas.0708659104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17984056">Dixit et al. (2007)</a> and <a href="#9" class="mim-tip-reference" title="Clapp, J., Mitchell, L. M., Bolland, D. J., Fantes, J., Corcoran, A. E., Scotting, P. J., Armour, J. A. L., Hewitt, J. E. <strong>Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 81: 264-279, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17668377/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17668377</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17668377[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/519311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17668377">Clapp et al. (2007)</a> confirmed expression of DUX4 in human and mouse, respectively, and showed conservation of the DUX4 ORF for more than 100 million years. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17984056+17668377+18974002" 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="Bosnakovski, D., Xu, Z., Gang, E. J., Galindo, C. L., Liu, M., Simsek, T., Garner, H. R., Agha-Mohammadi, S., Tassin, A., Coppee, F., Belayew, A., Perlingeiro, R. R., Kyba, M. <strong>An isogenic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies.</strong> EMBO J. 27: 2766-2779, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18833193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18833193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18833193[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/emboj.2008.201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18833193">Bosnakovski et al. (2008)</a> conditionally expressed cDNAs for FSHD candidate genes within the D4Z4 repeat, DUX4, FRG1 (<a href="/entry/601278">601278</a>), FRG2 (<a href="/entry/609032">609032</a>), and ANT1 (SLC25A4; <a href="/entry/103220">103220</a>), in mouse C2C12 myoblasts at both high and low expression levels and found that only DUX4 was overtly toxic, as indicated by cellular ATP content, morphologic changes, and apoptosis. DUX4 showed variable toxicity when expressed in mouse fibroblasts or embryoid bodies. DUX4 localized to C2C12 cell nuclei within 2 hours of induction. Microarray analysis revealed altered expression in a broad range of genes, with greatest changes in those involved in growth and development and signal transduction. Expression of Myod was also downregulated at an early time point. Oxidative stress and heat shock genes were downregulated at later time points, suggesting that they may be secondary targets. The DUX4 homeodomains are most similar to those of PAX3 (<a href="/entry/606597">606597</a>) and PAX7 (<a href="/entry/167410">167410</a>), and overexpression of these genes rescued viability and proliferation in DUX4-expressing C2C12 cells. <a href="#7" class="mim-tip-reference" title="Bosnakovski, D., Xu, Z., Gang, E. J., Galindo, C. L., Liu, M., Simsek, T., Garner, H. R., Agha-Mohammadi, S., Tassin, A., Coppee, F., Belayew, A., Perlingeiro, R. R., Kyba, M. <strong>An isogenic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies.</strong> EMBO J. 27: 2766-2779, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18833193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18833193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18833193[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/emboj.2008.201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18833193">Bosnakovski et al. (2008)</a> concluded that DUX4 may cause FSHD by interfering with normal PAX3 or PAX7 function in muscle satellite cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18833193" 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="#39" class="mim-tip-reference" title="Lemmers, R. J. L. F., van der Vliet, P. J., Klooster, R., Sacconi, S., Camano, P., Dauwerse, J. G., Snider, L., Straasheijm, K. R., van Ommen, G. J., Padberg, G. W., Miller, D. G., Tapscott, S. J., Tawil, R., Frants, R. R., van der Maarel, S. M. <strong>A unifying genetic model for facioscapulohumeral muscular dystrophy.</strong> Science 329: 1650-1653, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20724583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20724583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20724583[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/10.1126/science.1189044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20724583">Lemmers et al. (2010)</a> showed that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonic polyadenylation signal for transcripts derived from DUX4, a double homeobox gene that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. This particular chromosomal setting containing the pathogenic sequences was named 4APAS (4A polyadenylation signal; <a href="#74" class="mim-tip-reference" title="Scionti, I., Fabbri, G., Fiorillo, C., Ricci, G., Greco, F., D'Amico, R., Termanini, A., Vercelli, L., Tomelleri, G., Cao, M., Santoro, L., Percesepe, A., Tupler, R. <strong>Facioscapulohumeral muscular dystrophy: new insights from compound heterozygotes and implication for prenatal genetic counselling.</strong> J. Med. Genet. 49: 171-178, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22217918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22217918</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22217918">Scionti et al., 2012</a>). <a href="#39" class="mim-tip-reference" title="Lemmers, R. J. L. F., van der Vliet, P. J., Klooster, R., Sacconi, S., Camano, P., Dauwerse, J. G., Snider, L., Straasheijm, K. R., van Ommen, G. J., Padberg, G. W., Miller, D. G., Tapscott, S. J., Tawil, R., Frants, R. R., van der Maarel, S. M. <strong>A unifying genetic model for facioscapulohumeral muscular dystrophy.</strong> Science 329: 1650-1653, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20724583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20724583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20724583[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/10.1126/science.1189044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20724583">Lemmers et al. (2010)</a> concluded that their findings suggested that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20724583+22217918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By RT-PCR, <a href="#81" class="mim-tip-reference" title="Snider, L., Geng, L. N., Lemmers, R. J. L. F., Kyba, M., Ware, C. B., Nelson, A. M., Tawil, R., Filippova, G. N., van der Maarel, S. M., Tapscott, S. J., Miller, D. G. <strong>Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene.</strong> PLoS Genet. 6: e1001181, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21060811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21060811</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21060811[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.1001181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21060811">Snider et al. (2010)</a> found that full-length DUX4 (DUX4-fl) was aberrantly expressed in 5 of 10 FSHD muscle biopsy specimens, but not in normal muscle specimens. PCR analysis of myoblast cultures of varying pool size, and immunohistochemical analysis of cultured myoblasts revealed that only about 0.1% of FSHD muscle nuclei expressed a relatively abundant amount of DUX4-fl mRNA and protein. DUX4-fl was also aberrantly expressed in differentiated FSHD embryoid bodies. A short variant of DUX4 (DUX4-s) was expressed in both FSHD and control tissues and cells. Aberrant DUX4-fl was often associated with apoptotic changes, and in all cases was associated with the FSHD permissive 4qA haplotype (see below). <a href="#81" class="mim-tip-reference" title="Snider, L., Geng, L. N., Lemmers, R. J. L. F., Kyba, M., Ware, C. B., Nelson, A. M., Tawil, R., Filippova, G. N., van der Maarel, S. M., Tapscott, S. J., Miller, D. G. <strong>Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene.</strong> PLoS Genet. 6: e1001181, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21060811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21060811</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21060811[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.1001181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21060811">Snider et al. (2010)</a> concluded that repressive chromatin associated with D4Z4 in differentiated cells may facilitate usage of the noncanonical splice donor site to generate DUX4-s, and the more permissive chromatin in FSHD may favor polymerase progression through to the consensus splice donor and generate DUX4-fl. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21060811" 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="#107" class="mim-tip-reference" title="Wallace, L. M., Garwick, S. E., Mei, W., Belayew, A., Coppee, F., Ladner, K. J., Guttridge, D., Yang, J., Harper, S. Q. <strong>DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo.</strong> Ann. Neurol. 69: 540-552, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21446026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21446026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21446026[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.22275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21446026">Wallace et al. (2011)</a> showed that apoptotic changes observed in DUX4-expressing HEK293 cells were eliminated by inactivating mutation of the first DNA-binding homeobox domain of DUX4. The development of lesions in DUX4-injected mouse muscle was also abrogated by mutation of the DUX4 homeobox domain. Pharmacologic inhibition of p53 (TP53; <a href="/entry/191170">191170</a>) mitigated DUX4 toxicity in HEK293 cells, and muscle from p53-null mice were resistant to DUX4-induced damage. <a href="#107" class="mim-tip-reference" title="Wallace, L. M., Garwick, S. E., Mei, W., Belayew, A., Coppee, F., Ladner, K. J., Guttridge, D., Yang, J., Harper, S. Q. <strong>DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo.</strong> Ann. Neurol. 69: 540-552, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21446026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21446026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21446026[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.22275" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21446026">Wallace et al. (2011)</a> concluded that DUX4-induced myopathy is dependent on p53-induced apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21446026" 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>4qA and 4qB Polymorphic Segment</em></strong></p><p>
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Human 4qter and 10qter share a high degree of similarity, including the D4Z4 repeat array; however, contractions affecting the 10qter repeat are nonpathogenic. <a href="#101" class="mim-tip-reference" title="van Geel, M., Dickson, M. C., Beck, A. F., Bolland, D. J., Frants, R. R., van der Maarel, S. M., de Jong, P. J., Hewitt, J. E. <strong>Genomic analysis of human chromosome 10q and 4q telomeres suggests a common origin.</strong> Genomics 79: 210-217, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11829491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11829491</a>] [<a href="https://doi.org/10.1006/geno.2002.6690" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11829491">Van Geel et al. (2002)</a> detected a polymorphic segment of 10 kb directly distal to D4Z4, which they called alleles 4qA and 4qB. <a href="#36" class="mim-tip-reference" title="Lemmers, R. J. L. F., de Kievit, P., Sandkuijl, L., Padberg, G. W., van Ommen, G.-J. B., Frants, R. R., van der Maarel, S. M. <strong>Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. (Letter)</strong> Nature Genet. 32: 235-236, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355084/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355084</a>] [<a href="https://doi.org/10.1038/ng999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355084">Lemmers et al. (2002)</a> reported that although the 2 alleles are equally common in the general population, FSHD is associated solely with the 4qA allele. They suggested that this was the first example of an intrinsically benign subtelomeric polymorphism predisposing to the development of human disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11829491+12355084" 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="#35" class="mim-tip-reference" title="Lemmers, R. J. F. L., Wohlgemuth, M., Frants, R. R., Padberg, G. W., Morava, E., van der Maarel, S. M. <strong>Contractions of D4Z4 on 4qB subtelomeres do not cause facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 75: 1124-1130, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15467981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15467981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15467981[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/426035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15467981">Lemmers et al. (2004)</a> concluded that contractions of D4Z4 on 4qB subtelomeres do not cause FSHD. The 2 allelic variants of 4q, 4qA and 4qB, exist in the region distal to D4Z4. Although both variants are almost equally present in the population, FSHD is associated exclusively with the 4qA allele. <a href="#35" class="mim-tip-reference" title="Lemmers, R. J. F. L., Wohlgemuth, M., Frants, R. R., Padberg, G. W., Morava, E., van der Maarel, S. M. <strong>Contractions of D4Z4 on 4qB subtelomeres do not cause facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 75: 1124-1130, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15467981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15467981</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15467981[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/426035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15467981">Lemmers et al. (2004)</a> identified 3 families with FSHD in which each proband carried 2 FSHD-sized alleles and was heterozygous for the 4qA/4qB polymorphism. Segregation analysis demonstrated that FSHD-sized 4qB alleles are not associated with disease, since these were present in unaffected family members. Thus, in addition to a contraction of D4Z4, additional cis-acting elements on 4qA may be required for the development of FSHD. Alternatively, 4qB subtelomeres may contain elements that prevent FSHD pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15467981" 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="#42" class="mim-tip-reference" title="Lemmers, R. J. L. F., Wohlgemuth, M., van der Gaag, K. J., van der Vliet, P. J., van Teijlingen, C. M. M., de Knijff, P., Padberg, G. W., Frants, R. R., van der Maarel, S. M. <strong>Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 81: 884-894, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17924332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17924332</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17924332[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/521986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17924332">Lemmers et al. (2007)</a> hypothesized that allele-specific sequence differences among 4qA, 4qB, and 10q alleles underlie the 4qA specificity of FSHD. By examining sequence variations in the FSHD locus, they demonstrated that the subtelomeric domain of chromosome 4q can be subdivided into 9 distinct haplotypes, of which 3 carry the distal 4qA variation. They showed that repeat contractions in 2 of the 9 haplotypes, 1 of which is a 4qA haplotype, are not associated with FSHD. <a href="#42" class="mim-tip-reference" title="Lemmers, R. J. L. F., Wohlgemuth, M., van der Gaag, K. J., van der Vliet, P. J., van Teijlingen, C. M. M., de Knijff, P., Padberg, G. W., Frants, R. R., van der Maarel, S. M. <strong>Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 81: 884-894, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17924332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17924332</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17924332[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/521986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17924332">Lemmers et al. (2007)</a> showed that each of these haplotypes has its unique sequence signature, and proposed that specific SNPs in the disease haplotype are essential for the development of FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17924332" 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="#87" class="mim-tip-reference" title="Thomas, N. S. T., Wiseman, K., Spurlock, G., MacDonald, M., Ustek, D., Upadhyaya, M. <strong>A large patient study confirming that facioscapulohumeral muscular dystrophy (FSHD) disease expression is almost exclusively associated with an FSHD locus located on a 4qA-defined 4qter subtelomere.(Letter)</strong> J. Med. Genet. 44: 215-218, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16987949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16987949</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16987949[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/10.1136/jmg.2006.042804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16987949">Thomas et al. (2007)</a> measured the frequency of 4qA-defined and 4qB-defined subtelomeric sequences in 164 unrelated patients with FSHD from the UK and Turkey, all known to have large D4Z4 deletions. An almost complete association (162 of 164 patients) was found between large D4Z4 repeat array deletions located on 4qA-defined 4qter subtelomeres and disease expression. DNA samples from 50 controls displayed equivalent frequencies for 4qA and 4qB markers, as did the normal chromosome 4 in all 65 patients studied. The 4qA and 4qB probes failed to hybridize in 2 patients, confirming the presence of an additional rare type of 4qter subtelomeric sequence in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16987949" 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="#108" class="mim-tip-reference" title="Wang, Z.-Q., Wang, N., van der Maarel, S., Murong, S.-X., Wu, Z.-Y. <strong>Distinguishing the 4qA and 4qB variants is essential for the diagnosis of facioscapulohumeral muscular dystrophy in the Chinese population.</strong> Europ. J. Hum. Genet. 19: 64-69, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20736973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20736973</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20736973[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/ejhg.2010.143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20736973">Wang et al. (2011)</a> provided evidence that the 4qB-associated D4Z4 contraction is not pathogenic in Chinese individuals. Molecular reexamination of 3 unrelated Chinese patients originally diagnosed with FSHD on the basis of a D4Z4 contraction showed that all were nonpathogenic 4qB variants. All 3 patients were found to have different disorders with similar phenotypes, including LGMD2A (<a href="/entry/253600">253600</a>), LGMD2E (<a href="/entry/604286">604286</a>), and DM1 (<a href="/entry/160900">160900</a>), respectively. A fourth Chinese patient originally diagnosed with FSHD was found to have a pathogenic 18-kb D4Z4 4qA contraction that she inherited from her symptomatic mother. Her 2 daughters carried a paternally inherited 24-kb nonpathogenic contraction that was found to be a mixture of 4q and 10q. The daughters were thus considered unaffected, whereas previously they had been misdiagnosed as asymptomatic cases. <a href="#108" class="mim-tip-reference" title="Wang, Z.-Q., Wang, N., van der Maarel, S., Murong, S.-X., Wu, Z.-Y. <strong>Distinguishing the 4qA and 4qB variants is essential for the diagnosis of facioscapulohumeral muscular dystrophy in the Chinese population.</strong> Europ. J. Hum. Genet. 19: 64-69, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20736973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20736973</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20736973[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/ejhg.2010.143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20736973">Wang et al. (2011)</a> concluded that the D4Z4 repeat length analysis alone is insufficient for the diagnosis of FSHD, and should be accompanied by 4qA/4qB variant determination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20736973" 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>Expression of Other Genes within the FSHD Candidate Region</em></strong></p><p>
