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<title>
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Entry
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- #613267 - CORNEAL DYSTROPHY, FUCHS ENDOTHELIAL, 3; FECD3
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- OMIM
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<span class="h4">#613267</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/613267"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS136800"> <strong>Phenotypic Series</strong> </a>
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<a href="#description">Description</a>
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<a href="#nomenclature">Nomenclature</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="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=13991&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/gtr/all/tests/?term=613267[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=98974" 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.alliancegenome.org/disease/DOID:11555" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/613267" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:11555" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 98974<br />
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<strong>DO:</strong> 11555<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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613267
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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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CORNEAL DYSTROPHY, FUCHS ENDOTHELIAL, 3; FECD3
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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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<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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FCD2 LOCUS<br />
|
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CORNEAL DYSTROPHY, FUCHS ENDOTHELIAL, LATE-ONSET
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
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Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
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Phenotype <br /> mapping key
|
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</th>
|
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<th>
|
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Gene/Locus
|
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</th>
|
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<th>
|
|
Gene/Locus <br /> MIM number
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
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<tr>
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<td>
|
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<span class="mim-font">
|
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<a href="/geneMap/18/199?start=-3&limit=10&highlight=199">
|
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18q21.2
|
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Corneal dystrophy, Fuchs endothelial, 3
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/613267"> 613267 </a>
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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TCF4
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/602272"> 602272 </a>
|
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</span>
|
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</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
|
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<a href="/clinicalSynopsis/613267" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
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<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')">
|
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<span class="caret"></span>
|
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<span class="sr-only">Toggle Dropdown</span>
|
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</button>
|
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</div>
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|
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<div class="btn-group">
|
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|
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<a href="/phenotypicSeries/PS136800" class="btn btn-info" role="button"> Phenotypic Series </a>
|
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|
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<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>
|
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<span class="sr-only">Toggle Dropdown</span>
|
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</button>
|
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</div>
|
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/613267" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/613267" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
|
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<p />
|
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</div>
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|
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
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<strong> INHERITANCE </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
|
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|
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<div>
|
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<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 />
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|
|
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</span>
|
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</div>