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<a href="#99" class="mim-tip-reference" title="van Deutekom, J. C. T., Lemmers, R. J. L. F., Grewal, P. K., van Geel, M., Romberg, S., Dauwerse, H. G., Wright, T. J., Padberg, G. W., Hofker, M. H., Hewitt, J. E., Frants, R. R. <strong>Identification of the first gene (FRG1) from the FSHD region on human chromosome 4q35.</strong> Hum. Molec. Genet. 5: 581-590, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8733123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8733123</a>] [<a href="https://doi.org/10.1093/hmg/5.5.581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8733123">Van Deutekom et al. (1996)</a> identified a novel gene, which they referred to as FRG1 (<a href="/entry/601278">601278</a>), that mapped 100 kb centromeric of the repeated units on chromosome 4q35 that are deleted in FSHD. They identified a polymorphism in exon 1 of this gene and used RT-PCR to amplify reverse transcribed mRNA from lymphocytes and muscle biopsies of patients and controls. These studies indicated that both alleles were transcribed and gave no evidence of 'position effect' variegation leading to repression of allelic transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8733123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Gabellini, D., Green, M. R., Tupler, R. <strong>Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle.</strong> Cell 110: 339-348, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12176321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12176321</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00826-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12176321">Gabellini et al. (2002)</a> found that in FSHD muscle, genes located upstream of D4Z4 on 4q35, including FRG1, FRG2 (<a href="/entry/609032">609032</a>), and ANT1 (<a href="/entry/103220">103220</a>), are inappropriately overexpressed. They showed that an element within D4Z4 specifically binds a multiprotein complex consisting of transcriptional repressor YY1 (<a href="/entry/600013">600013</a>), HMGB2 (<a href="/entry/163906">163906</a>), and nucleolin (NCL; <a href="/entry/164035">164035</a>). This multiprotein complex binds D4Z4 in vitro and in vivo and mediates transcriptional repression of 4q35 genes. <a href="#20" class="mim-tip-reference" title="Gabellini, D., Green, M. R., Tupler, R. <strong>Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle.</strong> Cell 110: 339-348, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12176321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12176321</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00826-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12176321">Gabellini et al. (2002)</a> proposed that deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes, resulting in disease. In normal individuals, the presence of a threshold number of D4Z4 repeats leads to repression of 4q35 genes by virtue of the DNA-bound multiprotein complex that actively suppresses gene expression. In FSHD patients, deletion of an integral number of D4Z4 repeats reduces the number of bound repressor complexes and consequently decreases or abolishes transcriptional repression of 4q35 genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12176321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By oligonucleotide microarrays, <a href="#115" class="mim-tip-reference" title="Winokur, S. T., Chen, Y.-W., Masny, P. S., Martin, J. H., Ehmsen, J. T., Tapscott, S. J., van der Maarel, S. M., Hayashi, Y., Flanigan, K. M. <strong>Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation.</strong> Hum. Molec. Genet. 12: 2895-2907, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14519683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14519683</a>] [<a href="https://doi.org/10.1093/hmg/ddg327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14519683">Winokur et al. (2003)</a> compared FSHD expression profiles with those from normal muscle and DMD and LGMD2D (<a href="/entry/608099">608099</a>). Several genes whose expression was altered in an FSHD-specific and highly significant manner are involved in myogenic differentiation, suggesting a partial block in the normal differentiation program. Many of the transcripts affected in FSHD were direct targets of the transcription factor MYOD1 (<a href="/entry/159970">159970</a>). Additional misexpressed genes confirmed a diminished capacity to buffer oxidative stress, as demonstrated in FSHD myoblasts. This enhanced vulnerability of proliferative stage myoblasts to reactive oxygen species was also disease-specific, further implicating a defect in FSHD muscle satellite cells. None of the genes localizing to the FSHD region at 4q35 were found to exhibit a significantly altered pattern of expression in FSHD muscle. <a href="#115" class="mim-tip-reference" title="Winokur, S. T., Chen, Y.-W., Masny, P. S., Martin, J. H., Ehmsen, J. T., Tapscott, S. J., van der Maarel, S. M., Hayashi, Y., Flanigan, K. M. <strong>Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation.</strong> Hum. Molec. Genet. 12: 2895-2907, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14519683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14519683</a>] [<a href="https://doi.org/10.1093/hmg/ddg327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14519683">Winokur et al. (2003)</a> hypothesized that disruptions in FSHD myogenesis and oxidative capacity may not arise from a position effect mechanism, as has been previously suggested, but rather from a global effect on gene regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14519683" 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="#30" class="mim-tip-reference" title="Jiang, G., Yang, F., van Overveld, P. G. M., Vedanarayanan, V., van der Maarel, S., Ehrlich, M. <strong>Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q.</strong> Hum. Molec. Genet. 12: 2909-2921, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14506132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14506132</a>] [<a href="https://doi.org/10.1093/hmg/ddg323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14506132">Jiang et al. (2003)</a> found that H4 acetylation levels of a nonrepeated region adjacent to the 4q35 and 10q26 D4Z4 arrays in normal and FSHD lymphoid cells were like those in unexpressed euchromatin, rather than like constitutive heterochromatin. The control and FSHD cells also displayed similar H4 hyperacetylation (like that of expressed genes) at the 5-prime regions of 4q35 candidate genes FRG1 (<a href="/entry/601278">601278</a>) and ANT1. There was no position-dependent increase in transcript levels from these genes in FSHD skeletal muscle samples compared with controls. <a href="#30" class="mim-tip-reference" title="Jiang, G., Yang, F., van Overveld, P. G. M., Vedanarayanan, V., van der Maarel, S., Ehrlich, M. <strong>Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q.</strong> Hum. Molec. Genet. 12: 2909-2921, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14506132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14506132</a>] [<a href="https://doi.org/10.1093/hmg/ddg323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14506132">Jiang et al. (2003)</a> proposed a model for FSHD in which differential long-distance cis looping depends upon the presence of a 4q35 D4Z4 array with less than a threshold number of copies of the 3.3-kb repeat. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14506132" 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="#63" class="mim-tip-reference" title="Perini, G., Tupler, R. <strong>Altered gene silencing and human diseases.</strong> Clin. Genet. 69: 1-7, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16451126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16451126</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2005.00540.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16451126">Perini and Tupler (2006)</a> suggested that FSHD might be considered a useful model for the study of position effect in humans. D4Z4 deletion might result in stochastic variation in gene expression in muscle cells and explain the asymmetric involvement of muscles, the great variability of clinical expression between and within families, and the apparent threshold effect whereby there is a requirement for the deletion of a certain number of copies of D4Z4 to develop FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16451126" 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="#59" class="mim-tip-reference" title="Osborne, R. J., Welle, S., Venance, S. L., Thornton, C. A., Tawil, R. <strong>Expression profile of FSHD supports a link between retinal vasculopathy and muscular dystrophy.</strong> Neurology 68: 569-577, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17151338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17151338</a>] [<a href="https://doi.org/10.1212/01.wnl.0000251269.31442.d9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17151338">Osborne et al. (2007)</a> detected no change in expression of the FRG1, FRG2, or ANT1 genes in muscle biopsies from 19 FSHD patients compared to controls. Further studies of the 8-Mb region proximal to the D4Z4 array showed no significant changes in gene expression, no evidence of a position effect, and no evidence of unequal allele-specific expression. However, microarray analysis of global gene expression in FSHD muscle identified 11 upregulated genes with a role in vascular smooth muscle or endothelial cells, suggesting a possible link between muscular dystrophy and vasculopathy in FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17151338" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Davidovic, L., Sacconi, S., Bechara, E. G., Delplace, S., Allegra, M., Desnuelle, C., Bardoni, B. <strong>Alteration of expression of muscle specific isoforms of the fragile X related protein 1 (FXR1P) in facioscapulohumeral muscular dystrophy patients.</strong> J. Med. Genet. 45: 679-685, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18628314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18628314</a>] [<a href="https://doi.org/10.1136/jmg.2008.060541" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18628314">Davidovic et al. (2008)</a> found that myoblasts isolated from patients with FSHD showed an abnormal pattern of expression of isoforms of the FXR1P (<a href="/entry/600819">600819</a>) gene compared to controls. FXR1P encodes an RNA-binding protein involved in the metabolism of muscle-specific-mRNAs during myogenesis. The altered pattern of FXR1P expression was due to a specific reduced stability of muscle-specific FXR1 mRNA variants. The findings suggested that the molecular basis of FSHD not only involves splicing alterations, but may also involve a deregulation of mRNA stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18628314" 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 RNA-DNA FISH, <a href="#48" class="mim-tip-reference" title="Masny, P. S., Chan, O. Y. A., de Greef, J. C., Bengtsson, U., Ehrlich, M., Tawil, R., Lock, L. F., Hewitt, J. E., Stocksdale, J., Martin, J. H., van der Maarel, S. M., Winokur, S. T. <strong>Analysis of allele-specific RNA transcription in FSHD by RNA-DNA FISH in single myonuclei.</strong> Europ. J. Hum. Genet. 18: 448-456, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19888305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19888305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19888305[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/ejhg.2009.183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19888305">Masny et al. (2010)</a> found no change in gene transcription of 16 genes in cis in the 4q35 region in nuclei of differentiated myotubes derived from patients with FSHD compared to differentiated myotubes from controls. In particular, there was no change in expression in the FRG1, FRG2, or ANT1 genes, which had previously been implicated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19888305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Dmitriev, P., Petrov, A., Ansseau, E., Stankevicins, L., Charron, S., Kim, E., Bos, T. J., Robert, T., Turki, A., Coppee, F., Belayew, A., Lazar, V., Carnac, G., Laoudj, D., Lipinski, M., Vassetzky, Y. S. <strong>The Kruppel-like factor 15 as a molecular link between myogenic factors and a chromosome 4q transcriptional enhancer implicated in facioscapulohumeral dystrophy.</strong> J. Biol. Chem. 286: 44620-44631, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21937448[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/10.1074/jbc.M111.254052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937448">Dmitriev et al. (2011)</a> showed that KLF15 (<a href="/entry/606465">606465</a>) bound an enhancer element within the D4Z4 repeat unit. Binding of KLF15 to 2 sites within the D4Z4 enhancer drove expression of FRG2 and DUX4C (DUX4L9; <a href="/entry/615581">615581</a>), which are located over 40 kb centromeric to the D4Z4 repeat array. KLF15 expression was upregulated following differentiation of normal human myoblasts and following expression of MYOD, and it was upregulated in FSHD myoblasts, myotubes, and muscle biopsies. FSHD cells also showed upregulated expression of MYOD and the KLF15 target gene PPARG (<a href="/entry/601487">601487</a>), in addition to DUX4C and FRG2. <a href="#14" class="mim-tip-reference" title="Dmitriev, P., Petrov, A., Ansseau, E., Stankevicins, L., Charron, S., Kim, E., Bos, T. J., Robert, T., Turki, A., Coppee, F., Belayew, A., Lazar, V., Carnac, G., Laoudj, D., Lipinski, M., Vassetzky, Y. S. <strong>The Kruppel-like factor 15 as a molecular link between myogenic factors and a chromosome 4q transcriptional enhancer implicated in facioscapulohumeral dystrophy.</strong> J. Biol. Chem. 286: 44620-44631, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937448</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21937448[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/10.1074/jbc.M111.254052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937448">Dmitriev et al. (2011)</a> concluded that MYOD-dependent KLF15 expression is involved in partial activation of the differentiation program in FSHD myoblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937448" 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>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between FSHD and variation in the FAT1 gene, see <a href="/entry/600976">600976</a>.</p>
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<p>As indicated earlier, FSHD is associated with a short (less than 35 kb) EcoRI/BlnI fragment resulting from deletion of an integral number of units of a 3.3-kb repeat located at 4q35. <a href="#105" class="mim-tip-reference" title="Vitelli, F., Villanova, M., Malandrini, A., Bruttini, M., Piccini, M., Merlini, L., Guazzi, G., Renieri, A. <strong>Inheritance of a 38-kb fragment in apparently sporadic facioscapulohumeral muscular dystrophy.</strong> Muscle Nerve 22: 1437-1441, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10487912/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10487912</a>] [<a href="https://doi.org/10.1002/(sici)1097-4598(199910)22:10<1437::aid-mus15>3.0.co;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10487912">Vitelli et al. (1999)</a> determined fragment sizes separated by pulsed field gel electrophoresis in a patient with an apparently sporadic case of FSHD and in his healthy family members. A 38-kb fragment was detected in the proband, in his older brother, and in their father. This finding prompted a clinical reevaluation of the father and brother. A subclinical phenotype restricted to abdominal muscle weakness was detected, and serum creatine kinase values were found to be elevated in both. Thus, whereas in healthy individuals the size of the 4q35 polymorphic fragment varies from 48 to 300 kb, and most patients with FSHD show fragments less than 35 kb, fragment sizes between 35 and 48 kb must be interpreted with caution. An inverse correlation between fragment size and severity was described by <a href="#46" class="mim-tip-reference" title="Lunt, P. W., Jardine, P. E., Koch, M. C., Maynard, J., Osborn, M., Williams, M., Harper, P. S., Upadhyaya, M. <strong>Correlation between fragment size at D4F104S1 and age at onset or at wheelchair use, with a possible generation effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD).</strong> Hum. Molec. Genet. 4: 951-958, 1995. Note: Erratum: Hum. Molec. Genet. 4: 1243-1244, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7633457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7633457</a>] [<a href="https://doi.org/10.1093/hmg/4.5.951" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7633457">Lunt et al. (1995)</a> and <a href="#83" class="mim-tip-reference" title="Tawil, R., Forrester, J., Griggs, R. C., Mendell, J., Kissel, J., McDermott, M., King, W., Weiffenbach, B., Figlewicz, D., FSH-DY Group. <strong>Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy.</strong> Ann. Neurol. 39: 744-748, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651646</a>] [<a href="https://doi.org/10.1002/ana.410390610" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8651646">Tawil et al. (1996)</a>. In familial cases, although the size of the inherited fragment remains constant, FSHD seems to become more severe with each generation (anticipation), according to the findings of <a href="#25" class="mim-tip-reference" title="Griggs, R. C., Tawil, R., Storvick, D., Mendell, J. R., Altherr, M. R. <strong>Genetics of facioscapulohumeral muscular dystrophy: new mutations in sporadic cases.</strong> Neurology 43: 2369-2372, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8232958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8232958</a>] [<a href="https://doi.org/10.1212/wnl.43.11.2369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8232958">Griggs et al. (1993)</a>, <a href="#46" class="mim-tip-reference" title="Lunt, P. W., Jardine, P. E., Koch, M. C., Maynard, J., Osborn, M., Williams, M., Harper, P. S., Upadhyaya, M. <strong>Correlation between fragment size at D4F104S1 and age at onset or at wheelchair use, with a possible generation effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD).</strong> Hum. Molec. Genet. 4: 951-958, 1995. Note: Erratum: Hum. Molec. Genet. 4: 1243-1244, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7633457/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7633457</a>] [<a href="https://doi.org/10.1093/hmg/4.5.951" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7633457">Lunt et al. (1995)</a>, <a href="#58" class="mim-tip-reference" title="Nakagawa, M., Higuchi, I., Yoshidome, H., Isashiki, Y., Ohkubo, R., Kaseda, S., Iwaki, H., Fukunaga, H., Osame, M. <strong>Familial facioscapulohumeral muscular dystrophy: phenotypic diversity and genetic abnormality.</strong> Acta Neurol. Scand. 93: 189-192, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8741141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8741141</a>] [<a href="https://doi.org/10.1111/j.1600-0404.1996.tb00197.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8741141">Nakagawa et al. (1996)</a>, and <a href="#83" class="mim-tip-reference" title="Tawil, R., Forrester, J., Griggs, R. C., Mendell, J., Kissel, J., McDermott, M., King, W., Weiffenbach, B., Figlewicz, D., FSH-DY Group. <strong>Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy.</strong> Ann. Neurol. 39: 744-748, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8651646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8651646</a>] [<a href="https://doi.org/10.1002/ana.410390610" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8651646">Tawil et al. (1996)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8232958+10487912+8651646+8741141+7633457" 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="#118" class="mim-tip-reference" title="Wohlgemuth, M., Lemmers, R. J., van der Kooi, E. L., van der Wielen, M. J., van Overveld, P. G., Dauwerse, H., Bakker, E., Frants, R. R., Padberg, G. W., van der Maarel, S. M. <strong>Possible phenotypic dosage effect in patients compound heterozygous for FSHD-sized 4q35 alleles.</strong> Neurology 61: 909-913, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14557558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14557558</a>] [<a href="https://doi.org/10.1212/wnl.61.7.909" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14557558">Wohlgemuth et al. (2003)</a> reported 2 unrelated families with FSHD in which the probands were compound heterozygous for 2 FSHD-sized alleles: a severely affected woman had chromosome 4-type arrays of 17 and 24 kb, and in the other family, a man had arrays of 33 and 36 kb. All of these alleles resided on 4qA. In the first family, 1 unaffected member had the 24-kb allele and 1 affected member had the 17-kb allele; in the second family, 3 unaffected children of the proband carried either the 33-kb allele or the 36-kb allele. <a href="#118" class="mim-tip-reference" title="Wohlgemuth, M., Lemmers, R. J., van der Kooi, E. L., van der Wielen, M. J., van Overveld, P. G., Dauwerse, H., Bakker, E., Frants, R. R., Padberg, G. W., van der Maarel, S. M. <strong>Possible phenotypic dosage effect in patients compound heterozygous for FSHD-sized 4q35 alleles.</strong> Neurology 61: 909-913, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14557558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14557558</a>] [<a href="https://doi.org/10.1212/wnl.61.7.909" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14557558">Wohlgemuth et al. (2003)</a> noted that the findings showed that having 2 disease alleles is not lethal, and proposed that the phenotype in both probands reflected a dosage effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14557558" 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 21 FSHD1 patients who had 1 translocated chromosome 10-type array on chromosome 4, referred to as 'monosomic,' <a href="#102" class="mim-tip-reference" title="van Overveld, P. G. M., Enthoven, L., Ricci, E., Rossi, M., Felicetti, L., Jeanpierre, M., Winokur, S. T., Frants, R. R., Padberg, G. W., van der Maarel, S. M. <strong>Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy.</strong> Ann. Neurol. 58: 569-576, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16178028/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16178028</a>] [<a href="https://doi.org/10.1002/ana.20625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16178028">van Overveld et al. (2005)</a> found D4Z4 hypomethylation compared to monosomic controls. Further analysis delineated 2 classes of clinical severity: patients with repeat sizes of 10 to 20 kb were severely affected and showed pronounced hypomethylation, whereas patients with repeat sizes of 20 to 31 kb showed variation in clinical severity and in hypomethylation. However, the authors could not establish a linear relationship between methylation and disease severity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16178028" 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="#69" 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 the SMCHD1 gene (<a href="/entry/614982">614982</a>), mutation in which causes FSHD2, 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="#69" 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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<p><a href="#56" class="mim-tip-reference" title="Morton, N. E., Chung, C. S. <strong>Formal genetics of muscular dystrophy.</strong> Am. J. Hum. Genet. 11: 360-379, 1959.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14424475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14424475</a>]" pmid="14424475">Morton and Chung (1959)</a> estimated the frequency to be about 2 per million living persons, with a frequency of about 4 persons destined to develop the trait in each million births. Fertility is little reduced and the mutation rate is not more than 5 per 10 million gametes. <a href="#44" class="mim-tip-reference" title="Lunt, P. W., Compston, D. A. S., Harper, P. S. <strong>Estimation of age dependent penetrance in facioscapulohumeral muscular dystrophy by minimising ascertainment bias.</strong> J. Med. Genet. 26: 755-760, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2614794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2614794</a>] [<a href="https://doi.org/10.1136/jmg.26.12.755" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2614794">Lunt et al. (1989)</a> estimated that the penetrance of the FSHD gene is less than 5% for ages 0 to 4 years, 21% for ages 5 to 9, 58% for ages 10 to 14, 86% for ages 15 to 19, and 95% for age 20 years and over. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2614794+14424475" 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="#45" class="mim-tip-reference" title="Lunt, P. W., Harper, P. S. <strong>Genetic counselling in facioscapulohumeral muscular dystrophy.</strong> J. Med. Genet. 28: 655-664, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1941962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1941962</a>] [<a href="https://doi.org/10.1136/jmg.28.10.655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1941962">Lunt and Harper (1991)</a> studied the families of 41 probands. They found 6 isolated cases that might represent new mutation. Although penetrance reaches 95% by age 20, one-third of heterozygotes over age 40 are mildly affected; 19% over age 40 require wheelchairs. Most patients develop significant lower limb weakness--a fact that is not reflected in the term 'facioscapulohumeral.' Distribution of weakness, severity, age of onset, and serum creatine kinase levels varied among subjects, but provided no clinical evidence for genetic heterogeneity in a comparison of the 11 largest families. Genetic homogeneity, including subjects previously diagnosed with FSH-type spinal muscular atrophy, is strongly supported by the genetic linkage data. They estimated the minimum prevalence in Wales of 2 per 100,000. In this study only 2 of 113 affected persons from the 11 largest families showed no detectable facial weakness; one of these was an obligate carrier, aged 42 years, with complete nonpenetrance. <a href="#45" class="mim-tip-reference" title="Lunt, P. W., Harper, P. S. <strong>Genetic counselling in facioscapulohumeral muscular dystrophy.</strong> J. Med. Genet. 28: 655-664, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1941962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1941962</a>] [<a href="https://doi.org/10.1136/jmg.28.10.655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1941962">Lunt and Harper (1991)</a> concluded that there is a dominantly inherited scapulohumeral or scapuloperoneal syndrome genetically distinct from FSHD that does not have facial weakness as a feature. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1941962" 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 the EcoRI polymorphism demonstrated by <a href="#112" class="mim-tip-reference" title="Wijmenga, C., Hewitt, J. E., Sandkuijl, L. A., Clark, L. N., Wright, T. J., Dauwerse, H. G., Gruter, A.-M., Hofker, M. H., Moerer, P., Williamson, R., van Ommen, G.-J. B., Padberg, G. W., Frants, R. R. <strong>Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy.</strong> Nature Genet. 2: 26-30, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1363881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1363881</a>] [<a href="https://doi.org/10.1038/ng0992-26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1363881">Wijmenga et al. (1992)</a>, <a href="#110" class="mim-tip-reference" title="Weiffenbach, B., Dubois, J., Storvick, D., Tawil, R., Jacobsen, S. J., Gilbert, J., Wijmenga, C., Mendell, J. R., Winokur, S., Altherr, M. R., Schultz, P., Olandt, S., Frants, R. R., Pericak-Vance, M., Griggs, R. C. <strong>Mapping the facioscapulohumeral muscular dystrophy gene is complicated by chromosome 4q35 recombination events.</strong> Nature Genet. 4: 165-169, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8102297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8102297</a>] [<a href="https://doi.org/10.1038/ng0693-165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8102297">Weiffenbach et al. (1993)</a> found 12 recombinants in 5 families, giving a recombination fraction of 0.05 between this marker and the disease. Two families with apparent germline mosaicism were also identified. In these instances, 2 offspring were affected but both parents were clinically normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8102297+1363881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 34 Brazilian FSHD families, <a href="#122" class="mim-tip-reference" title="Zatz, M., Marie, S. K., Passos-Bueno, M. R., Vainof, M., Campiotto, S., Cerqueira, A., Wijmenga, C., Padberg, G., Frants, R. <strong>High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families.</strong> Am. J. Hum. Genet. 56: 99-105, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7825608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7825608</a>]" pmid="7825608">Zatz et al. (1995)</a> concluded that at least one-third of cases may represent new mutations. Somatic mosaicism, furthermore, may not be rare. Biologic fitness was reduced to the 0.6 to 0.82 range, with no difference in sexes. The age at onset of clinical signs, as well as the age at ascertainment, in patients from multigenerational families suggested that anticipation occurs for FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7825608" 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="#121" class="mim-tip-reference" title="Zatz, M., Marie, S. K., Cerqueira, A., Vainzof, M., Pavanello, R. C. M., Passos-Bueno, M. R. <strong>The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females.</strong> Am. J. Med. Genet. 77: 155-161, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9605290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9605290</a>]" pmid="9605290">Zatz et al. (1998)</a> extended their study to 52 families, including 172 patients (104 males and 68 females). Among 273 individuals, 131 (67 males and 64 females) were shown to carry an EcoRI fragment smaller than 35 kb. Of these 131, 114 were examined. The excess of affected males was explained by a greater proportion of asymptomatic females and significantly greater number of affected sons than daughters of asymptomatic mothers. The penetrance by age 30 was 95% for males but only 69% for females. New mutations occurred more frequently in females than in males among somatic/germinal mosaic cases. Severely affected cases were more commonly the result of new mutations or mutations transmitted through maternal lines, including through mosaic mothers. <a href="#121" class="mim-tip-reference" title="Zatz, M., Marie, S. K., Cerqueira, A., Vainzof, M., Pavanello, R. C. M., Passos-Bueno, M. R. <strong>The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females.</strong> Am. J. Med. Genet. 77: 155-161, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9605290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9605290</a>]" pmid="9605290">Zatz et al. (1998)</a> noted the implications of these results for prenatal and prognostic counseling depending on the gender of the affected patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9605290" 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="#89" class="mim-tip-reference" title="Tupler, R., Barbierato, L., Memmi, M., Sewry, C. A., De Grandis, D., Maraschio, P., Tiepolo, L., Ferlini, A. <strong>Identical de novo mutation at the D4F104S1 locus in monozygotic male twins affected by facioscapulohumeral muscular dystrophy (FSHD) with different clinical expression.</strong> J. Med. Genet. 35: 778-783, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9733041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9733041</a>] [<a href="https://doi.org/10.1136/jmg.35.9.778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9733041">Tupler et al. (1998)</a> reported monozygotic male twins with FSHD carrying an identical de novo p13E-11 EcoRI fragment of paternal origin. This had arisen in paternal gametogenesis or postzygotically in the paternal chromosome 4 before twinning. A mutated fragment was subsequently transmitted to one of the affected male children. The twins showed great difference in clinical expression with one being almost asymptomatic and the other severely affected. Medical history was the same with the exception of an antirabies vaccination performed at the age of 5 in the more severely affected twin. <a href="#89" class="mim-tip-reference" title="Tupler, R., Barbierato, L., Memmi, M., Sewry, C. A., De Grandis, D., Maraschio, P., Tiepolo, L., Ferlini, A. <strong>Identical de novo mutation at the D4F104S1 locus in monozygotic male twins affected by facioscapulohumeral muscular dystrophy (FSHD) with different clinical expression.</strong> J. Med. Genet. 35: 778-783, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9733041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9733041</a>] [<a href="https://doi.org/10.1136/jmg.35.9.778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9733041">Tupler et al. (1998)</a> hypothesized that the vaccination might have triggered an inflammatory immune reaction contributory to the more severe phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9733041" 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="#97" class="mim-tip-reference" title="van der Maarel, S. M., Deidda, G., Lemmers, R. J. L. F., van Overveld, P. G. M., van der Wielen, M., Hewitt, J. E., Sandkuijl, L., Bakker, B., van Ommen, G.-J. B., Padberg, G. W., Frants, R. R. <strong>De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10.</strong> Am. J. Hum. Genet. 66: 26-35, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10631134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10631134</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10631134[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302730" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10631134">Van der Maarel et al. (2000)</a> surveyed 35 de novo FSHD families and found somatic mosaicism in 40% of cases, in either the patient or an asymptomatic parent. Mosaic males were typically affected; mosaic females were more often the unaffected parent of a nonmosaic de novo patient. A genotypic-severity score, composed of the residual repeat size and the degree of somatic mosaicism, yielded a consistent relationship with severity and age at onset of disease. Mosaic females had a higher proportion of somatic mosaicism than did mosaic males. The somatic mosaicism suggested a mainly mitotic origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10631134" 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>Almost half of de novo FSHD cases originate from a mitotic change leading to somatic mosaicism for the FSHD allele. <a href="#40" class="mim-tip-reference" title="Lemmers, R. J. L. F., van der Wielen, M. J. R., Bakker, E., Padberg, G. W., Frants, R. R., van der Maarel, S. M. <strong>Somatic mosaicism in FSHD often goes undetected.</strong> Ann. Neurol. 55: 845-850, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15174019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15174019</a>] [<a href="https://doi.org/10.1002/ana.20106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15174019">Lemmers et al. (2004)</a> found that 9 of 37 (24%) patients with presumed de novo FSHD were somatic mosaic, with contraction of D4Z4 identified in 40 to 90% cells. In 7 cases (19%), 1 of the minimally affected or asymptomatic parents was a mosaic 'carrier,' with 10 to 50% affected cells. The authors concluded that although mosaic patients have a lower recurrence risk of having affected offspring than nonmosaic patients, the offspring of a mildly affected patient may have a more severe phenotype than expected based on the phenotype of the parent. Pulsed-field gel electrophoresis (PFGE) was more sensitive in detecting the D4Z4 contraction than linear gel electrophoresis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15174019" 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="#74" class="mim-tip-reference" title="Scionti, I., Fabbri, G., Fiorillo, C., Ricci, G., Greco, F., D'Amico, R., Termanini, A., Vercelli, L., Tomelleri, G., Cao, M., Santoro, L., Percesepe, A., Tupler, R. <strong>Facioscapulohumeral muscular dystrophy: new insights from compound heterozygotes and implication for prenatal genetic counselling.</strong> J. Med. Genet. 49: 171-178, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22217918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22217918</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22217918">Scionti et al. (2012)</a> examined 11 nonconsanguineous Italian families in which 15 individuals were compound heterozygous for 2 D4Z4-reduced alleles. Most had the typical FSHD phenotype, although 1 man was asymptomatic at age 55 years. The phenotype was more severe in compound heterozygotes compared to carriers of 1 reduced allele, but the differences were not statistically significant. Analysis of relatives showed significantly reduced penetrance in those with a single reduced allele (25%) compared to those who were compound heterozygous for 2 reduced alleles (50%). In 4 families, the only FSHD-affected subject was the compound heterozygote for the D4Z4-reduced allele, and 52.6% of individuals with a single D4Z4-reduced 4A161PAS haplotype were nonpenetrant carriers. Analysis of surrounding polymorphisms did not support the predictive value of any specific 4q35 haplotype, and the population frequency of the 4A161PAS haplotype associated with a D4Z4-reduced allele was calculated to be as high as 1.2%. Overall, the findings challenged the notion that FSHD is a fully penetrant autosomal dominant disorder uniquely associated with the 4A161PAS haplotype, with repercussions for genetic counseling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22217918" 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="#93" class="mim-tip-reference" title="Upadhyaya, M., Lunt, P. W., Sarfarazi, M., Broadhead, W., Daniels, J., Owen, M., Harper, P. S. <strong>DNA marker applicable to presymptomatic and prenatal diagnosis of facioscapulohumeral disease. (Letter)</strong> Lancet 336: 1320-1321, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1978143/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1978143</a>] [<a href="https://doi.org/10.1016/0140-6736(90)93005-a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1978143">Upadhyaya et al. (1990)</a> reported markers useful in the presymptomatic and prenatal diagnosis of FSHD. Their findings confirmed the chromosome 4 location and suggested homogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1978143" 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="#96" class="mim-tip-reference" title="van der Maarel, S. M., Deidda, G., Lemmers, R. J. L. F., Bakker, E., van der Wielen, M. J. R., Sandkuijl, L., Hewitt, J. E., Padberg, G. W., Frants, R. R. <strong>A new dosage test for subtelomeric 4;10 translocations improves conventional diagnosis of facioscapulohumeral muscular dystrophy (FSHD).</strong> J. Med. Genet. 36: 823-828, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10544225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10544225</a>]" pmid="10544225">Van der Maarel et al. (1999)</a> described the limitations of molecular diagnostic techniques then available. They reported a Southern blot-based method, a BglII-BlnI dosage test that identified translocations between the repeat arrays on chromosomes 4 and 10 and deletion of p13E-11. The test also identified complex combinations of these events. <a href="#96" class="mim-tip-reference" title="van der Maarel, S. M., Deidda, G., Lemmers, R. J. L. F., Bakker, E., van der Wielen, M. J. R., Sandkuijl, L., Hewitt, J. E., Padberg, G. W., Frants, R. R. <strong>A new dosage test for subtelomeric 4;10 translocations improves conventional diagnosis of facioscapulohumeral muscular dystrophy (FSHD).</strong> J. Med. Genet. 36: 823-828, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10544225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10544225</a>]" pmid="10544225">Van der Maarel et al. (1999)</a> suggested that this test would increase the sensitivity and specificity of FSHD diagnosis. They also noted that this study delimited the FSHD candidate region by mapping the 4;10 translocation breakpoint proximal to the polymorphic BlnI site in the first repeat unit. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10544225" 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>Homologous polymorphic repeat arrays on chromosomes 4 and 10 have made definitive diagnosis of FSHD difficult. <a href="#37" class="mim-tip-reference" title="Lemmers, R. J. L. F., de Kievit, P., van Geel, M., van der Wielen, M. J. R., Bakker, E., Padberg, G. W., Frants, R. R., van der Maarel, S. M. <strong>Complete allele information in the diagnosis of facioscapulohumeral muscular dystrophy by triple DNA analysis.</strong> Ann. Neurol. 50: 816-819, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11761483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11761483</a>] [<a href="https://doi.org/10.1002/ana.10057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11761483">Lemmers et al. (2001)</a> found that the restriction enzyme Xap1 complements Bln1, as the former uniquely digests repeat units derived from chromosome 4 and the latter uniquely digests those derived from chromosome 10. A triple analysis with EcoRI, EcoRI/Bln1, and Xap1 allowed unequivocal characterization of each of the alleles. Analysis of 2 patients with symptoms of possible FSHD showed 1 to be a carrier of a partial deletion of chromosome 4, and thus to have the disease, whereas the other patient had a normal-sized allele on chromosome 4 and thus did not have the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11761483" 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>Some FSHD patients have proximally extended D4Z4 deletions that include the D4F104S1 region. Such extended deletions can lead to problems of interpretation of the diagnostic test. <a href="#38" class="mim-tip-reference" title="Lemmers, R. J. L. F., Osborn, M., Haaf, T., Rogers, M., Frants, R. R., Padberg, G. W., Cooper, D. N., van der Maarel, S. M., Upadhyaya, M. <strong>D4F104S1 deletion in facioscapulohumeral muscular dystrophy: phenotype, size, and detection.</strong> Neurology 61: 178-183, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12874395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12874395</a>] [<a href="https://doi.org/10.1212/01.wnl.0000078889.51444.81" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12874395">Lemmers et al. (2003)</a> described use of a telomeric probe, 4qA, that identifies large genomic deletions involving both D4Z4 and D4F104S1 using conventional gel electrophoresis. These extended deletions can be found in patients with a normal spectrum of the disease. Use of the assay should improve the accuracy and reliability of molecular diagnostic testing for FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12874395" 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>Almost half of new FSHD-related mutations, i.e., contractions of the polymorphic D4Z4 repeat on 4qter, occur postfertilization, resulting in somatic mosaicism for D4Z4. On detailed D4Z4 analysis of 11 mosaic individuals with FSHD, <a href="#41" class="mim-tip-reference" title="Lemmers, R. J. L. F., van Overveld, P. G. M., Sandkuijl, L. A., Vrieling, H., Padberg, G. W., Frants, R. R., van der Maarel, S. M. <strong>Mechanism and timing of mitotic rearrangements in the subtelomeric D4Z4 repeat involved in facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 75: 44-53, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15154112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15154112</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15154112[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/422175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15154112">Lemmers et al. (2004)</a> found a mosaic mixture of a contracted FSHD-sized allele and the unchanged ancestral allele in 8 cases, which is suggestive of a mitotic gene conversion without crossover. However, in the other 3 cases, the D4Z4 rearrangement resulted in 2 different-sized D4Z4 repeats, indicative of a gene conversion with crossover. In all 11 cases, DNA markers proximal and distal to D4Z4 showed no allelic exchanges, suggesting that all rearrangements were intrachromosomal. <a href="#41" class="mim-tip-reference" title="Lemmers, R. J. L. F., van Overveld, P. G. M., Sandkuijl, L. A., Vrieling, H., Padberg, G. W., Frants, R. R., van der Maarel, S. M. <strong>Mechanism and timing of mitotic rearrangements in the subtelomeric D4Z4 repeat involved in facioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 75: 44-53, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15154112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15154112</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15154112[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/422175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15154112">Lemmers et al. (2004)</a> proposed that D4Z4 rearrangements occur via a synthesis-dependent strand annealing model that relatively frequently allows for crossovers. Furthermore, the distribution of different cell populations in mosaic patients with FSHD suggested that mosaicism results from D4Z4 rearrangements occurring during the first few zygotic cell divisions after fertilization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15154112" 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 an asymptomatic female FSHD carrier, <a href="#88" class="mim-tip-reference" title="Tonini, M. M. O., Lemmers, R. J. L. F., Pavanello, R. C. M., Cerqueira, A. M. P., Frants, R. R., van der Maarel, S. M., Zatz, M. <strong>Equal proportions of affected cells in muscle and blood of a mosaic carrier of facioscapulohumeral muscular dystrophy.</strong> Hum. Genet. 119: 23-28, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16341710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16341710</a>] [<a href="https://doi.org/10.1007/s00439-005-0100-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16341710">Tonini et al. (2006)</a> detected mosaicism for a pathogenic D4Z4 contraction in peripheral blood cells and muscle tissue: the normal allele and the pathogenic 12-kb allele were present in 75% and 25% of both types of cells, respectively. The 12-kb allele was identified in virtually 100% of peripheral blood cells from the carrier's affected daughter, confirming the diagnosis and inheritance. The finding of comparable mosaicism in peripheral blood cells and muscle from an asymptomatic mother suggested that a mitotic contraction of D4Z4 is an early embryonic event and indicated that the degree of mosaicism in peripheral blood cells is representative of that in muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16341710" 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="#11" class="mim-tip-reference" title="Deak, K. L., Lemmers, R. J. L. F., Stajich, J. M., Klooster, R., Tawil, R., Frants, R. R., Speer, M. C., van der Maarel, S. M., Gilbert, J. R. <strong>Genotype-phenotype study in an FSHD family with a proximal deletion encompassing p13E-11 and D4Z4.</strong> Neurology 68: 578-582, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17229919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17229919</a>] [<a href="https://doi.org/10.1212/01.wnl.0000254991.21818.f3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17229919">Deak et al. (2007)</a> reported an FSHD family in which 11 affected members had a contracted D4Z4 allele and a large 78-kb proximal deletion. The family was initially designated as having non-chromosome-4 linked FSHD (<a href="/entry/158901">158901</a>) because commercial diagnostic testing of the proband failed to detect the deletion allele. The probe used, p13E-11, was unable to recognize proximally extended deletion alleles. Updated molecular analysis using a triple digest method revealed 10 D4Z4 repeat units, which the authors considered borderline. The extended deletion included the p13E-11 and B31 binding sites, the inverted repeat D4S463, and the FRG2 and TUBB4Q genes. The phenotype was typical for FSHD. <a href="#11" class="mim-tip-reference" title="Deak, K. L., Lemmers, R. J. L. F., Stajich, J. M., Klooster, R., Tawil, R., Frants, R. R., Speer, M. C., van der Maarel, S. M., Gilbert, J. R. <strong>Genotype-phenotype study in an FSHD family with a proximal deletion encompassing p13E-11 and D4Z4.</strong> Neurology 68: 578-582, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17229919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17229919</a>] [<a href="https://doi.org/10.1212/01.wnl.0000254991.21818.f3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17229919">Deak et al. (2007)</a> noted that this was the largest proximal deletion reported to date and emphasized the complexity of molecular diagnosis of FSHD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17229919" 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="#68" 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> performed molecular analysis of 16 patients with a clinical phenotype resembling FSHD. Affected individuals had 3 or more of the following features: (1) evidence of autosomal dominant inheritance and/or weakness in (2) facial muscles, (3) shoulder girdle muscles, (4) anterior foreleg muscles, and (5) asymmetric muscle involvement. All had a myopathic pattern on EMG. One patient carried a complex rearrangement in the FSHD locus that masked the D4Z4 contraction associated with FSHD1, and 1 patient was somatic mosaic for the D4Z4 contraction. The pathogenic chromosome in the first patient (also reported by <a href="#39" class="mim-tip-reference" title="Lemmers, R. J. L. F., van der Vliet, P. J., Klooster, R., Sacconi, S., Camano, P., Dauwerse, J. G., Snider, L., Straasheijm, K. R., van Ommen, G. J., Padberg, G. W., Miller, D. G., Tapscott, S. J., Tawil, R., Frants, R. R., van der Maarel, S. M. <strong>A unifying genetic model for facioscapulohumeral muscular dystrophy.</strong> Science 329: 1650-1653, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20724583/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20724583</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20724583[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/10.1126/science.1189044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20724583">Lemmers et al., 2010</a>) was the result of a meiotic exchange between chromosomes 10q and 4q, creating a contracted hybrid D4Z4 repeat array on a permissive background; it was associated with a mild phenotype. The second patient, who was somatic mosaic for a contracted D4Z4 repeat on a 4A161 allele, also had a mild phenotype. Of the remaining patients, 6 were diagnosed as having FSHD2, 4 had a CAPN3 (<a href="/entry/114240">114240</a>) mutation consistent with LGMD2A (<a href="/entry/253600">253600</a>); 2 had a VCP (<a href="/entry/601023">601023</a>) mutation, consistent with VCP-related myopathy (<a href="/entry/167320">167320</a>); and 2 had no identifiable genetic defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20724583+21984748" 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>As a follow-up to the study of <a href="#74" class="mim-tip-reference" title="Scionti, I., Fabbri, G., Fiorillo, C., Ricci, G., Greco, F., D'Amico, R., Termanini, A., Vercelli, L., Tomelleri, G., Cao, M., Santoro, L., Percesepe, A., Tupler, R. <strong>Facioscapulohumeral muscular dystrophy: new insights from compound heterozygotes and implication for prenatal genetic counselling.