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</div>
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</div>
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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<div>
|
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Corneal guttae <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/373424008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">373424008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0271288&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0271288</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012038" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012038</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012038" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012038</a>]</span><br /> -
|
|
Progressive corneal opacification <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4229870&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4229870</a>]</span><br /> -
|
|
Decreased vision due to loss of transparency of cornea <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4227385&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4227385</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246635007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246635007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7973008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7973008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397540003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397540003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/225581002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">225581002</a>]</span><br /> -
|
|
Corneal edema <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/27194006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">27194006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H18.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H18.20</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/371.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">371.2</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/371.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">371.20</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0010037&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0010037</a>]</span><br /> -
|
|
Punctate CUG-repeat RNA foci in nuclei of corneal epithelial cells by FISH <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4229869&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4229869</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
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</div>
|
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|
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</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Diagnosis rarely made before the fourth decade of life<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 a trinucleotide repeat expansion (CTG)n in the transcription factor-4 gene (TCF4, <a href="/entry/602272#0007">602272.0007</a>)<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">
|
|
|
|
|
|
|
|
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|
|
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|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Corneal dystrophy, Fuchs endothelial
|
|
- <a href="/phenotypicSeries/PS136800">PS136800</a>
|
|
- 8 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/1/439?start=-3&limit=10&highlight=439"> 1p34.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/136800"> Corneal dystrophy, Fuchs endothelial, 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="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/136800"> 136800 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/120252"> COL8A2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/120252"> 120252 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/5/668?start=-3&limit=10&highlight=668"> 5q33.1-q35.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613269"> Corneal dystrophy, Fuchs endothelial, 5 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613269"> 613269 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613269"> FECD5 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613269"> 613269 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/9/21?start=-3&limit=10&highlight=21"> 9p24.1-p22.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613271"> Corneal dystrophy, Fuchs endothelial, 7 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
|
|
|
|
</span>
|
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<a href="/entry/613267"> Corneal dystrophy, Fuchs endothelial, 3 </a>
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<a href="/entry/613268"> Corneal dystrophy, Fuchs endothelial, 4 </a>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that Fuchs endothelial corneal dystrophy-3 (FECD3) is caused by heterozygous intronic trinucleotide repeat expansion (CTG)n in the TCF4 gene (<a href="/entry/602272">602272</a>) on chromosome 18q21.</p>
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<p>Late-onset Fuchs endothelial corneal dystrophy (FECD) is a degenerative disorder affecting roughly 4% of the population older than 40 years. It is distinguished from other corneal disorders by the progressive formation of guttae, which are microscopic refractile excrescences of the Descemet membrane, a collagen-rich basal lamina secreted by the corneal endothelium. From onset, it usually takes 2 decades for FECD to impair endothelial cell function seriously, leading to stromal edema and impaired vision (<a href="#10" class="mim-tip-reference" title="Sundin, O. H., Broman, K. W., Chang, H. H., Vito, E. C. L., Stark, W. J., Gottsch, J. D. <strong>A common locus for late-onset Fuchs corneal dystrophy maps to 18q21.2-q21.32.</strong> Invest. Ophthal. Vis. Sci. 47: 3919-3926, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16936105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16936105</a>] [<a href="https://doi.org/10.1167/iovs.05-1619" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16936105">Sundin et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16936105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For a discussion of genetic heterogeneity of Fuchs endothelial corneal dystrophy, see FECD1 (<a href="/entry/136800">136800</a>).</p>