</strong> J. Med. Genet. 49: 171-178, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22217918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22217918</a>] [<a href="https://doi.org/10.1136/jmedgenet-2011-100454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22217918">Scionti et al. (2012)</a>, <a href="#75" class="mim-tip-reference" title="Scionti, I., Greco, F., Ricci, G., Govi, M., Arashiro, P., Vercelli, L., Berardinelli, A., Angelini, C., Antonini, G., Cao, M., Di Muzio, A., Moggio, M., and 12 others. <strong>Large-scale population analysis challenges the current criteria for the molecular diagnosis of fascioscapulohumeral muscular dystrophy.</strong> Am. J. Hum. Genet. 90: 628-635, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22482803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22482803</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22482803[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.2012.02.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22482803">Scionti et al. (2012)</a> analyzed D4Z4-related DNA elements in 801 controls, including 560 Italian and 241 Brazilian healthy individuals. Three percent of these individuals carried alleles with a reduced number (4 to 8) of D4Z4 repeats on chromosome 4q, and 1.3% carried the reduction on the supposedly pathogenic 4A161PAS haplotype. In addition, only 127 (50.1%) of 253 unrelated patients with FSHD carried alleles with 1 to 8 D4Z4 repeats associated with 4A161PAS; the remaining FSHD probands carried different haplotypes or alleles with a greater number of D4Z4 repeats. The study demonstrated that the current genetic signature of FSHD (4A161PAS) is a common polymorphism and that only half of FSHD probands carry this molecular signature. The findings indicated that the genetic basis of FSHD needs to be revisited because of the important implications for genetic counseling and prenatal diagnosis of at-risk families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22482803+22217918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By comparing the RNA-sequencing data from magnetic resonance imaging-guided muscle biopsies, <a href="#3" class="mim-tip-reference" title="Banerji, C. R. S., Zammit, P. S. <strong>PAX7 target gene repression is a superior FSHD biomarker than DUX4 target gene activation, associating with pathological severity and identifying FSHD at the single-cell level.</strong> Hum. Molec. Genet. 28: 2224-2236, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31067297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31067297</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31067297[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/ddz043" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31067297">Banerji and Zammit (2019)</a> found that PAX7 (<a href="/entry/167410">167410</a>) target gene repression was an equivalent biomarker to DUX4 target gene expression for FSHD. PAX7 target gene repression also correlated with histopathologic measures of disease activity independently of DUX4 target gene expression. PAX7 target genes were significantly repressed in single cells from FSHD patients and were able to discriminate DUX4 target gene-negative FSHD myocytes from controls. The authors concluded that PAX7 target gene repression is a superior and more reliable discriminator of FSHD cells than DUX4 target gene expression. They also outlined a pipeline for evaluating PAX7 target gene repression biomarkers and DUX4 target gene expression biomarkers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31067297" 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="#16" class="mim-tip-reference" title="Erdmann, H., Scharf, F., Gehling, S., Benet-Pages, A., Jakubiczka, S., Becker, K., Seipelt, M., Kleefeld, F., Knop, K. C., Prott, E. C., Hiebeler, M., Montagnese, F., and 10 others. <strong>Methylation of the 4q35 D4Z4 repeat defines disease status in facioscapulohumeral muscular dystrophy.</strong> Brain 146: 1388-1402, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36100962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36100962</a>] [<a href="https://doi.org/10.1093/brain/awac336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36100962">Erdmann et al. (2023)</a> developed and validated a diagnostic workflow for the diagnosis of FSHD1 and FSHD2, which consisted of haplotyping to determine the presence of a permissive D4Z4 haplotype (4qA or 4qAL), followed by next generation-based bisulfite sequencing to determine the regional methylation at the last repeat unit of 4qA or 4qAL and global methylation of DUX4. <a href="#16" class="mim-tip-reference" title="Erdmann, H., Scharf, F., Gehling, S., Benet-Pages, A., Jakubiczka, S., Becker, K., Seipelt, M., Kleefeld, F., Knop, K. C., Prott, E. C., Hiebeler, M., Montagnese, F., and 10 others. <strong>Methylation of the 4q35 D4Z4 repeat defines disease status in facioscapulohumeral muscular dystrophy.</strong> Brain 146: 1388-1402, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36100962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36100962</a>] [<a href="https://doi.org/10.1093/brain/awac336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36100962">Erdmann et al. (2023)</a> found that this diagnostic approach reliably identified patients with FSHD, and discriminated between FSHD1 and FSHD2, with FSHD1 patients showing distal 4qA or 4qAL hypomethylation and FSHD2 patients showing global DUX4 hypomethylation including the distal region. Interestingly, the regional methylation level of 4qA or 4qAL and the D4Z4 repeat length correlated to an age-corrected clinical severity score in patients with FSHD1, with the regional methylation level showing the stronger correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36100962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a population-based study in northeastern Italy, <a href="#57" class="mim-tip-reference" title="Mostacciuolo, M. L., Pastorello, E., Vazza, G., Miorin, M., Angelini, C., Tomelleri, G., Galluzzi, G., Trevisan, C. P. <strong>Facioscapulohumeral muscular dystrophy: epidemiological and molecular study in a north-east Italian population sample.</strong> Clin. Genet. 75: 550-555, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19320656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19320656</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01158.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19320656">Mostacciuolo et al. (2009)</a> identified 40 patients with a clinical diagnosis of FSHD. Thirty (76%) patients from 13 families had a family history of the disorder, whereas 10 had sporadic disease. Of the 40 patients, 33 (82.5%) had a contraction at chromosome 4q35 ranging from 14 to 35 kb, whereas 4 patients from 1 family had a borderline 38-kb fragment, and 3 had a fragment greater than 40 kb. The 4 patients with the 38-kb fragment had onset of slowly progressive mild proximal muscle weakness between age 15 and 35 years without facial weakness. In contrast, 2 related patients with the fragment greater than 40 kb had a typical FSHD phenotype with facial involvement and profound weakness in the lower and upper region muscles, but the fragment was also found in an unaffected family member, thus excluding it as disease-causing. One asymptomatic 43-year-old man with a 20-kb fragment was identified, yielding an overall penetrance of 97%. <a href="#57" class="mim-tip-reference" title="Mostacciuolo, M. L., Pastorello, E., Vazza, G., Miorin, M., Angelini, C., Tomelleri, G., Galluzzi, G., Trevisan, C. P. <strong>Facioscapulohumeral muscular dystrophy: epidemiological and molecular study in a north-east Italian population sample.</strong> Clin. Genet. 75: 550-555, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19320656/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19320656</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01158.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19320656">Mostacciuolo et al. (2009)</a> estimated the prevalence of genetically confirmed FSHD in this population to be 44 in 1,000,000. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19320656" 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="#112" class="mim-tip-reference" title="Wijmenga, C., Hewitt, J. E., Sandkuijl, L. A., Clark, L. N., Wright, T. J., Dauwerse, H. G., Gruter, A.-M., Hofker, M. H., Moerer, P., Williamson, R., van Ommen, G.-J. B., Padberg, G. W., Frants, R. R. <strong>Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy.</strong> Nature Genet. 2: 26-30, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1363881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1363881</a>] [<a href="https://doi.org/10.1038/ng0992-26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1363881">Wijmenga et al. (1992)</a> demonstrated rearrangements in the cosmid clone p13E-11 in patients with FSHD. This cosmid clone had been isolated in a search for homeobox genes and was mapped to chromosome 4q35 just distal to D4S139. In normal individuals the clone detected a polymorphic EcoRI fragment usually larger than 28 kb. A shorter EcoRI fragment was found in 5 out of 6 new FSHD cases. In 10 Dutch families analyzed, a specific shorter fragment between 14 and 28 kb cosegregated with FSHD. FSHD is associated with contraction of a tandem repeat rather than an expansion such as occurs in the fragile X syndrome (<a href="/entry/300624">300624</a>) and in myotonic dystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1363881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Fischbeck, K. H., Garbern, J. Y. <strong>Facioscapulohumeral muscular dystrophy defect identified.</strong> Nature Genet. 2: 3-4, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1363882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1363882</a>] [<a href="https://doi.org/10.1038/ng0992-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1363882">Fischbeck and Garbern (1992)</a> reviewed the possibility that a previously uncharacterized homeobox gene or genes might be involved in the disorder; a graded, rostro-caudal expression of the gene(s) would explain the regional muscle degeneration. Previously known homeobox mutations cause congenital malformations; if FSHD is the result of a homeobox gene rearrangement, this would be the first example of a developmental control gene producing a phenotype with onset later in life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1363882" 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="#84" class="mim-tip-reference" title="Tawil, R., Storvick, D., Feasby, T. E., Weiffenbach, B., Griggs, R. C. <strong>Extreme variability of expression in monozygotic twins with FSH muscular dystrophy.</strong> Neurology 43: 345-348, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094896/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094896</a>] [<a href="https://doi.org/10.1212/wnl.43.2.345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8094896">Tawil et al. (1993)</a> reported monozygotic twins discordant for the FSHD phenotype and with no family history of FSHD. Using a new marker, D4S809, which is close to or within the FSHD gene, <a href="#85" class="mim-tip-reference" title="Tawil, R., Storvick, D., Weiffenbach, B., Altherr, M. R., Feasby, T. E., Griggs, R. C. <strong>Chromosome 4q DNA rearrangement in monozygotic twins discordant for facioscapulohumeral muscular dystrophy.</strong> Hum. Mutat. 2: 492-494, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8111417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8111417</a>] [<a href="https://doi.org/10.1002/humu.1380020612" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8111417">Tawil et al. (1993)</a> demonstrated a unique 4q35 DNA rearrangement in the affected twin. The most likely explanation for the discordance was occurrence of a de novo postzygotic mutation on 4q35 during or after the twinning process. Most studied sporadic cases demonstrate similar 4q35 rearrangements not present in their parents (<a href="#112" class="mim-tip-reference" title="Wijmenga, C., Hewitt, J. E., Sandkuijl, L. A., Clark, L. N., Wright, T. J., Dauwerse, H. G., Gruter, A.-M., Hofker, M. H., Moerer, P., Williamson, R., van Ommen, G.-J. B., Padberg, G. W., Frants, R. R. <strong>Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy.</strong> Nature Genet. 2: 26-30, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1363881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1363881</a>] [<a href="https://doi.org/10.1038/ng0992-26" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1363881">Wijmenga et al., 1992</a>; <a href="#110" class="mim-tip-reference" title="Weiffenbach, B., Dubois, J., Storvick, D., Tawil, R., Jacobsen, S. J., Gilbert, J., Wijmenga, C., Mendell, J. R., Winokur, S., Altherr, M. R., Schultz, P., Olandt, S., Frants, R. R., Pericak-Vance, M., Griggs, R. C. <strong>Mapping the facioscapulohumeral muscular dystrophy gene is complicated by chromosome 4q35 recombination events.</strong> Nature Genet. 4: 165-169, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8102297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8102297</a>] [<a href="https://doi.org/10.1038/ng0693-165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8102297">Weiffenbach et al., 1993</a>). Using D4S809 probes that map near or within the FSHD gene, <a href="#25" class="mim-tip-reference" title="Griggs, R. C., Tawil, R., Storvick, D., Mendell, J. R., Altherr, M. R. <strong>Genetics of facioscapulohumeral muscular dystrophy: new mutations in sporadic cases.</strong> Neurology 43: 2369-2372, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8232958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8232958</a>] [<a href="https://doi.org/10.1212/wnl.43.11.2369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8232958">Griggs et al. (1993)</a> investigated 8 sporadic patients with FSHD whose parents showed no signs of the disease. The probe detected novel DNA fragments in 7 of the 8 sporadic individuals and not in the parents. A novel DNA fragment was found in each of 2 sisters with FSHD whose parents were clinically normal; the finding was taken as evidence of germline mosaicism. Use of the D4S809 probe in genetic counseling is limited; however, because the probe may also detect a locus unlinked to chromosome 4, because of possible genetic heterogeneity in FSHD and because of the presence of recombinants in families with the inherited form. Hence, closer markers or gene definition will be required. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8232958+1363881+8111417+8094896+8102297" 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="#27" class="mim-tip-reference" title="Hewitt, J. E., Lyle, R., Clark, L. N., Valleley, E. M., Wright, T. J., Wijmenga, C., van Deutekom, J. C. T., Francis, F., Sharpe, P. T., Hofker, M., Frants, R. R., Williamson, R. <strong>Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy.</strong> Hum. Molec. Genet. 3: 1287-1295, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7987304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7987304</a>] [<a href="https://doi.org/10.1093/hmg/3.8.1287" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7987304">Hewitt et al. (1994)</a> and <a href="#116" class="mim-tip-reference" title="Winokur, S. T., Schutte, B., Weiffenbach, B., Washington, S. S., McElligott, D., Chakravarti, A., Wasmuth, J. H., Altherr, M. R. <strong>A radiation hybrid map of 15 loci on the distal long arm of chromosome 4, the region containing the gene responsible for facioscapulohumeral muscular dystrophy (FSHD).</strong> Am. J. Hum. Genet. 53: 874-880, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8213815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8213815</a>]" pmid="8213815">Winokur et al. (1993)</a> postulated that FSHD may be due to a position effect. <a href="#4" class="mim-tip-reference" title="Bengtsson, U., Altherr, M. R., Wasmuth, J. J., Winokur, S. T. <strong>High resolution fluorescence in situ hybridization to linearly extended DNA visually maps a tandem repeat associated with facioscapulohumeral muscular dystrophy immediately adjacent to the telomere of 4q.</strong> Hum. Molec. Genet. 3: 1801-1805, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7849703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7849703</a>] [<a href="https://doi.org/10.1093/hmg/3.10.1801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7849703">Bengtsson et al. (1994)</a> reported results indicating that the tandem array of 3.2-kb repeats, disrupted in FSHD, lies immediately adjacent to the telomere of 4q and that the gene responsible for FSHD is probably located proximal to the tandem repeat. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7987304+8213815+7849703" 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>Because of its mapping to a region of homology to human 4q, <a href="#54" class="mim-tip-reference" title="Mills, K. A., Mathews, K. D., Scherpbier-Heddema, T., Schelper, R. L., Schmalzel, R., Bailey, H. L., Nadeau, J. H., Buetow, K. H., Murray, J. C. <strong>Genetic mapping near the myd locus on mouse chromosome 8.</strong> Mammalian Genome 6: 278-280, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7613034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7613034</a>] [<a href="https://doi.org/10.1007/BF00352416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7613034">Mills et al. (1995)</a> suggested that 'myodystrophy' (myd), an autosomal recessive mutation in the mouse, is a homolog of FSHD. The mouse disorder is characterized by progressive weakness and dystrophic muscle histology and maps to the central portion of mouse chromosome 8. This portion of mouse chromosome 8 contains the genes for mitochondrial uncoupling protein (UCP; <a href="/entry/113730">113730</a>) and kallikrein (KLKB1; <a href="/entry/229000">229000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7613034" 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>Contrary to the suggestion of <a href="#54" class="mim-tip-reference" title="Mills, K. A., Mathews, K. D., Scherpbier-Heddema, T., Schelper, R. L., Schmalzel, R., Bailey, H. L., Nadeau, J. H., Buetow, K. H., Murray, J. C. <strong>Genetic mapping near the myd locus on mouse chromosome 8.</strong> Mammalian Genome 6: 278-280, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7613034/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7613034</a>] [<a href="https://doi.org/10.1007/BF00352416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7613034">Mills et al. (1995)</a>, <a href="#24" class="mim-tip-reference" title="Grewal, P. K., Holzfeind, P. J., Bittner, R. E., Hewitt, J. E. <strong>Mutant glycosyltransferase and altered glycosylation of alpha-dystroglycan in the myodystrophy mouse.</strong> Nature Genet. 28: 151-154, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381262</a>] [<a href="https://doi.org/10.1038/88865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381262">Grewal et al. (2001)</a> found that the gene mutated in myd, Large, encodes a glycosyltransferase. The human homolog of this gene maps to 22q; see <a href="/entry/603590">603590</a>. In myd, <a href="#24" class="mim-tip-reference" title="Grewal, P. K., Holzfeind, P. J., Bittner, R. E., Hewitt, J. E. <strong>Mutant glycosyltransferase and altered glycosylation of alpha-dystroglycan in the myodystrophy mouse.</strong> Nature Genet. 28: 151-154, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381262</a>] [<a href="https://doi.org/10.1038/88865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381262">Grewal et al. (2001)</a> identified an intragenic deletion of exons 4-7 that causes a frameshift in the resultant mRNA and a premature termination codon before the first of the 2 catalytic domains. On immunoblots, a monoclonal antibody to alpha-dystroglycan (<a href="/entry/128239">128239</a>), a component of the dystrophin (<a href="/entry/300377">300377</a>)-associated glycoprotein complex, showed reduced binding in myd, which <a href="#24" class="mim-tip-reference" title="Grewal, P. K., Holzfeind, P. J., Bittner, R. E., Hewitt, J. E. <strong>Mutant glycosyltransferase and altered glycosylation of alpha-dystroglycan in the myodystrophy mouse.</strong> Nature Genet. 28: 151-154, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381262</a>] [<a href="https://doi.org/10.1038/88865" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381262">Grewal et al. (2001)</a> attributed to altered glycosylation of the protein. They speculated that abnormal posttranslational modification of alpha-dystroglycan may contribute to the myd phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7613034+11381262" 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>To identify the gene responsible for facioscapulohumeral muscular dystrophy pathogenesis, <a href="#19" class="mim-tip-reference" title="Gabellini, D., D'Antona, G., Moggio, M., Prelle, A., Zecca, C., Adami, R., Angeletti, B., Ciscato, P., Pellegrino, M. A., Bottinelli, R., Green, M. R., Tupler, R. <strong>Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1.</strong> Nature 439: 973-977, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16341202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16341202</a>] [<a href="https://doi.org/10.1038/nature04422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16341202">Gabellini et al. (2006)</a> generated transgenic mice selectively overexpressing in skeletal muscle the 4q35 genes FRG1 (<a href="/entry/601278">601278</a>), FRG2 (<a href="/entry/609032">609032</a>), or ANT1 (<a href="/entry/103220">103220</a>). The authors found that FRG1 transgenic mice developed a muscular dystrophy with features characteristic of the human disease; by contrast, FRG2 and ANT1 transgenic mice seemed normal. FRG1 is a nuclear protein, and several lines of evidence suggest it is involved in pre-mRNA splicing. <a href="#19" class="mim-tip-reference" title="Gabellini, D., D'Antona, G., Moggio, M., Prelle, A., Zecca, C., Adami, R., Angeletti, B., Ciscato, P., Pellegrino, M. A., Bottinelli, R., Green, M. R., Tupler, R. <strong>Facioscapulohumeral muscular dystrophy in mice overexpressing FRG1.</strong> Nature 439: 973-977, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16341202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16341202</a>] [<a href="https://doi.org/10.1038/nature04422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16341202">Gabellini et al. (2006)</a> found changes in the alternative splicing pattern of the pre-mRNAs of TNNT3 (<a href="/entry/600692">600692</a>) and myotubularin related-protein 1 (MTMR1; <a href="/entry/300171">300171</a>) in muscle of FRG1 transgenic mice and FSHD patients. Collectively, the results suggested that FSHD results from inappropriate overexpression of FRG1 in skeletal muscle, which leads to abnormal alternative splicing of specific pre-mRNAs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16341202" 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/10.1093/hmg/3.10.1801" target="_blank">Full Text</a>]
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Bosnakovski, D., Xu, Z., Gang, E. J., Galindo, C. L., Liu, M., Simsek, T., Garner, H. R., Agha-Mohammadi, S., Tassin, A., Coppee, F., Belayew, A., Perlingeiro, R. R., Kyba, M.
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[<a href="https://doi.org/10.1212/wnl.41.12.1878" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/519311" target="_blank">Full Text</a>]
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<strong>Alteration of expression of muscle specific isoforms of the fragile X related protein 1 (FXR1P) in facioscapulohumeral muscular dystrophy patients.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18628314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18628314</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18628314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2008.060541" target="_blank">Full Text</a>]
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Deak, K. L., Lemmers, R. J. L. F., Stajich, J. M., Klooster, R., Tawil, R., Frants, R. R., Speer, M. C., van der Maarel, S. M., Gilbert, J. R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17229919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17229919</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17229919" 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/10.1212/01.wnl.0000254991.21818.f3" target="_blank">Full Text</a>]
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Dixit, M., Ansseau, E., Tassin, A., Winokur, S., Shi, R., Qian, H., Sauvage, S., Matteotti, C., van Acker, A. M., Leo, O., Figlewicz, D., Barro, M., Laoudj-Chenivesse, D., Belayew, A., Coppee, F., Chen, Y.-W.
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<strong>DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1.</strong>
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Proc. Nat. Acad. Sci. 104: 18157-18162, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17984056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17984056</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17984056[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=17984056" 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/10.1073/pnas.0708659104" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.26.8.485" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.26.12.755" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ana.20750" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-011-1100-z" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000007456" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2011-100101" target="_blank">Full Text</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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[<a href="https://doi.org/10.1086/302730" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.2002.6690" target="_blank">Full Text</a>]
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Wijmenga, C., Padberg, G. W., Moerer, P., Wiegant, J., Liem, L., Brouwer, O. F., Milner, E. C. B., Weber, J. L., van Ommen, G. B., Sandkuyl, L. A., Frants, R. R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2037288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2037288</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2037288" 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/10.1016/0888-7543(91)90348-i" target="_blank">Full Text</a>]
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Wijmenga, C., Sandkuijl, L. A., Moerer, P., van der Boorn, N., Bodrug, S. E., Ray, P. N., Brouwer, O. F., Murray, J. C., van Ommen, G. J. B., Padberg, G. W., Frants, R. R.
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Winokur, S. T., Chen, Y.-W., Masny, P. S., Martin, J. H., Ehmsen, J. T., Tapscott, S. J., van der Maarel, S. M., Hayashi, Y., Flanigan, K. M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14519683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14519683</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14519683" 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/ddg327" target="_blank">Full Text</a>]
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Winokur, S. T., Schutte, B., Weiffenbach, B., Washington, S. S., McElligott, D., Chakravarti, A., Wasmuth, J. H., Altherr, M. R.
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<strong>A radiation hybrid map of 15 loci on the distal long arm of chromosome 4, the region containing the gene responsible for facioscapulohumeral muscular dystrophy (FSHD).</strong>
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Am. J. Hum. Genet. 53: 874-880, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8213815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8213815</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8213815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Wohlgemuth, M., de Swart, B. J. M., Kalf, J. G., Joosten, F. B. M., Van der Vliet, A. M., Padberg, G. W.
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<strong>Dysphagia in facioscapulohumeral muscular dystrophy.</strong>
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Neurology 66: 1926-1928, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16801662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16801662</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16801662" 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/10.1212/01.wnl.0000219760.76441.f8" target="_blank">Full Text</a>]
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Wohlgemuth, M., Lemmers, R. J., van der Kooi, E. L., van der Wielen, M. J., van Overveld, P. G., Dauwerse, H., Bakker, E., Frants, R. R., Padberg, G. W., van der Maarel, S. M.
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<strong>Possible phenotypic dosage effect in patients compound heterozygous for FSHD-sized 4q35 alleles.</strong>
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Neurology 61: 909-913, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14557558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14557558</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14557558" 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/10.1212/wnl.61.7.909" target="_blank">Full Text</a>]
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Yamanaka, G., Goto, K., Matsumura, T., Funakoshi, M., Komori, T., Hayashi, Y. K., Arahata, K.
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<strong>Tongue atrophy in facioscapulohumeral muscular dystrophy.</strong>
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Neurology 57: 733-735, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11524495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11524495</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11524495" 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/10.1212/wnl.57.4.733" target="_blank">Full Text</a>]
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Yasukohchi, S., Yagi, Y., Akabane, T., Terauchi, A., Tamagawa, K., Mizuno, Y.
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<strong>Facioscapulohumeral dystrophy associated with sensorineural hearing loss, tortuosity of retinal arterioles, and an early onset and rapid progression of respiratory failure.</strong>
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Brain Dev. 10: 319-324, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3239698/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3239698</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3239698" 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/s0387-7604(88)80063-9" target="_blank">Full Text</a>]
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Zatz, M., Marie, S. K., Cerqueira, A., Vainzof, M., Pavanello, R. C. M., Passos-Bueno, M. R.
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<strong>The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females.</strong>
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Am. J. Med. Genet. 77: 155-161, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9605290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9605290</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9605290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Zatz, M., Marie, S. K., Passos-Bueno, M. R., Vainof, M., Campiotto, S., Cerqueira, A., Wijmenga, C., Padberg, G., Frants, R.
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<strong>High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families.</strong>
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Am. J. Hum. Genet. 56: 99-105, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7825608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7825608</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7825608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</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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Hilary J. Vernon - updated : 10/10/2023
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Cassandra L. Kniffin - updated : 08/12/2021<br>Bao Lige - updated : 11/11/2019<br>Cassandra L. Kniffin - updated : 11/4/2013<br>Patricia A. Hartz - updated : 1/17/2013<br>Cassandra L. Kniffin - updated : 5/3/2012<br>Cassandra L. Kniffin - updated : 4/25/2012<br>Cassandra L. Kniffin - updated : 4/9/2012<br>Cassandra L. Kniffin - updated : 3/26/2012<br>Cassandra L. Kniffin - updated : 1/10/2012<br>Cassandra L. Kniffin - updated : 11/2/2011<br>Patricia A. Hartz - updated : 9/27/2011<br>Ada Hamosh - updated : 11/10/2010<br>Cassandra L. Kniffin - updated : 5/28/2010<br>Cassandra L. Kniffin - updated : 6/5/2009<br>Cassandra L. Kniffin - updated : 2/12/2009<br>Cassandra L. Kniffin - updated : 12/3/2007<br>Jane Kelly - updated : 11/8/2007<br>Victor A. McKusick - updated : 11/1/2007<br>Cassandra L. Kniffin - updated : 10/8/2007<br>Victor A. McKusick - updated : 8/17/2007<br>Marla J. F. O'Neill - updated : 6/7/2007<br>George E. Tiller - updated : 1/16/2007<br>Ada Hamosh - updated : 12/6/2006<br>Cassandra L. Kniffin - updated : 5/23/2006<br>Cassandra L. Kniffin - updated : 5/16/2006<br>Cassandra L. Kniffin - updated : 4/3/2006<br>Victor A. McKusick - updated : 3/7/2006<br>George E. Tiller - updated : 1/11/2006<br>Cassandra L. Kniffin - updated : 12/8/2005<br>George E. Tiller - updated : 9/30/2005<br>Victor A. McKusick - updated : 3/10/2005<br>Cassandra L. Kniffin - updated : 1/20/2005<br>Victor A. McKusick - updated : 11/12/2004<br>Victor A. McKusick - updated : 6/30/2004<br>Cassandra L. Kniffin - updated : 1/23/2004<br>Cassandra L. Kniffin - updated : 1/9/2004<br>Victor A. McKusick - updated : 12/2/2003<br>Victor A. McKusick - updated : 8/7/2003<br>Cassandra L. Kniffin - updated : 11/27/2002<br>Cassandra L. Kniffin - updated : 11/13/2002<br>Victor A. McKusick - updated : 9/23/2002<br>Stylianos E. Antonarakis - updated : 9/6/2002<br>Victor A. McKusick - updated : 6/19/2001<br>Michael J. Wright - updated : 2/7/2000<br>Victor A. McKusick - updated : 1/4/2000<br>Victor A. McKusick - updated : 12/13/1999<br>Victor A. McKusick - updated : 2/2/1999<br>Ada Hamosh - updated : 10/29/1998<br>Michael J. Wright - updated : 10/7/1998<br>Victor A. McKusick - updated : 5/11/1998<br>Orest Hurko - updated : 4/7/1998<br>Moyra Smith - updated : 1/28/1997<br>Moyra Smith - updated : 5/23/1996
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Victor A. McKusick : 6/2/1986
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carol : 10/10/2023<br>alopez : 05/26/2023<br>carol : 08/16/2021<br>ckniffin : 08/12/2021<br>mgross : 11/11/2019<br>carol : 11/17/2017<br>ckniffin : 11/16/2017<br>ckniffin : 11/16/2017<br>mgross : 12/20/2013<br>carol : 11/6/2013<br>ckniffin : 11/4/2013<br>carol : 4/26/2013<br>mgross : 2/4/2013<br>mgross : 1/18/2013<br>terry : 1/17/2013<br>carol : 12/18/2012<br>carol : 5/3/2012<br>terry : 5/3/2012<br>ckniffin : 5/3/2012<br>carol : 4/26/2012<br>ckniffin : 4/25/2012<br>alopez : 4/10/2012<br>terry : 4/10/2012<br>ckniffin : 4/9/2012<br>ckniffin : 3/26/2012<br>ckniffin : 3/26/2012<br>carol : 1/13/2012<br>ckniffin : 1/10/2012<br>carol : 11/23/2011<br>carol : 11/23/2011<br>ckniffin : 11/21/2011<br>ckniffin : 11/2/2011<br>carol : 10/5/2011<br>terry : 9/28/2011<br>terry : 9/27/2011<br>alopez : 11/15/2010<br>terry : 11/10/2010<br>wwang : 6/3/2010<br>ckniffin : 5/28/2010<br>wwang : 9/23/2009<br>wwang : 6/25/2009<br>ckniffin : 6/5/2009<br>wwang : 2/20/2009<br>ckniffin : 2/12/2009<br>carol : 11/20/2008<br>wwang : 12/11/2007<br>ckniffin : 12/3/2007<br>ckniffin : 12/3/2007<br>carol : 11/8/2007<br>alopez : 11/1/2007<br>wwang : 10/16/2007<br>ckniffin : 10/8/2007<br>alopez : 8/21/2007<br>terry : 8/17/2007<br>wwang : 6/13/2007<br>terry : 6/7/2007<br>wwang : 1/24/2007<br>terry : 1/16/2007<br>alopez : 12/13/2006<br>terry : 12/6/2006<br>carol : 11/27/2006<br>wwang : 6/2/2006<br>ckniffin : 5/23/2006<br>wwang : 5/17/2006<br>ckniffin : 5/16/2006<br>wwang : 4/5/2006<br>ckniffin : 4/3/2006<br>terry : 3/7/2006<br>wwang : 1/20/2006<br>terry : 1/11/2006<br>wwang : 12/27/2005<br>ckniffin : 12/8/2005<br>alopez : 9/30/2005<br>wwang : 3/23/2005<br>wwang : 3/15/2005<br>terry : 3/10/2005<br>tkritzer : 1/26/2005<br>ckniffin : 1/20/2005<br>mgross : 11/18/2004<br>alopez : 11/18/2004<br>terry : 11/12/2004<br>terry : 11/4/2004<br>alopez : 10/14/2004<br>alopez : 10/14/2004<br>alopez : 10/14/2004<br>terry : 6/30/2004<br>terry : 3/18/2004<br>joanna : 3/17/2004<br>tkritzer : 2/4/2004<br>ckniffin : 1/23/2004<br>tkritzer : 1/14/2004<br>ckniffin : 1/9/2004<br>alopez : 12/2/2003<br>terry : 12/2/2003<br>alopez : 8/8/2003<br>terry : 8/7/2003<br>carol : 12/6/2002<br>tkritzer : 12/6/2002<br>ckniffin : 11/27/2002<br>cwells : 11/26/2002<br>ckniffin : 11/13/2002<br>alopez : 9/25/2002<br>tkritzer : 9/23/2002<br>mgross : 9/6/2002<br>terry : 4/3/2002<br>alopez : 3/13/2002<br>alopez : 3/13/2002<br>mcapotos : 6/25/2001<br>mcapotos : 6/19/2001<br>terry : 6/19/2001<br>carol : 2/14/2000<br>yemi : 2/11/2000<br>terry : 2/10/2000<br>alopez : 2/7/2000<br>alopez : 2/7/2000<br>alopez : 1/10/2000<br>mcapotos : 1/5/2000<br>terry : 1/4/2000<br>mcapotos : 12/17/1999<br>mcapotos : 12/15/1999<br>mcapotos : 12/14/1999<br>terry : 12/13/1999<br>mgross : 11/4/1999<br>carol : 2/15/1999<br>terry : 2/2/1999<br>alopez : 10/29/1998<br>carol : 10/12/1998<br>terry : 10/7/1998<br>carol : 5/11/1998<br>terry : 4/7/1998<br>alopez : 7/23/1997<br>terry : 1/28/1997<br>mark : 1/27/1997<br>carol : 5/23/1996<br>mark : 5/13/1996<br>mark : 5/11/1995<br>carol : 2/1/1995<br>mimadm : 12/2/1994<br>terry : 10/18/1994<br>warfield : 3/31/1994<br>carol : 12/20/1993
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<span class="mim-font">
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<strong>#</strong> 158900
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FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY 1; FSHD1
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<em>Alternative titles; symbols</em>
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MUSCULAR DYSTROPHY, FACIOSCAPULOHUMERAL, TYPE 1<br />
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FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY; FSHD; FMD<br />
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MUSCULAR DYSTROPHY, FACIOSCAPULOHUMERAL, TYPE 1A; FSHD1A<br />
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LANDOUZY-DEJERINE MUSCULAR DYSTROPHY
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Other entities represented in this entry:
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FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY, INFANTILE, INCLUDED
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FACIOSCAPULOHUMERAL DYSTROPHY WITH SENSORINEURAL HEARING LOSS AND TORTUOSITY OF RETINAL ARTERIOLES, INCLUDED
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<strong>SNOMEDCT:</strong> 399091004;
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<strong>ICD10CM:</strong> G71.02;
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<strong>ORPHA:</strong> 269;
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<strong>DO:</strong> 0111192;
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Cytogenetic location: 4q35
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Genomic coordinates <span class="small">(GRCh38)</span> : 4:182,300,001-190,214,555 </span>
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<strong>Gene-Phenotype 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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4q35
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Facioscapulohumeral muscular dystrophy 1
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158900
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Autosomal dominant
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4
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because facioscapulohumeral muscular dystrophy-1 (FSHD1) is associated with contraction of the D4Z4 macrosatellite repeat (see 606009) in the subtelomeric region of chromosome 4q35.</p><p>In unaffected individuals, the D4Z4 array consists of 11 to 150 repeat units (corresponding to EcoRI fragments of 41 to 350 kb), whereas FSHD patients have contraction of the repeat units from 1 to 10 (corresponding to EcoRI fragments of 10 to 35 kb). Borderline fragment sizes (35 to 40 kb) must be interpreted with caution (summary by Mostacciuolo et al., 2009). </p>
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<strong>Description</strong>
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<p>Facioscapulohumeral muscular dystrophy (FSHD) is a progressive skeletal muscle disorder with a highly variable phenotype. Most patients present as adults, although about 10% show symptoms before the age of 5 years, including from infancy in some cases. In general, the disease initially involves the upper body, including the face and the scapulae, followed by weakness at the foot dorsiflexors and hip girdles. Typical features are striking asymmetry of muscle involvement from side to side and sparing of bulbar extraocular and respiratory muscles. There is significant clinical variability, even within families, as well as incomplete penetrance. FSHD1 accounts for about 95% of patients. Facioscapulohumeral muscular dystrophy is the third most common hereditary disease of muscle after Duchenne (DMD; 310200) and myotonic (160900) dystrophy (Tawil et al., 1998; van den Boogaard et al., 2016; Johnson and Ankala, 2020; Schatzl et al., 2021). </p><p>Richards et al. (2012) and Schatzl et al. (2021) provided detailed reviews of FSHD, including clinical features, genetics, diagnosis, pathogenesis, and potential therapeutic avenues. </p><p><strong><em>Genetic Heterogeneity of FSHD</em></strong></p><p>
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Several other genetic forms of FSHD that are clinically indistinguishable from FSHD1, but not associated with physical contraction of the D4Z4 microsatellite repeat, have been identified. Historically, these forms have collectively been called 'FSHD2.' Tissue from patients with 'FSHD2' shows D4Z4 hypomethylation on chromosomes 4 and 10, suggesting the presence of unique transactivating factors, some of which have been identified. Genetic forms of FSHD other than FSHD1 account for about 5% of patients overall (summary by Hamanaka et al., 2020; Johnson and Ankala, 2020; review by Schatzl et al., 2021). </p><p>FSHD2 (158901) is caused by mutation in the SMCHD1 gene (614982) on chromosome 18p11; FSHD3 (619477) by mutation in the LRIF1 gene (615354) on chromosome 1p13; and FSHD4 (619478) by mutation in the DMNT3B gene (602900) on chromosome 20q11. Patients with FSHD2, FSHD3, and FSHD4 also carry a 'permissive haplotype' on chromosome 4 (4qA) that promotes DUX4 (606009) expression. There is significant clinical variability and incomplete penetrance.</p>
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<strong>Clinical Features</strong>