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<p>The late-onset form of Fuchs endothelial corneal dystrophy mapping to chromosome 18q21.2-q21.32 is referred to in OMIM as FECD3. Some references in the literature (e.g., <a href="#8" class="mim-tip-reference" title="Riazuddin, S. A., Zaghloul, N. A., Al-Saif, A., Davey, L., Diplas, B. H., Meadows, D. N., Eghrari, A. O., Minear, M. A., Li, Y.-J., Klintworth, G. K., Afshari, N., Gregory, S. G., Gottsch, J. D., Katsanis, N. <strong>Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p.</strong> Am. J. Hum. Genet. 86: 45-53, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20036349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20036349</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20036349[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.2009.12.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20036349">Riazuddin et al., 2010</a>) have used the designation 'FCD2 locus' to refer to the genetic locus for FECD on chromosome 18. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20036349" 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="#10" class="mim-tip-reference" title="Sundin, O. H., Broman, K. W., Chang, H. H., Vito, E. C. L., Stark, W. J., Gottsch, J. D. <strong>A common locus for late-onset Fuchs corneal dystrophy maps to 18q21.2-q21.32.</strong> Invest. Ophthal. Vis. Sci. 47: 3919-3926, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16936105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16936105</a>] [<a href="https://doi.org/10.1167/iovs.05-1619" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16936105">Sundin et al. (2006)</a> performed linkage analysis in 43 affected and 33 unaffected individuals from 3 large late-onset FECD families and obtained the highest 2-point lod score for each family at D18S1129 on chromosome 18q21.2-q21.3 (3.41, 2.89, and 2.45, respectively), with a combined 2-point lod score of 7.70. Multipoint analysis yielded a maximum lod score of 5.94 at D18S1129 for a dominant mendelian trait exhibiting 85% penetrance and 15% phenocopy rate. The disease-associated haplotype of 1 of the kindreds defined a 7-Mb critical interval from D18S487 to D18S1134. Noting the incomplete penetrance and high phenocopy rate, <a href="#10" class="mim-tip-reference" title="Sundin, O. H., Broman, K. W., Chang, H. H., Vito, E. C. L., Stark, W. J., Gottsch, J. D. <strong>A common locus for late-onset Fuchs corneal dystrophy maps to 18q21.2-q21.32.</strong> Invest. Ophthal. Vis. Sci. 47: 3919-3926, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16936105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16936105</a>] [<a href="https://doi.org/10.1167/iovs.05-1619" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16936105">Sundin et al. (2006)</a> suggested that the origin of FECD in these 3 families was complex and might depend on other genetic loci or environmental factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16936105" 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="#1" class="mim-tip-reference" title="Baratz, K. H., Tosakulwong, N., Ryu, E., Brown, W. L., Branham, K., Chen, W., Tran, K. D., Schmid-Kubista, K. E., Heckenlively, J. R., Swaroop, A., Abecasis, G., Bailey, K. R., Edwards, A. O. <strong>E2-2 protein and Fuchs's corneal dystrophy.</strong> New Eng. J. Med. 363: 1016-1024, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20825314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20825314</a>] [<a href="https://doi.org/10.1056/NEJMoa1007064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20825314">Baratz et al. (2010)</a> performed a genomewide association study in 130 patients with FECD and 260 age- and sex-matched controls and found association to a region on chromosome 18q spanning the gene encoding transcription factor-4 (TCF4; <a href="/entry/602272">602272</a>), with replication in 150 independent patients. The most significant association was found with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs613872;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs613872</a> in intron 3 of the TCF4 gene on 18q21.1 (combined p = 2.3 x 10(-26)). The odds of having FECD increased by a factor of 30 for persons with 2 copies of the disease variant and discriminated between cases and controls with about 76% accuracy. The authors noted that many SNPs across the TCF4 locus were associated with FECD, and stepwise regression analysis implicated 4 SNPs as being independently associated with FECD. <a href="#1" class="mim-tip-reference" title="Baratz, K. H., Tosakulwong, N., Ryu, E., Brown, W. L., Branham, K., Chen, W., Tran, K. D., Schmid-Kubista, K. E., Heckenlively, J. R., Swaroop, A., Abecasis, G., Bailey, K. R., Edwards, A. O. <strong>E2-2 protein and Fuchs's corneal dystrophy.</strong> New Eng. J. Med. 363: 1016-1024, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20825314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20825314</a>] [<a href="https://doi.org/10.1056/NEJMoa1007064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20825314">Baratz et al. (2010)</a> concluded that genetic variation across the TCF4 locus might explain the linkage signal with FECD previously observed on chromosome 18q21. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20825314" 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="Riazuddin, S. A., McGlumphy, E. J., Yeo, W. S., Wang, J., Katsanis, N., Gottsch, J. D. <strong>Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus.</strong> Invest. Ophthal. Vis. Sci. 52: 2825-2829, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21245398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21245398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21245398[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/10.1167/iovs.10-6497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21245398">Riazuddin et al. (2011)</a> examined the association of the TCF4 intronic variant <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs613872;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs613872</a> in their cohort of 170 patients with late-onset Fuchs corneal dystrophy and 180 age-matched controls. They found that the risk allele, G, of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs613872;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs613872</a> was significantly associated with late-onset FECD (odds ratio, 4.2; p = 4.28 x 10(-15)) and was present in male and female affected persons without any sex bias, replicating the findings of <a href="#1" class="mim-tip-reference" title="Baratz, K. H., Tosakulwong, N., Ryu, E., Brown, W. L., Branham, K., Chen, W., Tran, K. D., Schmid-Kubista, K. E., Heckenlively, J. R., Swaroop, A., Abecasis, G., Bailey, K. R., Edwards, A. O. <strong>E2-2 protein and Fuchs's corneal dystrophy.</strong> New Eng. J. Med. 363: 1016-1024, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20825314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20825314</a>] [<a href="https://doi.org/10.1056/NEJMoa1007064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20825314">Baratz et al. (2010)</a>, although no apparent correlation with the severity of the disease phenotype was found. <a href="#7" class="mim-tip-reference" title="Riazuddin, S. A., McGlumphy, E. J., Yeo, W. S., Wang, J., Katsanis, N., Gottsch, J. D. <strong>Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus.</strong> Invest. Ophthal. Vis. Sci. 52: 2825-2829, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21245398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21245398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21245398[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/10.1167/iovs.10-6497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21245398">Riazuddin et al. (2011)</a> found that the risk allele did not cosegregate with the disease phenotype in any of the 3 FCD2-linked families. The authors also did not identify any pathogenic variants within the coding region of TCF4. <a href="#7" class="mim-tip-reference" title="Riazuddin, S. A., McGlumphy, E. J., Yeo, W. S., Wang, J., Katsanis, N., Gottsch, J. D. <strong>Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus.</strong> Invest. Ophthal. Vis. Sci. 52: 2825-2829, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21245398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21245398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21245398[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/10.1167/iovs.10-6497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21245398">Riazuddin et al. (2011)</a> concluded that theirs was the first independent replication of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs613872;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs613872</a> conferring risk of late-onset FECD, and stated that their data suggested that this risk factor was likely independent of the FCD2 locus, the causality of which remained undetermined. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21245398+20825314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Li, Y.-J., Minear, M. A., Rimmler, J., Zhao, B., Balajonda, E., Hauser, M. A., Allingham, R. R., Eghrari, A. O., Riazuddin, S. A., Katsanis, N., Gottsch, J. D., Gregory, S. G., Klintworth, G. K., Afshari, N. A. <strong>Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy.</strong> PLoS One 6: e18044, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533127</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533127[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.pone.0018044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533127">Li et al. (2011)</a> reported the findings of their independent validation study for TCF4 using the largest FECD dataset to that time (450 FECD cases; 340 normal controls). <a href="#4" class="mim-tip-reference" title="Li, Y.-J., Minear, M. A., Rimmler, J., Zhao, B., Balajonda, E., Hauser, M. A., Allingham, R. R., Eghrari, A. O., Riazuddin, S. A., Katsanis, N., Gottsch, J. D., Gregory, S. G., Klintworth, G. K., Afshari, N. A. <strong>Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy.</strong> PLoS One 6: e18044, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533127</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533127[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.pone.0018044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533127">Li et al. (2011)</a> found significant association with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs613872;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs613872</a>, the target marker reported by <a href="#1" class="mim-tip-reference" title="Baratz, K. H., Tosakulwong, N., Ryu, E., Brown, W. L., Branham, K., Chen, W., Tran, K. D., Schmid-Kubista, K. E., Heckenlively, J. R., Swaroop, A., Abecasis, G., Bailey, K. R., Edwards, A. O. <strong>E2-2 protein and Fuchs's corneal dystrophy.