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<p>Justin-Besancon et al. (1964) added 3 affected generations to the 4 described by Landouzy and Dejerine (1885) and gave autopsy findings in 1 of the original patients who died at age 86 years. Some cases show congenital absence of part or all of certain muscles such as a pectoral muscle. The relationship of the congenital defect of muscle to the dystrophy is unclear. Tyler and Stephens (1950) and Tyler (1954) reported 17 families. In 1 kindred 150 members were affected over 6 generations. A girl, whose face alone was affected at age 9 when examined by Landouzy and Dejerine (1885), did not develop weakness of the arms until age 60 and of the legs until age 70, and survived to age 85 years. In her family, affected members were distributed through 8 generations. </p><p>Meyerson et al. (1984) reported sensorineural hearing loss in 2 sibs with FSH muscular dystrophy which affected other members of the family in typical manner. The studies of Brouwer et al. (1991) suggest that a 'change of hearing function is part of the disease and may lead to severe hearing loss in some patients.' Deafness and abnormalities of retinal vessels (see later) are probably integral parts of the disorder. </p><p>Sayli et al. (1984) found at least 53 affected persons in a Turkish kindred originating in the village of Cullar. Initial signs and symptoms seemed to appear early in infancy in many. The disorder progressed slowly without interfering significantly with survival and reproduction. Symptoms first involved the face, upper arms, and shoulder muscles. Creatine kinase levels were 1.5 to 2 times normal. Many of the affected persons were identified on examination; only 13 reported complaints and their mean age was 40.1 years. After the kindred reported by Tyler and Stephens (1950), this is the most extensively affected family studied to date. Awerbuch et al. (1990) found that the Beevor sign was present in 27 of 30 patients with FSHD but absent in all 40 patients with other neuromuscular disorders. They concluded that it is a common finding in FSHD patients even before functional weakness of abdominal wall muscles is apparent. Because of weakness of the lower rectus abdominis muscles, the umbilicus moves upward when the subject in the supine position raises his or her head, producing the Beevor sign. (This sign was originally proposed by English neurologist Charles E. Beevor as an indication of the level of involvement in spinal cord lesions.) Bodensteiner and Schochet (1986) suggested the supraspinatus muscle as the site of choice for biopsy in this disorder. Reardon et al. (1991) pointed out the difficulties in some cases in distinguishing FSHD from the Becker type of muscular dystrophy (300376). Calf hypertrophy, although rare, has been reported in FSHD. Jardine et al. (1993) reexamined the 3 affected members in the family reported by Reardon et al. (1991) and demonstrated that they had a rearrangement in the region of the FSHD gene as indicated by studies with probe p13E-11. </p><p>Shen and Madsen (1991) described symptomatic atrial tachycardia, for which an antitachycardic pacing device was implanted, in a 44-year-old woman. Her severe scapular and shoulder weakness led to recurrent dislodgment of the atrial pacemaker lead. </p><p>According to Bailey et al. (1986), infantile facioscapulohumeral muscular dystrophy was recognized by Duchenne (1862) and differentiated from pseudohypertrophic muscular dystrophy over 20 years before the description of the usual form of facioscapulohumeral muscular dystrophy by Landouzy and Dejerine (1885). Whereas FSHD is generally a benign, slowly progressive myopathy that begins in late childhood or adolescence and leads to disability only late in its course, occasional families contain individuals with a severe infantile form of the disorder who have 1 asymptomatic or minimally affected parent. Bailey et al. (1986) reported a family in which the severe infantile presentation predominated. They suggested 'that the gene coding for this disorder may be different from that responsible for conventional facioscapulohumeral muscular dystrophy.' The genes for the 2 forms of the disease may, of course, be allelic. </p><p>In 56 of 75 persons with clinical or genetic evidence of FSH muscular dystrophy, Fitzsimons et al. (1987) found peripheral retinal capillary abnormalities including telangiectasia, closure, leakage, and microaneurysm formation. They were prompted to do this study by the occasional reports of exudative retinal detachment and deafness with this disorder. The study included 1 FSH family in which the proband was treated for exudative retinopathy and 13 other members had retinal telangiectasia. There were 8 cases, including 3 parents of apparently 'sporadic' FSH cases, in which fluorescein angiography 'confirmed the abnormal genotype, even though clinical examination of skeletal muscle revealed no clear abnormality.' Fitzsimons et al. (1987) concluded that retinal capillary abnormalities are an integral part of FSH muscular dystrophy and raised the question as to whether analogous capillary abnormalities may be implicated in the pathogenesis of the muscle disease. Padberg et al. (1992) came to similar conclusions on the basis of studies using fluorescein retinal angiography in 32 patients from 19 families. In 16 of the 32, representing 11 families, retinal capillary changes were found consisting of telangiectasia, microaneurysms, vessel occlusions, and small exudates and hemorrhages in the macular as well as in the peripheral retina. In addition, tone audiometry was performed, with the finding that 20 sibs from 14 families had some degree of high-tone deafness. Similar findings were observed in 8 sporadic cases: 4 had retinal vasculopathy and 5 had high-tone deafness. Combined with linkage data, these observations demonstrated that retinal vasculopathy and high-tone sensorineural deafness are part of the clinical picture of FSHD and are no grounds for assuming genetic heterogeneity. </p><p>Small (1968) described 4 sibs with facioscapulohumeral dystrophy and bilateral retinal exudative telangiectasia, labeled Coats disease (see 300216). Neurosensory deafness and mental retardation were present in all 4. Taylor et al. (1982) and Voit et al. (1986) described the same association. Yasukohchi et al. (1988) described a brother and sister with facioscapulohumeral dystrophy. The brother, aged 13 years, also had sensorineural hearing loss, marked tortuosity of retinal arterioles, early onset and progression of severe restrictive pulmonary dysfunction, and cor pulmonale. The 8-year-old sister had only muscle manifestations. Bilateral sensorineural hearing loss in the high frequency range was described in the above patients. In some, the hearing loss was clearly progressive and with time tended to involve lower frequencies (Voit et al., 1986). As noted from the cases cited, autosomal dominant inheritance was not always clear; recessive inheritance was possible and might point to this being an entity separate from FSHD. Brouwer et al. (1991) performed screening audiometry in 56 patients with autosomal dominant FSHD and in 72 healthy family members, and found that the difference in hearing levels between 4,000 Hz and 6,000 Hz was significantly greater in FSHD patients than in their unaffected relatives. This led them to conclude that a change in hearing function is part of the disease and may lead to severe hearing loss in some patients. Gieron et al. (1985) described a mother and 3 children with FSHD, sensorineural hearing loss, and marked tortuosity of retinal vessels. The deafness, which varied from mild to moderate, was bilateral and early in onset. Audiologic studies indicated the cochlea as the site of the abnormality. Matsuzaka et al. (1986) reported a sporadic case of this constellation of manifestations plus mental retardation and suggested that these cases constitute a nosologically specific form of FSHD. </p><p>Shields et al. (2007) noted that retinal telangiectasia compatible with Coats disease (300216) can be an extramuscular manifestation of FSHD but that most affected patients have asymptomatic retinal telangiectasia found at ocular screening after diagnosis of FSHD. They described a young child who had advanced eye findings of unilateral neovascular glaucoma from bilateral retinal telangiectasia 3 years before FSHD became apparent. </p><p>Miura et al. (1998) reported 2 sporadic cases of early-onset scapulohumeral muscular dystrophy with mental retardation and epilepsy in unrelated, severely affected females. In both cases, Southern blot analysis of the EcoRI-digested genomic DNA, using 2 probes, detected 10-kb EcoRI fragments, the shortest reported to that time. Patient 1 showed infantile spasms at the age of 4 months and localization-related epilepsy at the age of 2.5 years. Muscular atrophy in the face, shoulder girdle, and upper arms was observed from the age of 4 years. In patient 2, lack of facial expression was noticed since the age of 1 year, and at 4 years she was noted to have loss of upward gaze bilaterally. She developed localization-related epilepsy at the age of 9 years. From the age of 10 years, weakness of the lower limbs progressed and she became wheelchair-bound at the age of 14 years. She had moderate sensorineural hearing loss, a loss of upward gaze bilaterally, and tongue atrophy. Their IQs were 33 and 45, respectively. Miura et al. (1998) suggested that mental retardation and epilepsy may be part of the clinical spectrum of FSHD, especially in very early-onset patients with large deletions. </p><p>Among 151 Japanese patients with FSHD, Yamanaka et al. (2001) reported 7 patients with tongue atrophy with abnormal tongue MRI findings (disorganized architecture) and typical myogenic patterns of electromyography. All patients were classified as having early-onset FSHD with large gene deletions within the 4q35 gene region. </p><p>Krasnianski et al. (2003) described atypical features in 6 of 41 patients with FSHD and the 4q35 deletion. Three patients from 1 family showed the typical phenotype with the additional feature of chronic progressive external ophthalmoplegia. Three patients, 2 from 1 family, showed sparing of the facial muscles, and 2 of these patients had severe, diffuse myalgia. There was no correlation between the atypical features and the DNA fragment size due to the deletion. </p><p>Wohlgemuth et al. (2006) found that 10 of 87 individuals with FSHD had signs of weakness in the jaw, lips, or tongue. Oropharyngeal evaluation in 8 of these patients detected mild to moderate swallowing abnormalities in 7 patients and tongue atrophy in 6. </p><p>See 182970 for a form of spinal muscular atrophy simulating FSH muscular dystrophy.</p><p><strong><em>Pathologic Features</em></strong></p><p>
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In a 20-year-old woman who had inherited FSHD from her father and who also had an affected brother, Slipetz et al. (1991) found that muscle biopsy showed fiber atrophy with patchy staining for oxidative enzymes; that electron microscopy of liver showed many enlarged mitochondria with paracrystalline inclusions; and that skin fibroblasts showed decreased oxidation of the respiratory substrates alanine and succinate, suggesting deficiency of complex III of the electron-transport chain. Cytochrome c oxidase activity (complex IV) was normal. Biochemical analysis of liver supported the fibroblast data, since succinate oxidase activity (electron-transport activity through complexes II-IV) was reduced and complex IV activity was normal. Cytochrome b, a component of complex III, was undetectable in liver, although typical peaks were found for other cytochromes. Southern blot analysis of fibroblast mtDNA showed no major deletions or rearrangements. </p><p>Using confocal microscopy, Reed et al. (2006) found that some of the structures at the sarcolemma in FSHD skeletal muscle biopsies were misaligned with respect to the underlying contractile apparatus. Electron microscopy showed a significant increase in the distance between the sarcolemma and the nearest myofibrils, from less than 100 nm in controls to 550 nm in FSHD. Reed et al. (2006) concluded that the pathophysiology of FSHD includes novel changes in the organization of the sarcolemma and the subsarcolemmal membrane cytoskeleton. </p>
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<strong>Mapping</strong>
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<p>Padberg et al. (1984) found possible linkage to Gm (147100) (maximum lod score = 1.428 at theta = 0.2). Padberg et al. (1988) followed up on this observation by testing linkage with D14S1 (107750). They excluded linkage, thus suggesting that the FSH muscular dystrophy locus is not situated on the distal part of the long arm of chromosome 14. Sarfarazi et al. (1989) presented exclusion data, resulting from an international collaboration, showing that more than 85% of the human genome has been excluded as a likely location for the FSHD gene. Chromosomes 3, 5, 10, 11, 15, and 19 remained largely unexcluded. Lucotte et al. (1989) excluded 3 chromosomal regions, including proximal 19q. Lunt et al. (1989) presented linkage data for 22 different DNA markers in 24 families with FSHD. They achieved a maximum lod score of 1.87 at a theta of 0.15 with anonymous marker D18S3, which has been localized to 18p11.3. In a clinically homogeneous group of families, Jacobsen et al. (1990) excluded chromosomes 1, 2, 5, 7, 10, and 16 as the site of the FMD mutation. They estimated that 23% of the human genome was excluded. </p><p>In a study of 10 Dutch families, Wijmenga et al. (1990) found linkage of FSH muscular dystrophy to a microsatellite marker Mfd22 (D4S171) on chromosome 4; maximum lod score = 6.34 at theta = 0.13. Only 1 family was uninformative for this marker. No evidence of heterogeneity was found. From the map location of the marker, it appeared that the FSHD gene was located near the distal end of 4q. Siddique et al. (1989) studied 2 multigeneration families with the neurogenic form of facioscapulohumeral disease considered to be a form of spinal muscular atrophy. Possible linkage to MNS on 4q was found. </p><p>In a linkage study of FSHD families, Upadhyaya et al. (1991) found 3 recombinants in a total of 140 meioses for linkage with a hypervariable DNA probe on 4q (pH30, locus D4S139), giving a maximum lod score of 36.77 at a recombination fraction of 0.02. Wijmenga et al. (1991) found a VNTR locus, D4S139, to be much more closely linked to FSHD than to D4S171. This marker was mapped to 4q35-qter by in situ hybridization. One small family yielded a negative lod score for D4S139, but otherwise there was no evidence of genetic heterogeneity. In 9 informative families, they found a maximum lod score of 17.28 at theta = 0.027. </p><p>Mathews et al. (1991) defined the location of FSHD as 4q35. They used a probe derived from the breakpoint of an X;4 translocation with a breakpoint at 4q35. The patient had facial weakness at age 4 years. A peak lod score of 8.23 at theta = 0.00 was found with a 4q35 probe, D4S139. Reporting for a consortium, Sarfarazi et al. (1992) defined the relationship of the FSHD locus to markers in the 4q35 region in 65 families containing a total of 504 affected persons. No evidence of heterogeneity was found in the initial study; however, after completion of the analysis, 1 large family that might show heterogeneity was identified. In view of this and the fact that all of the linked markers were on the centromeric side of the FSHD locus, Sarfarazi et al. (1992) recommended that these markers not yet be used in clinical applications. Upadhyaya et al. (1992) found that FSHD was situated telomeric to all 4 DNA markers that they used in a series of 23 families. However, Wijmenga et al. (1992) found at least one recombination event which suggested that 1 of the 4 markers, D4S139, might lie distal to FSHD. In a study of 4 families with FSHD, Mathews et al. (1992) found close linkage to three 4q35 probes, D4S163, D4S139, and D4S171. Two of their families included males with a rapidly progressive muscle disease that had been diagnosed, on the basis of clinical features, as Duchenne muscular dystrophy. One of these males was available for linkage study and shared the haplotype of his FSHD-affected cousin and aunt. </p><p>Mills et al. (1992) generated a fine-structured genetic map of the distal long arm of chromosome 4 by a combination of classical RFLPs and PCR-based polymorphisms including CA repeats and single-strand conformation polymorphisms (SSCP). Gilbert et al. (1992) and Weiffenbach et al. (1992) demonstrated that both D4S139 and D4S163 are closely linked to FSHD, with D4S139 being the closest proximal marker to FSHD. No telomeric marker to FSHD had been demonstrated. </p><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. See 158901. </p>
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<strong>Molecular Genetics</strong>
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<p>All patients with a confirmed diagnosis of FSHD and for whom detailed molecular studies have been performed carry a chromosomal rearrangement within the subtelomeric region of 4q (4q35). This subtelomeric region is composed mainly of a polymorphic repeat structure consisting of 3.3-kb repeated elements, designated D4Z4 (see 606009). The number of repeat units varies from 10 to more than 100 in the population, and, in FSHD patients, an allele of 1 to 10 residual units is observed because of the deletion of an integral number of these units (Wijmenga et al., 1992; Hewitt et al., 1994). </p><p>Sacconi et al. (2019) examined the molecular genetics and epigenetic modifiers of 103 patients with FSHD, including 64 with FSHD1 and 20 with FSHD2. There was variation in the size of the D4Z4 repeat and in hypomethylation status. An inverse correlation between the size of the repeat and FSHD1 disease severity was observed: patients with 8-10 units had a milder disease compared to those with 4-7 repeats. There was also variability in the presence of the permissive 4q allele in patients with FSHD2. Sacconi et al. (2019) concluded that various genetic types of FSHD form a clinical and genetic disease continuum. They suggested that repeat size thresholds used in diagnosis may need to be reconsidered. </p><p><strong><em>D4Z4 Macrosatellite Repeat</em></strong></p><p>
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For a full discussion of the D4Z4 macrosatellite repeat, see 606009.</p><p>Lemmers et al. (2004) summarized the relationship of the D4Z4 repeat to FSHD. The polymorphic D4Z4 repeat is highly recombinogenic, since somatic mosaicism for rearrangement of D4Z4 is found in as much as 3% of the general population (van Overveld et al., 2000). The D4Z4 repeat consists of identical units defined by the restriction enzyme KpnI, each 3.3 kb, ordered in a head-to-tail fashion, and varying between 11 and 100 units on 'healthy' chromosomes (van Deutekom et al., 1993). Patients with FSHD carry a repeat of 1 to 10 units on one of their chromosomes 4 (Wijmenga et al., 1992). A rough and inverse correlation has been observed between the severity and age at onset of the disease and the residual repeat unit number. </p><p>In a review of genetic disorders associated with aberrant chromatin structure, Bickmore and van der Maarel (2003) noted that FSHD represents a potential example of gene activation through loss of repression complexes. </p><p>A review of the D4Z4 repeat-mediated pathogenesis of FSHD was provided by van der Maarel and Frants (2005). They pointed out that in contrast to most monogenic disorders, in which the genetic lesion typically affects the structure or function of a specific disease gene, evidence suggested that FSHD is caused by a complex epigenetic mechanism involving the contraction of a subtelomeric macrosatellite repeat. It is likely not the structure but rather the (spatiotemporal-restricted) transcriptional control of one or more disease genes that is perturbed in FSHD as a result of repeat-contraction-mediated chromatin alterations. Their review focused on the cause and consequence of the repeat-array contraction. Van der Maarel and Frants (2005) designated FSHD a macrosatellite repeat-contraction disease. </p><p>Van Overveld et al. (2003) showed that contraction of the D4Z4 repeat array causes marked hypomethylation of the contracted D4Z4 allele in individuals with FSHD1. Individuals with FSHD clinically identical to other cases but with an unaltered D4Z4 (FSHD2; 158901) 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>DUX4 Expression</em></strong></p><p>
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Dmitriev et al. (2008) noted that the DUX4 gene (606009) found within the D4Z4 repeat was initially considered to be nonfunctional because it lacked introns and polyadenylation signals. Furthermore, expression of DUX4 could not be detected despite the efforts of several groups using various methods including screening of cDNA libraries, RT-PCR, microarray, and Pol II ChIP. Subsequently, work by Dixit et al. (2007) and Clapp et al. (2007) confirmed expression of DUX4 in human and mouse, respectively, and showed conservation of the DUX4 ORF for more than 100 million years. </p><p>Bosnakovski et al. (2008) conditionally expressed cDNAs for FSHD candidate genes within the D4Z4 repeat, DUX4, FRG1 (601278), FRG2 (609032), and ANT1 (SLC25A4; 103220), in mouse C2C12 myoblasts at both high and low expression levels and found that only DUX4 was overtly toxic, as indicated by cellular ATP content, morphologic changes, and apoptosis. DUX4 showed variable toxicity when expressed in mouse fibroblasts or embryoid bodies. DUX4 localized to C2C12 cell nuclei within 2 hours of induction. Microarray analysis revealed altered expression in a broad range of genes, with greatest changes in those involved in growth and development and signal transduction. Expression of Myod was also downregulated at an early time point. Oxidative stress and heat shock genes were downregulated at later time points, suggesting that they may be secondary targets. The DUX4 homeodomains are most similar to those of PAX3 (606597) and PAX7 (167410), and overexpression of these genes rescued viability and proliferation in DUX4-expressing C2C12 cells. Bosnakovski et al. (2008) concluded that DUX4 may cause FSHD by interfering with normal PAX3 or PAX7 function in muscle satellite cells. </p><p>Lemmers et al. (2010) showed that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonic polyadenylation signal for transcripts derived from DUX4, a double homeobox gene that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. This particular chromosomal setting containing the pathogenic sequences was named 4APAS (4A polyadenylation signal; Scionti et al., 2012). Lemmers et al. (2010) concluded that their findings suggested that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript. </p><p>By RT-PCR, Snider et al. (2010) found that full-length DUX4 (DUX4-fl) was aberrantly expressed in 5 of 10 FSHD muscle biopsy specimens, but not in normal muscle specimens. PCR analysis of myoblast cultures of varying pool size, and immunohistochemical analysis of cultured myoblasts revealed that only about 0.1% of FSHD muscle nuclei expressed a relatively abundant amount of DUX4-fl mRNA and protein. DUX4-fl was also aberrantly expressed in differentiated FSHD embryoid bodies. A short variant of DUX4 (DUX4-s) was expressed in both FSHD and control tissues and cells. Aberrant DUX4-fl was often associated with apoptotic changes, and in all cases was associated with the FSHD permissive 4qA haplotype (see below). Snider et al. (2010) concluded that repressive chromatin associated with D4Z4 in differentiated cells may facilitate usage of the noncanonical splice donor site to generate DUX4-s, and the more permissive chromatin in FSHD may favor polymerase progression through to the consensus splice donor and generate DUX4-fl. </p><p>Wallace et al. (2011) showed that apoptotic changes observed in DUX4-expressing HEK293 cells were eliminated by inactivating mutation of the first DNA-binding homeobox domain of DUX4. The development of lesions in DUX4-injected mouse muscle was also abrogated by mutation of the DUX4 homeobox domain. Pharmacologic inhibition of p53 (TP53; 191170) mitigated DUX4 toxicity in HEK293 cells, and muscle from p53-null mice were resistant to DUX4-induced damage. Wallace et al. (2011) concluded that DUX4-induced myopathy is dependent on p53-induced apoptosis. </p><p><strong><em>4qA and 4qB Polymorphic Segment</em></strong></p><p>
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Human 4qter and 10qter share a high degree of similarity, including the D4Z4 repeat array; however, contractions affecting the 10qter repeat are nonpathogenic. Van Geel et al. (2002) detected a polymorphic segment of 10 kb directly distal to D4Z4, which they called alleles 4qA and 4qB. Lemmers et al. (2002) reported that although the 2 alleles are equally common in the general population, FSHD is associated solely with the 4qA allele. They suggested that this was the first example of an intrinsically benign subtelomeric polymorphism predisposing to the development of human disease. </p><p>Lemmers et al. (2004) concluded that contractions of D4Z4 on 4qB subtelomeres do not cause FSHD. The 2 allelic variants of 4q, 4qA and 4qB, exist in the region distal to D4Z4. Although both variants are almost equally present in the population, FSHD is associated exclusively with the 4qA allele. Lemmers et al. (2004) identified 3 families with FSHD in which each proband carried 2 FSHD-sized alleles and was heterozygous for the 4qA/4qB polymorphism. Segregation analysis demonstrated that FSHD-sized 4qB alleles are not associated with disease, since these were present in unaffected family members. Thus, in addition to a contraction of D4Z4, additional cis-acting elements on 4qA may be required for the development of FSHD. Alternatively, 4qB subtelomeres may contain elements that prevent FSHD pathogenesis. </p><p>Lemmers et al. (2007) hypothesized that allele-specific sequence differences among 4qA, 4qB, and 10q alleles underlie the 4qA specificity of FSHD. By examining sequence variations in the FSHD locus, they demonstrated that the subtelomeric domain of chromosome 4q can be subdivided into 9 distinct haplotypes, of which 3 carry the distal 4qA variation. They showed that repeat contractions in 2 of the 9 haplotypes, 1 of which is a 4qA haplotype, are not associated with FSHD. Lemmers et al. (2007) showed that each of these haplotypes has its unique sequence signature, and proposed that specific SNPs in the disease haplotype are essential for the development of FSHD. </p><p>Thomas et al. (2007) measured the frequency of 4qA-defined and 4qB-defined subtelomeric sequences in 164 unrelated patients with FSHD from the UK and Turkey, all known to have large D4Z4 deletions. An almost complete association (162 of 164 patients) was found between large D4Z4 repeat array deletions located on 4qA-defined 4qter subtelomeres and disease expression. DNA samples from 50 controls displayed equivalent frequencies for 4qA and 4qB markers, as did the normal chromosome 4 in all 65 patients studied. The 4qA and 4qB probes failed to hybridize in 2 patients, confirming the presence of an additional rare type of 4qter subtelomeric sequence in humans. </p><p>Wang et al. (2011) provided evidence that the 4qB-associated D4Z4 contraction is not pathogenic in Chinese individuals. Molecular reexamination of 3 unrelated Chinese patients originally diagnosed with FSHD on the basis of a D4Z4 contraction showed that all were nonpathogenic 4qB variants. All 3 patients were found to have different disorders with similar phenotypes, including LGMD2A (253600), LGMD2E (604286), and DM1 (160900), respectively. A fourth Chinese patient originally diagnosed with FSHD was found to have a pathogenic 18-kb D4Z4 4qA contraction that she inherited from her symptomatic mother. Her 2 daughters carried a paternally inherited 24-kb nonpathogenic contraction that was found to be a mixture of 4q and 10q. The daughters were thus considered unaffected, whereas previously they had been misdiagnosed as asymptomatic cases. Wang et al. (2011) concluded that the D4Z4 repeat length analysis alone is insufficient for the diagnosis of FSHD, and should be accompanied by 4qA/4qB variant determination. </p><p><strong><em>Expression of Other Genes within the FSHD Candidate Region</em></strong></p><p>
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Van Deutekom et al. (1996) identified a novel gene, which they referred to as FRG1 (601278), that mapped 100 kb centromeric of the repeated units on chromosome 4q35 that are deleted in FSHD. They identified a polymorphism in exon 1 of this gene and used RT-PCR to amplify reverse transcribed mRNA from lymphocytes and muscle biopsies of patients and controls. These studies indicated that both alleles were transcribed and gave no evidence of 'position effect' variegation leading to repression of allelic transcription. </p><p>Gabellini et al. (2002) found that in FSHD muscle, genes located upstream of D4Z4 on 4q35, including FRG1, FRG2 (609032), and ANT1 (103220), are inappropriately overexpressed. They showed that an element within D4Z4 specifically binds a multiprotein complex consisting of transcriptional repressor YY1 (600013), HMGB2 (163906), and nucleolin (NCL; 164035). This multiprotein complex binds D4Z4 in vitro and in vivo and mediates transcriptional repression of 4q35 genes. Gabellini et al. (2002) proposed that deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes, resulting in disease. In normal individuals, the presence of a threshold number of D4Z4 repeats leads to repression of 4q35 genes by virtue of the DNA-bound multiprotein complex that actively suppresses gene expression. In FSHD patients, deletion of an integral number of D4Z4 repeats reduces the number of bound repressor complexes and consequently decreases or abolishes transcriptional repression of 4q35 genes. </p><p>By oligonucleotide microarrays, Winokur et al. (2003) compared FSHD expression profiles with those from normal muscle and DMD and LGMD2D (608099). Several genes whose expression was altered in an FSHD-specific and highly significant manner are involved in myogenic differentiation, suggesting a partial block in the normal differentiation program. Many of the transcripts affected in FSHD were direct targets of the transcription factor MYOD1 (159970). Additional misexpressed genes confirmed a diminished capacity to buffer oxidative stress, as demonstrated in FSHD myoblasts. This enhanced vulnerability of proliferative stage myoblasts to reactive oxygen species was also disease-specific, further implicating a defect in FSHD muscle satellite cells. None of the genes localizing to the FSHD region at 4q35 were found to exhibit a significantly altered pattern of expression in FSHD muscle. Winokur et al. (2003) hypothesized that disruptions in FSHD myogenesis and oxidative capacity may not arise from a position effect mechanism, as has been previously suggested, but rather from a global effect on gene regulation. </p><p>Jiang et al. (2003) found that H4 acetylation levels of a nonrepeated region adjacent to the 4q35 and 10q26 D4Z4 arrays in normal and FSHD lymphoid cells were like those in unexpressed euchromatin, rather than like constitutive heterochromatin. The control and FSHD cells also displayed similar H4 hyperacetylation (like that of expressed genes) at the 5-prime regions of 4q35 candidate genes FRG1 (601278) and ANT1. There was no position-dependent increase in transcript levels from these genes in FSHD skeletal muscle samples compared with controls. Jiang et al. (2003) proposed a model for FSHD in which differential long-distance cis looping depends upon the presence of a 4q35 D4Z4 array with less than a threshold number of copies of the 3.3-kb repeat. </p><p>Perini and Tupler (2006) suggested that FSHD might be considered a useful model for the study of position effect in humans. D4Z4 deletion might result in stochastic variation in gene expression in muscle cells and explain the asymmetric involvement of muscles, the great variability of clinical expression between and within families, and the apparent threshold effect whereby there is a requirement for the deletion of a certain number of copies of D4Z4 to develop FSHD. </p><p>Osborne et al. (2007) detected no change in expression of the FRG1, FRG2, or ANT1 genes in muscle biopsies from 19 FSHD patients compared to controls. Further studies of the 8-Mb region proximal to the D4Z4 array showed no significant changes in gene expression, no evidence of a position effect, and no evidence of unequal allele-specific expression. However, microarray analysis of global gene expression in FSHD muscle identified 11 upregulated genes with a role in vascular smooth muscle or endothelial cells, suggesting a possible link between muscular dystrophy and vasculopathy in FSHD. </p><p>Davidovic et al. (2008) found that myoblasts isolated from patients with FSHD showed an abnormal pattern of expression of isoforms of the FXR1P (600819) gene compared to controls. FXR1P encodes an RNA-binding protein involved in the metabolism of muscle-specific-mRNAs during myogenesis. The altered pattern of FXR1P expression was due to a specific reduced stability of muscle-specific FXR1 mRNA variants. The findings suggested that the molecular basis of FSHD not only involves splicing alterations, but may also involve a deregulation of mRNA stability. </p><p>Using RNA-DNA FISH, Masny et al. (2010) found no change in gene transcription of 16 genes in cis in the 4q35 region in nuclei of differentiated myotubes derived from patients with FSHD compared to differentiated myotubes from controls. In particular, there was no change in expression in the FRG1, FRG2, or ANT1 genes, which had previously been implicated. </p><p>Dmitriev et al. (2011) showed that KLF15 (606465) bound an enhancer element within the D4Z4 repeat unit. Binding of KLF15 to 2 sites within the D4Z4 enhancer drove expression of FRG2 and DUX4C (DUX4L9; 615581), which are located over 40 kb centromeric to the D4Z4 repeat array. KLF15 expression was upregulated following differentiation of normal human myoblasts and following expression of MYOD, and it was upregulated in FSHD myoblasts, myotubes, and muscle biopsies. FSHD cells also showed upregulated expression of MYOD and the KLF15 target gene PPARG (601487), in addition to DUX4C and FRG2. Dmitriev et al. (2011) concluded that MYOD-dependent KLF15 expression is involved in partial activation of the differentiation program in FSHD myoblasts. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible association between FSHD and variation in the FAT1 gene, see 600976.</p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>As indicated earlier, FSHD is associated with a short (less than 35 kb) EcoRI/BlnI fragment resulting from deletion of an integral number of units of a 3.3-kb repeat located at 4q35. Vitelli et al. (1999) determined fragment sizes separated by pulsed field gel electrophoresis in a patient with an apparently sporadic case of FSHD and in his healthy family members. A 38-kb fragment was detected in the proband, in his older brother, and in their father. This finding prompted a clinical reevaluation of the father and brother. A subclinical phenotype restricted to abdominal muscle weakness was detected, and serum creatine kinase values were found to be elevated in both. Thus, whereas in healthy individuals the size of the 4q35 polymorphic fragment varies from 48 to 300 kb, and most patients with FSHD show fragments less than 35 kb, fragment sizes between 35 and 48 kb must be interpreted with caution. An inverse correlation between fragment size and severity was described by Lunt et al. (1995) and Tawil et al. (1996). In familial cases, although the size of the inherited fragment remains constant, FSHD seems to become more severe with each generation (anticipation), according to the findings of Griggs et al. (1993), Lunt et al. (1995), Nakagawa et al. (1996), and Tawil et al. (1996). </p><p>Wohlgemuth et al. (2003) reported 2 unrelated families with FSHD in which the probands were compound heterozygous for 2 FSHD-sized alleles: a severely affected woman had chromosome 4-type arrays of 17 and 24 kb, and in the other family, a man had arrays of 33 and 36 kb. All of these alleles resided on 4qA. In the first family, 1 unaffected member had the 24-kb allele and 1 affected member had the 17-kb allele; in the second family, 3 unaffected children of the proband carried either the 33-kb allele or the 36-kb allele. Wohlgemuth et al. (2003) noted that the findings showed that having 2 disease alleles is not lethal, and proposed that the phenotype in both probands reflected a dosage effect. </p><p>In 21 FSHD1 patients who had 1 translocated chromosome 10-type array on chromosome 4, referred to as 'monosomic,' van Overveld et al. (2005) found D4Z4 hypomethylation compared to monosomic controls. Further analysis delineated 2 classes of clinical severity: patients with repeat sizes of 10 to 20 kb were severely affected and showed pronounced hypomethylation, whereas patients with repeat sizes of 20 to 31 kb showed variation in clinical severity and in hypomethylation. However, the authors could not establish a linear relationship between methylation and disease severity. </p><p>Sacconi et al. (2013) found that the SMCHD1 gene (614982), mutation in which causes FSHD2, 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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<p>Morton and Chung (1959) estimated the frequency to be about 2 per million living persons, with a frequency of about 4 persons destined to develop the trait in each million births. Fertility is little reduced and the mutation rate is not more than 5 per 10 million gametes. Lunt et al. (1989) estimated that the penetrance of the FSHD gene is less than 5% for ages 0 to 4 years, 21% for ages 5 to 9, 58% for ages 10 to 14, 86% for ages 15 to 19, and 95% for age 20 years and over. </p><p>Lunt and Harper (1991) studied the families of 41 probands. They found 6 isolated cases that might represent new mutation. Although penetrance reaches 95% by age 20, one-third of heterozygotes over age 40 are mildly affected; 19% over age 40 require wheelchairs. Most patients develop significant lower limb weakness--a fact that is not reflected in the term 'facioscapulohumeral.' Distribution of weakness, severity, age of onset, and serum creatine kinase levels varied among subjects, but provided no clinical evidence for genetic heterogeneity in a comparison of the 11 largest families. Genetic homogeneity, including subjects previously diagnosed with FSH-type spinal muscular atrophy, is strongly supported by the genetic linkage data. They estimated the minimum prevalence in Wales of 2 per 100,000. In this study only 2 of 113 affected persons from the 11 largest families showed no detectable facial weakness; one of these was an obligate carrier, aged 42 years, with complete nonpenetrance. Lunt and Harper (1991) concluded that there is a dominantly inherited scapulohumeral or scapuloperoneal syndrome genetically distinct from FSHD that does not have facial weakness as a feature. </p><p>Using the EcoRI polymorphism demonstrated by Wijmenga et al. (1992), Weiffenbach et al. (1993) found 12 recombinants in 5 families, giving a recombination fraction of 0.05 between this marker and the disease. Two families with apparent germline mosaicism were also identified. In these instances, 2 offspring were affected but both parents were clinically normal. </p><p>In a study of 34 Brazilian FSHD families, Zatz et al. (1995) concluded that at least one-third of cases may represent new mutations. Somatic mosaicism, furthermore, may not be rare. Biologic fitness was reduced to the 0.6 to 0.82 range, with no difference in sexes. The age at onset of clinical signs, as well as the age at ascertainment, in patients from multigenerational families suggested that anticipation occurs for FSHD. </p><p>Zatz et al. (1998) extended their study to 52 families, including 172 patients (104 males and 68 females). Among 273 individuals, 131 (67 males and 64 females) were shown to carry an EcoRI fragment smaller than 35 kb. Of these 131, 114 were examined. The excess of affected males was explained by a greater proportion of asymptomatic females and significantly greater number of affected sons than daughters of asymptomatic mothers. The penetrance by age 30 was 95% for males but only 69% for females. New mutations occurred more frequently in females than in males among somatic/germinal mosaic cases. Severely affected cases were more commonly the result of new mutations or mutations transmitted through maternal lines, including through mosaic mothers. Zatz et al. (1998) noted the implications of these results for prenatal and prognostic counseling depending on the gender of the affected patient. </p><p>Tupler et al. (1998) reported monozygotic male twins with FSHD carrying an identical de novo p13E-11 EcoRI fragment of paternal origin. This had arisen in paternal gametogenesis or postzygotically in the paternal chromosome 4 before twinning. A mutated fragment was subsequently transmitted to one of the affected male children. The twins showed great difference in clinical expression with one being almost asymptomatic and the other severely affected. Medical history was the same with the exception of an antirabies vaccination performed at the age of 5 in the more severely affected twin. Tupler et al. (1998) hypothesized that the vaccination might have triggered an inflammatory immune reaction contributory to the more severe phenotype. </p><p>Van der Maarel et al. (2000) surveyed 35 de novo FSHD families and found somatic mosaicism in 40% of cases, in either the patient or an asymptomatic parent. Mosaic males were typically affected; mosaic females were more often the unaffected parent of a nonmosaic de novo patient. A genotypic-severity score, composed of the residual repeat size and the degree of somatic mosaicism, yielded a consistent relationship with severity and age at onset of disease. Mosaic females had a higher proportion of somatic mosaicism than did mosaic males. The somatic mosaicism suggested a mainly mitotic origin. </p><p>Almost half of de novo FSHD cases originate from a mitotic change leading to somatic mosaicism for the FSHD allele. Lemmers et al. (2004) found that 9 of 37 (24%) patients with presumed de novo FSHD were somatic mosaic, with contraction of D4Z4 identified in 40 to 90% cells. In 7 cases (19%), 1 of the minimally affected or asymptomatic parents was a mosaic 'carrier,' with 10 to 50% affected cells. The authors concluded that although mosaic patients have a lower recurrence risk of having affected offspring than nonmosaic patients, the offspring of a mildly affected patient may have a more severe phenotype than expected based on the phenotype of the parent. Pulsed-field gel electrophoresis (PFGE) was more sensitive in detecting the D4Z4 contraction than linear gel electrophoresis. </p><p>Scionti et al. (2012) examined 11 nonconsanguineous Italian families in which 15 individuals were compound heterozygous for 2 D4Z4-reduced alleles. Most had the typical FSHD phenotype, although 1 man was asymptomatic at age 55 years. The phenotype was more severe in compound heterozygotes compared to carriers of 1 reduced allele, but the differences were not statistically significant. Analysis of relatives showed significantly reduced penetrance in those with a single reduced allele (25%) compared to those who were compound heterozygous for 2 reduced alleles (50%). In 4 families, the only FSHD-affected subject was the compound heterozygote for the D4Z4-reduced allele, and 52.6% of individuals with a single D4Z4-reduced 4A161PAS haplotype were nonpenetrant carriers. Analysis of surrounding polymorphisms did not support the predictive value of any specific 4q35 haplotype, and the population frequency of the 4A161PAS haplotype associated with a D4Z4-reduced allele was calculated to be as high as 1.2%. Overall, the findings challenged the notion that FSHD is a fully penetrant autosomal dominant disorder uniquely associated with the 4A161PAS haplotype, with repercussions for genetic counseling. </p>
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<h4>
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<span class="mim-font">
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<strong>Diagnosis</strong>
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</span>
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</h4>