</strong> New Eng. J. Med. 363: 1016-1024, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20825314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20825314</a>] [<a href="https://doi.org/10.1056/NEJMoa1007064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20825314">Baratz et al. (2010)</a>, for all 3 genetic models (dominant: p = 9.33 x 10(-35); additive: p = 7.48 x 10(-30); recessive: p = 5.27 x = 10(-6)). To strengthen the association study, <a href="#4" class="mim-tip-reference" title="Li, Y.-J., Minear, M. A., Rimmler, J., Zhao, B., Balajonda, E., Hauser, M. A., Allingham, R. R., Eghrari, A. O., Riazuddin, S. A., Katsanis, N., Gottsch, J. D., Gregory, S. G., Klintworth, G. K., Afshari, N. A. <strong>Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy.</strong> PLoS One 6: e18044, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533127</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533127[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.pone.0018044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533127">Li et al. (2011)</a> also conducted a genomewide linkage scan on 64 multiplex families, composed primarily of affected sib pairs, using both parametric and nonparametric 2-point and multipoint analyses. The most significant linkage region localized to chromosome 18 from 69.94 cM to 85.28 cM, with a peak multipoint hlod = 2.5 at <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1145315;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1145315</a> (75.58 cM) under the dominant model, mapping 1.5 Mb proximal to <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs613872;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs613872</a>. <a href="#4" class="mim-tip-reference" title="Li, Y.-J., Minear, M. A., Rimmler, J., Zhao, B., Balajonda, E., Hauser, M. A., Allingham, R. R., Eghrari, A. O., Riazuddin, S. A., Katsanis, N., Gottsch, J. D., Gregory, S. G., Klintworth, G. K., Afshari, N. A. <strong>Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy.</strong> PLoS One 6: e18044, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533127</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533127[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.pone.0018044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21533127">Li et al. (2011)</a> concluded that their study presented evidence to support the role of the intronic TCF4 single-nucleotide polymorphism <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs613872;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs613872</a> in late-onset FECD through both association and linkage studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21533127+20825314" 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 3-stage discovery/replication/validation study involving 66 patients with severe FECD and 63 individuals with normal corneas, <a href="#12" class="mim-tip-reference" title="Wieben, E. D., Aleff, R. A., Tosakulwong, N., Butz, M. L., Highsmith, W. E., Edwards, A. O., Baratz, K. H. <strong>A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy.</strong> PLoS One 7: e49083, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23185296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23185296</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23185296[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.pone.0049083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23185296">Wieben et al. (2012)</a> tested for association between FECD and an intronic TCG repeat in the TCF4 gene (<a href="/entry/602272#0007">602272.0007</a>), designated CTG18.1 by <a href="#2" class="mim-tip-reference" title="Breschel, T. S., McInnis, M. G., Margolis, R. L., Sirugo, G., Corneliussen, B., Simpson, S. G., McMahon, F. J., MacKinnon, D. F., Xu, J. F., Pleasant, N., Huo, Y., Ashworth, R. G., Grundstrom, C., Grundstrom, T., Kidd, K. K., DePaulo, J. R., Ross, C. A. <strong>A novel, heritable, expanding CTG repeat in an intron of the SEF2-1 gene on chromosome 18q21.1.</strong> Hum. Molec. Genet. 6: 1855-1863, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9302263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9302263</a>] [<a href="https://doi.org/10.1093/hmg/6.11.1855" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9302263">Breschel et al. (1997)</a>. Overall, 52 (79%) of 66 FECD patients had more than 50 TGC repeats and 13 (20%) had fewer than 40 repeats, compared to 2 (3%) and 60 (95%) of 63 controls, respectively. The sensitivity and specificity of more than 50 TGC repeats for identifying FECD was 79% and 96%, respectively; <a href="#12" class="mim-tip-reference" title="Wieben, E. D., Aleff, R. A., Tosakulwong, N., Butz, M. L., Highsmith, W. E., Edwards, A. O., Baratz, K. H. <strong>A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy.</strong> PLoS One 7: e49083, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23185296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23185296</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23185296[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.pone.0049083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23185296">Wieben et al. (2012)</a> noted that the expanded TGC repeat was more specific for FECD cases than the previously identified SNP <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs613872;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs613872</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9302263+23185296" 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 120 Caucasian FECD probands and 100 controls, <a href="#5" class="mim-tip-reference" title="Mootha, V. V., Gong, X., Ku, H.-C., Xing, C. <strong>Association and familial segregation of CTG18.1 trinucleotide repeat expansion of TCF4 gene in Fuchs' endothelial corneal dystrophy.