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<p>Upadhyaya et al. (1990) reported markers useful in the presymptomatic and prenatal diagnosis of FSHD. Their findings confirmed the chromosome 4 location and suggested homogeneity. </p><p>Van der Maarel et al. (1999) described the limitations of molecular diagnostic techniques then available. They reported a Southern blot-based method, a BglII-BlnI dosage test that identified translocations between the repeat arrays on chromosomes 4 and 10 and deletion of p13E-11. The test also identified complex combinations of these events. Van der Maarel et al. (1999) suggested that this test would increase the sensitivity and specificity of FSHD diagnosis. They also noted that this study delimited the FSHD candidate region by mapping the 4;10 translocation breakpoint proximal to the polymorphic BlnI site in the first repeat unit. </p><p>Homologous polymorphic repeat arrays on chromosomes 4 and 10 have made definitive diagnosis of FSHD difficult. Lemmers et al. (2001) found that the restriction enzyme Xap1 complements Bln1, as the former uniquely digests repeat units derived from chromosome 4 and the latter uniquely digests those derived from chromosome 10. A triple analysis with EcoRI, EcoRI/Bln1, and Xap1 allowed unequivocal characterization of each of the alleles. Analysis of 2 patients with symptoms of possible FSHD showed 1 to be a carrier of a partial deletion of chromosome 4, and thus to have the disease, whereas the other patient had a normal-sized allele on chromosome 4 and thus did not have the disease. </p><p>Some FSHD patients have proximally extended D4Z4 deletions that include the D4F104S1 region. Such extended deletions can lead to problems of interpretation of the diagnostic test. Lemmers et al. (2003) described use of a telomeric probe, 4qA, that identifies large genomic deletions involving both D4Z4 and D4F104S1 using conventional gel electrophoresis. These extended deletions can be found in patients with a normal spectrum of the disease. Use of the assay should improve the accuracy and reliability of molecular diagnostic testing for FSHD. </p><p>Almost half of new FSHD-related mutations, i.e., contractions of the polymorphic D4Z4 repeat on 4qter, occur postfertilization, resulting in somatic mosaicism for D4Z4. On detailed D4Z4 analysis of 11 mosaic individuals with FSHD, Lemmers et al. (2004) found a mosaic mixture of a contracted FSHD-sized allele and the unchanged ancestral allele in 8 cases, which is suggestive of a mitotic gene conversion without crossover. However, in the other 3 cases, the D4Z4 rearrangement resulted in 2 different-sized D4Z4 repeats, indicative of a gene conversion with crossover. In all 11 cases, DNA markers proximal and distal to D4Z4 showed no allelic exchanges, suggesting that all rearrangements were intrachromosomal. Lemmers et al. (2004) proposed that D4Z4 rearrangements occur via a synthesis-dependent strand annealing model that relatively frequently allows for crossovers. Furthermore, the distribution of different cell populations in mosaic patients with FSHD suggested that mosaicism results from D4Z4 rearrangements occurring during the first few zygotic cell divisions after fertilization. </p><p>In an asymptomatic female FSHD carrier, Tonini et al. (2006) detected mosaicism for a pathogenic D4Z4 contraction in peripheral blood cells and muscle tissue: the normal allele and the pathogenic 12-kb allele were present in 75% and 25% of both types of cells, respectively. The 12-kb allele was identified in virtually 100% of peripheral blood cells from the carrier's affected daughter, confirming the diagnosis and inheritance. The finding of comparable mosaicism in peripheral blood cells and muscle from an asymptomatic mother suggested that a mitotic contraction of D4Z4 is an early embryonic event and indicated that the degree of mosaicism in peripheral blood cells is representative of that in muscle. </p><p>Deak et al. (2007) reported an FSHD family in which 11 affected members had a contracted D4Z4 allele and a large 78-kb proximal deletion. The family was initially designated as having non-chromosome-4 linked FSHD (158901) because commercial diagnostic testing of the proband failed to detect the deletion allele. The probe used, p13E-11, was unable to recognize proximally extended deletion alleles. Updated molecular analysis using a triple digest method revealed 10 D4Z4 repeat units, which the authors considered borderline. The extended deletion included the p13E-11 and B31 binding sites, the inverted repeat D4S463, and the FRG2 and TUBB4Q genes. The phenotype was typical for FSHD. Deak et al. (2007) noted that this was the largest proximal deletion reported to date and emphasized the complexity of molecular diagnosis of FSHD. </p><p>Sacconi et al. (2012) performed molecular analysis of 16 patients with a clinical phenotype resembling FSHD. Affected individuals had 3 or more of the following features: (1) evidence of autosomal dominant inheritance and/or weakness in (2) facial muscles, (3) shoulder girdle muscles, (4) anterior foreleg muscles, and (5) asymmetric muscle involvement. All had a myopathic pattern on EMG. One patient carried a complex rearrangement in the FSHD locus that masked the D4Z4 contraction associated with FSHD1, and 1 patient was somatic mosaic for the D4Z4 contraction. The pathogenic chromosome in the first patient (also reported by Lemmers et al., 2010) was the result of a meiotic exchange between chromosomes 10q and 4q, creating a contracted hybrid D4Z4 repeat array on a permissive background; it was associated with a mild phenotype. The second patient, who was somatic mosaic for a contracted D4Z4 repeat on a 4A161 allele, also had a mild phenotype. Of the remaining patients, 6 were diagnosed as having FSHD2, 4 had a CAPN3 (114240) mutation consistent with LGMD2A (253600); 2 had a VCP (601023) mutation, consistent with VCP-related myopathy (167320); and 2 had no identifiable genetic defect. </p><p>As a follow-up to the study of Scionti et al. (2012), Scionti et al. (2012) analyzed D4Z4-related DNA elements in 801 controls, including 560 Italian and 241 Brazilian healthy individuals. Three percent of these individuals carried alleles with a reduced number (4 to 8) of D4Z4 repeats on chromosome 4q, and 1.3% carried the reduction on the supposedly pathogenic 4A161PAS haplotype. In addition, only 127 (50.1%) of 253 unrelated patients with FSHD carried alleles with 1 to 8 D4Z4 repeats associated with 4A161PAS; the remaining FSHD probands carried different haplotypes or alleles with a greater number of D4Z4 repeats. The study demonstrated that the current genetic signature of FSHD (4A161PAS) is a common polymorphism and that only half of FSHD probands carry this molecular signature. The findings indicated that the genetic basis of FSHD needs to be revisited because of the important implications for genetic counseling and prenatal diagnosis of at-risk families. </p><p>By comparing the RNA-sequencing data from magnetic resonance imaging-guided muscle biopsies, Banerji and Zammit (2019) found that PAX7 (167410) target gene repression was an equivalent biomarker to DUX4 target gene expression for FSHD. PAX7 target gene repression also correlated with histopathologic measures of disease activity independently of DUX4 target gene expression. PAX7 target genes were significantly repressed in single cells from FSHD patients and were able to discriminate DUX4 target gene-negative FSHD myocytes from controls. The authors concluded that PAX7 target gene repression is a superior and more reliable discriminator of FSHD cells than DUX4 target gene expression. They also outlined a pipeline for evaluating PAX7 target gene repression biomarkers and DUX4 target gene expression biomarkers. </p><p>Erdmann et al. (2023) developed and validated a diagnostic workflow for the diagnosis of FSHD1 and FSHD2, which consisted of haplotyping to determine the presence of a permissive D4Z4 haplotype (4qA or 4qAL), followed by next generation-based bisulfite sequencing to determine the regional methylation at the last repeat unit of 4qA or 4qAL and global methylation of DUX4. Erdmann et al. (2023) found that this diagnostic approach reliably identified patients with FSHD, and discriminated between FSHD1 and FSHD2, with FSHD1 patients showing distal 4qA or 4qAL hypomethylation and FSHD2 patients showing global DUX4 hypomethylation including the distal region. Interestingly, the regional methylation level of 4qA or 4qAL and the D4Z4 repeat length correlated to an age-corrected clinical severity score in patients with FSHD1, with the regional methylation level showing the stronger correlation. </p>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>In a population-based study in northeastern Italy, Mostacciuolo et al. (2009) identified 40 patients with a clinical diagnosis of FSHD. Thirty (76%) patients from 13 families had a family history of the disorder, whereas 10 had sporadic disease. Of the 40 patients, 33 (82.5%) had a contraction at chromosome 4q35 ranging from 14 to 35 kb, whereas 4 patients from 1 family had a borderline 38-kb fragment, and 3 had a fragment greater than 40 kb. The 4 patients with the 38-kb fragment had onset of slowly progressive mild proximal muscle weakness between age 15 and 35 years without facial weakness. In contrast, 2 related patients with the fragment greater than 40 kb had a typical FSHD phenotype with facial involvement and profound weakness in the lower and upper region muscles, but the fragment was also found in an unaffected family member, thus excluding it as disease-causing. One asymptomatic 43-year-old man with a 20-kb fragment was identified, yielding an overall penetrance of 97%. Mostacciuolo et al. (2009) estimated the prevalence of genetically confirmed FSHD in this population to be 44 in 1,000,000. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Wijmenga et al. (1992) demonstrated rearrangements in the cosmid clone p13E-11 in patients with FSHD. This cosmid clone had been isolated in a search for homeobox genes and was mapped to chromosome 4q35 just distal to D4S139. In normal individuals the clone detected a polymorphic EcoRI fragment usually larger than 28 kb. A shorter EcoRI fragment was found in 5 out of 6 new FSHD cases. In 10 Dutch families analyzed, a specific shorter fragment between 14 and 28 kb cosegregated with FSHD. FSHD is associated with contraction of a tandem repeat rather than an expansion such as occurs in the fragile X syndrome (300624) and in myotonic dystrophy. </p><p>Fischbeck and Garbern (1992) reviewed the possibility that a previously uncharacterized homeobox gene or genes might be involved in the disorder; a graded, rostro-caudal expression of the gene(s) would explain the regional muscle degeneration. Previously known homeobox mutations cause congenital malformations; if FSHD is the result of a homeobox gene rearrangement, this would be the first example of a developmental control gene producing a phenotype with onset later in life. </p><p>Tawil et al. (1993) reported monozygotic twins discordant for the FSHD phenotype and with no family history of FSHD. Using a new marker, D4S809, which is close to or within the FSHD gene, Tawil et al. (1993) demonstrated a unique 4q35 DNA rearrangement in the affected twin. The most likely explanation for the discordance was occurrence of a de novo postzygotic mutation on 4q35 during or after the twinning process. Most studied sporadic cases demonstrate similar 4q35 rearrangements not present in their parents (Wijmenga et al., 1992; Weiffenbach et al., 1993). Using D4S809 probes that map near or within the FSHD gene, Griggs et al. (1993) investigated 8 sporadic patients with FSHD whose parents showed no signs of the disease. The probe detected novel DNA fragments in 7 of the 8 sporadic individuals and not in the parents. A novel DNA fragment was found in each of 2 sisters with FSHD whose parents were clinically normal; the finding was taken as evidence of germline mosaicism. Use of the D4S809 probe in genetic counseling is limited; however, because the probe may also detect a locus unlinked to chromosome 4, because of possible genetic heterogeneity in FSHD and because of the presence of recombinants in families with the inherited form. Hence, closer markers or gene definition will be required. </p><p>Hewitt et al. (1994) and Winokur et al. (1993) postulated that FSHD may be due to a position effect. Bengtsson et al. (1994) reported results indicating that the tandem array of 3.2-kb repeats, disrupted in FSHD, lies immediately adjacent to the telomere of 4q and that the gene responsible for FSHD is probably located proximal to the tandem repeat. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Because of its mapping to a region of homology to human 4q, Mills et al. (1995) suggested that 'myodystrophy' (myd), an autosomal recessive mutation in the mouse, is a homolog of FSHD. The mouse disorder is characterized by progressive weakness and dystrophic muscle histology and maps to the central portion of mouse chromosome 8. This portion of mouse chromosome 8 contains the genes for mitochondrial uncoupling protein (UCP; 113730) and kallikrein (KLKB1; 229000). </p><p>Contrary to the suggestion of Mills et al. (1995), Grewal et al. (2001) found that the gene mutated in myd, Large, encodes a glycosyltransferase. The human homolog of this gene maps to 22q; see 603590. In myd, Grewal et al. (2001) identified an intragenic deletion of exons 4-7 that causes a frameshift in the resultant mRNA and a premature termination codon before the first of the 2 catalytic domains. On immunoblots, a monoclonal antibody to alpha-dystroglycan (128239), a component of the dystrophin (300377)-associated glycoprotein complex, showed reduced binding in myd, which Grewal et al. (2001) attributed to altered glycosylation of the protein. They speculated that abnormal posttranslational modification of alpha-dystroglycan may contribute to the myd phenotype. </p><p>To identify the gene responsible for facioscapulohumeral muscular dystrophy pathogenesis, Gabellini et al. (2006) generated transgenic mice selectively overexpressing in skeletal muscle the 4q35 genes FRG1 (601278), FRG2 (609032), or ANT1 (103220). The authors found that FRG1 transgenic mice developed a muscular dystrophy with features characteristic of the human disease; by contrast, FRG2 and ANT1 transgenic mice seemed normal. FRG1 is a nuclear protein, and several lines of evidence suggest it is involved in pre-mRNA splicing. Gabellini et al. (2006) found changes in the alternative splicing pattern of the pre-mRNAs of TNNT3 (600692) and myotubularin related-protein 1 (MTMR1; 300171) in muscle of FRG1 transgenic mice and FSHD patients. Collectively, the results suggested that FSHD results from inappropriate overexpression of FRG1 in skeletal muscle, which leads to abnormal alternative splicing of specific pre-mRNAs. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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Awerbuch, G. I., Nigro, M. A., Wishnow, R.
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<strong>Beevor's sign and facioscapulohumeral dystrophy.</strong>
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Arch. Neurol. 47: 1208-1209, 1990.
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Bailey, R. O., Marzulo, D. C., Hans, M. B.
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Banerji, C. R. S., Zammit, P. S.
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Bengtsson, U., Altherr, M. R., Wasmuth, J. J., Winokur, S. T.
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<strong>High resolution fluorescence in situ hybridization to linearly extended DNA visually maps a tandem repeat associated with facioscapulohumeral muscular dystrophy immediately adjacent to the telomere of 4q.</strong>
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Bickmore, W. A., van der Maarel, S. M.
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<strong>Perturbations of chromatin structure in human genetic disease: recent advances.</strong>
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Bodensteiner, J. B., Schochet, S. S.
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<strong>Facioscapulohumeral muscular dystrophy: the choice of a biopsy site.</strong>
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Bosnakovski, D., Xu, Z., Gang, E. J., Galindo, C. L., Liu, M., Simsek, T., Garner, H. R., Agha-Mohammadi, S., Tassin, A., Coppee, F., Belayew, A., Perlingeiro, R. R., Kyba, M.
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<strong>An isogenic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies.</strong>
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EMBO J. 27: 2766-2779, 2008.
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<p class="mim-text-font">
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Brouwer, O. F., Padberg, G. W., Ruys, C. J. M., Brand, R., de Laat, J. A. P. M., Grote, J. J.
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<strong>Hearing loss in facioscapulohumeral muscular dystrophy.</strong>
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<p class="mim-text-font">
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Clapp, J., Mitchell, L. M., Bolland, D. J., Fantes, J., Corcoran, A. E., Scotting, P. J., Armour, J. A. L., Hewitt, J. E.
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<strong>Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy.</strong>
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Am. J. Hum. Genet. 81: 264-279, 2007.
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<strong>Distinguishing the 4qA and 4qB variants is essential for the diagnosis of facioscapulohumeral muscular dystrophy in the Chinese population.</strong>
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Wijmenga, C., Sandkuijl, L. A., Moerer, P., van der Boorn, N., Bodrug, S. E., Ray, P. N., Brouwer, O. F., Murray, J. C., van Ommen, G. J. B., Padberg, G. W., Frants, R. R.
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<strong>A radiation hybrid map of 15 loci on the distal long arm of chromosome 4, the region containing the gene responsible for facioscapulohumeral muscular dystrophy (FSHD).</strong>
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Am. J. Hum. Genet. 53: 874-880, 1993.
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[PubMed: 8213815]
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<strong>Possible phenotypic dosage effect in patients compound heterozygous for FSHD-sized 4q35 alleles.</strong>
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<strong>Facioscapulohumeral dystrophy associated with sensorineural hearing loss, tortuosity of retinal arterioles, and an early onset and rapid progression of respiratory failure.</strong>
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<strong>The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females.</strong>
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Zatz, M., Marie, S. K., Passos-Bueno, M. R., Vainof, M., Campiotto, S., Cerqueira, A., Wijmenga, C., Padberg, G., Frants, R.
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<strong>High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families.</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 : 10/10/2023<br>Cassandra L. Kniffin - updated : 08/12/2021<br>Bao Lige - updated : 11/11/2019<br>Cassandra L. Kniffin - updated : 11/4/2013<br>Patricia A. Hartz - updated : 1/17/2013<br>Cassandra L. Kniffin - updated : 5/3/2012<br>Cassandra L. Kniffin - updated : 4/25/2012<br>Cassandra L. Kniffin - updated : 4/9/2012<br>Cassandra L. Kniffin - updated : 3/26/2012<br>Cassandra L. Kniffin - updated : 1/10/2012<br>Cassandra L. Kniffin - updated : 11/2/2011<br>Patricia A. Hartz - updated : 9/27/2011<br>Ada Hamosh - updated : 11/10/2010<br>Cassandra L. Kniffin - updated : 5/28/2010<br>Cassandra L. Kniffin - updated : 6/5/2009<br>Cassandra L. Kniffin - updated : 2/12/2009<br>Cassandra L. Kniffin - updated : 12/3/2007<br>Jane Kelly - updated : 11/8/2007<br>Victor A. McKusick - updated : 11/1/2007<br>Cassandra L. Kniffin - updated : 10/8/2007<br>Victor A. McKusick - updated : 8/17/2007<br>Marla J. F. O'Neill - updated : 6/7/2007<br>George E. Tiller - updated : 1/16/2007<br>Ada Hamosh - updated : 12/6/2006<br>Cassandra L. Kniffin - updated : 5/23/2006<br>Cassandra L. Kniffin - updated : 5/16/2006<br>Cassandra L. Kniffin - updated : 4/3/2006<br>Victor A. McKusick - updated : 3/7/2006<br>George E. Tiller - updated : 1/11/2006<br>Cassandra L. Kniffin - updated : 12/8/2005<br>George E. Tiller - updated : 9/30/2005<br>Victor A. McKusick - updated : 3/10/2005<br>Cassandra L. Kniffin - updated : 1/20/2005<br>Victor A. McKusick - updated : 11/12/2004<br>Victor A. McKusick - updated : 6/30/2004<br>Cassandra L. Kniffin - updated : 1/23/2004<br>Cassandra L. Kniffin - updated : 1/9/2004<br>Victor A. McKusick - updated : 12/2/2003<br>Victor A. McKusick - updated : 8/7/2003<br>Cassandra L. Kniffin - updated : 11/27/2002<br>Cassandra L. Kniffin - updated : 11/13/2002<br>Victor A. McKusick - updated : 9/23/2002<br>Stylianos E. Antonarakis - updated : 9/6/2002<br>Victor A. McKusick - updated : 6/19/2001<br>Michael J. Wright - updated : 2/7/2000<br>Victor A. McKusick - updated : 1/4/2000<br>Victor A. McKusick - updated : 12/13/1999<br>Victor A. McKusick - updated : 2/2/1999<br>Ada Hamosh - updated : 10/29/1998<br>Michael J. Wright - updated : 10/7/1998<br>Victor A. McKusick - updated : 5/11/1998<br>Orest Hurko - updated : 4/7/1998<br>Moyra Smith - updated : 1/28/1997<br>Moyra Smith - updated : 5/23/1996
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Victor A. McKusick : 6/2/1986
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