</strong> Invest. Ophthal. Vis. Sci. 55: 33-42, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24255041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24255041</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24255041[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/10.1167/iovs.13-12611" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24255041">Mootha et al. (2014)</a> tested the association between 2 intronic polymorphisms in the TCF4 gene, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs613872;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs613872</a> and CTG18.1, and found that the 2 polymorphisms are in linkage disequilibrium. Significant associations were found between FECD and both the <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs613872;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs613872</a> polymorphism (p = 3.1 x 10(-17)) and the expanded CTG18.1 allele (p = 6.5 x 10(-25)), as well as their haplotypes (p = 5.9 x 10(-19)). The odds ratios of each copy of the <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs613872;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs613872</a> or the expanded CTG18.1 alleles for FECD were estimated to be 9.5 and 32.3, respectively. In a study of segregation of the CTG18.1 allele, the expansion was found in 24 of 29 FECD families; it segregated with disease in 18 families, but showed incomplete penetrance in 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24255041" 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 markers for FECD, <a href="#11" class="mim-tip-reference" title="Wieben, E. D., Aleff, R. A., Eckloff, B. W., Atkinson, E. J., Baheti, S., Middha, S., Brown, W. L., Patel, S. V., Kocher, J.-P. A., Baratz, K. H. <strong>Comprehensive assessment of genetic variants within TCF4 in Fuchs' endothelial corneal dystrophy.</strong> Invest. Ophthal. Vis. Sci. 55: 6101-6107, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25168903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25168903</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25168903[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/10.1167/iovs.14-14958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25168903">Wieben et al. (2014)</a> sequenced the TCF4 gene region in 68 patients with FECD and 16 unaffected individuals. TGC expansion of greater than 50 repeats was present in 46 (68%) of 68 FECD patients and 1 (6%) of 16 controls. No variant, including TGC expansion, correlated perfectly with disease status. <a href="#11" class="mim-tip-reference" title="Wieben, E. D., Aleff, R. A., Eckloff, B. W., Atkinson, E. J., Baheti, S., Middha, S., Brown, W. L., Patel, S. V., Kocher, J.-P. A., Baratz, K. H. <strong>Comprehensive assessment of genetic variants within TCF4 in Fuchs' endothelial corneal dystrophy.</strong> Invest. Ophthal. Vis. Sci. 55: 6101-6107, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25168903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25168903</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25168903[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/10.1167/iovs.14-14958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25168903">Wieben et al. (2014)</a> noted that even within some families, repeat expansions occurred in both affected and unaffected individuals, including individuals over age 70 with more than 80 TGC repeats who remained unaffected. However, they stated that the CTG18.1 intronic trinucleotide repeat expansion within TCF4 was a better predictor of disease than any other variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25168903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Mootha, V. V., Hussain, I., Cunnusamy, K., Graham, E., Gong, X., Neelam, S., Xing, C., Kittler, R., Petroll, W. M. <strong>TCF4 triplet repeat expansion and nuclear RNA foci in Fuchs' endothelial corneal dystrophy.</strong> Invest. Ophthal. Vis. Sci. 56: 2003-2011, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25722209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25722209</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25722209[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/10.1167/iovs.14-16222" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25722209">Mootha et al. (2015)</a> studied corneal endothelial tissue samples from 8 FECD patients carrying the TCF4 CTG18.1 repeat expansion (<a href="/entry/602272#0007">602272.0007</a>), all of whom had greater than 5-mm diameter confluent guttae with edema (Krachmer scale grade 6). Abundant discrete, punctate nuclear CUG-repeat RNA foci, the hallmark of toxic RNA, were observed in endothelial samples from all 8 FECD patients with the CTG18.1 expansion; however, no RNA foci were seen in endothelium from 7 individuals without the CTG18.1 expansion, including 1 FECD patient, 1 patient with corneal edema without guttae, and 5 controls. Nuclear RNA foci were also detected in 2 control endothelial samples; subsequent genotyping revealed CTG18.1 repeat expansion in both samples, and cellular polymorphism and polymegethism were seen on specular microscopy of the corneal endothelium. Noting that there was no significant difference in TCF4 expression by quantitative PCR in FECD endothelial samples with CTG18.1 expansion compared to control endothelium, <a href="#6" class="mim-tip-reference" title="Mootha, V. V., Hussain, I., Cunnusamy, K., Graham, E., Gong, X., Neelam, S., Xing, C., Kittler, R., Petroll, W. M. <strong>TCF4 triplet repeat expansion and nuclear RNA foci in Fuchs' endothelial corneal dystrophy.</strong> Invest. Ophthal. Vis. Sci. 56: 2003-2011, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25722209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25722209</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25722209[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/10.1167/iovs.14-16222" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25722209">Mootha et al. (2015)</a> concluded that rather than haploinsufficiency of TCF4, toxic RNA is the primary mechanism of disease in FECD with CTG18.1 triplet repeat expansion, mediated by CUG-repeat RNA foci. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25722209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Du, J., Aleff, R. A., Soragni, E., Kalari, K., Nie, J., Tang, X., Davila, J., Kocher, J.-P., Patel, S. V., Gottesfeld, J. M., Baratz, K. H., Wieben, E. D. <strong>RNA toxicity and missplicing in the common eye disease Fuchs endothelial corneal dystrophy.</strong> J. Biol. Chem. 290: 5979-5990, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25593321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25593321</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25593321[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.M114.621607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25593321">Du et al. (2015)</a> studied corneal endothelium and fibroblasts from FECD patients and controls and determined that the CTG-CAG trinucleotide repeat expansion is transcribed into a stable sense-strand RNA, which causes the formation of CUG RNA foci in the affected tissue. There was selective abundance of poly(CUG) RNA foci in FECD corneal endothelial cells compared to fibroblasts, suggesting that TCF4 poly(CUG) transcripts predominantly accumulate in the corneal endothelium, leading to FECD pathogenesis. The authors observed colocalization of CUG RNA foci with the mRNA-splicing factor MBNL1 (<a href="/entry/606516">606516</a>) in patient corneal endothelial cells; they also identified 342 genes with robust expression in the corneal endothelium that exhibited differential expression of at least 1 isoform in FECD patients with the expansion compared to patients without the expansion and controls. In addition, RT-PCR results for a splicing event known to be unresponsive to changes in MBNL1 showed no difference between FECD patients and controls. <a href="#3" class="mim-tip-reference" title="Du, J., Aleff, R. A., Soragni, E., Kalari, K., Nie, J., Tang, X., Davila, J., Kocher, J.-P., Patel, S. V., Gottesfeld, J. M., Baratz, K. H., Wieben, E. D. <strong>RNA toxicity and missplicing in the common eye disease Fuchs endothelial corneal dystrophy.</strong> J. Biol. Chem. 290: 5979-5990, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25593321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25593321</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25593321[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.M114.621607" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25593321">Du et al. (2015)</a> concluded that expansion of the CTG-CAG repeat in the TCF4 gene contributes to FECD through a mechanism that involves sequestration of MBNL1 in RNA foci, similar to the mechanism underlying myotonic dystrophy-1 (DM1; <a href="/entry/160900">160900</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25593321" 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 role of variation in the LOXHD1 gene in Fuchs endothelial corneal dystrophy-3, see <a href="/entry/613072#0003">613072.0003</a>.</p>
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<p>In a study of 122 white index cases of FECD, <a href="#9" class="mim-tip-reference" title="Soliman, A. Z., Xing, C., Radwan, S. H., Gong, X., Mootha, V. V. <strong>Correlation of severity of Fuchs endothelial corneal dystrophy with triplet repeat expansion in TCF4.</strong> JAMA Ophthal. 133: 1386-1391, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26401622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26401622</a>] [<a href="https://doi.org/10.1001/jamaophthalmol.2015.3430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26401622">Soliman et al. (2015)</a> found that 85 (69.7%) harbored the TCF4 triplet repeat expansion. Patients with the triplet repeat expansion had a more severe form of FECD, with clinical and surgical implications. The mean (SD) Krachmer grade was 5.61 (0.76) in the group with the repeat expansion compared with 5.11 (1.05) in the group without the expanded repeats (p = .01. Forty-seven individuals with the repeat expansion (55.3%) had undergone keratoplasty at the time of study, compared with 13 (35.1%) of those without the expansion (p = .0497). There was a positive correlation of Krachmer grade to triplet repeat number (p = .0002)) and a nominal association of the keratoplasty proportion with triplet repeat number (p = .04). The mean (SD) central corneal thickness was 605.9 (50.5) micrometers in the group with the expanded repeats compared with 581.3 (50.5) micrometers in the group without the expansion (p = .04). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26401622" 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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Baratz, K. H., Tosakulwong, N., Ryu, E., Brown, W. L., Branham, K., Chen, W., Tran, K. D., Schmid-Kubista, K. E., Heckenlively, J. R., Swaroop, A., Abecasis, G., Bailey, K. R., Edwards, A. O.
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<strong>E2-2 protein and Fuchs's corneal dystrophy.</strong>
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New Eng. J. Med. 363: 1016-1024, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20825314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20825314</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20825314" 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/10.1056/NEJMoa1007064" target="_blank">Full Text</a>]
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Breschel, T. S., McInnis, M. G., Margolis, R. L., Sirugo, G., Corneliussen, B., Simpson, S. G., McMahon, F. J., MacKinnon, D. F., Xu, J. F., Pleasant, N., Huo, Y., Ashworth, R. G., Grundstrom, C., Grundstrom, T., Kidd, K. K., DePaulo, J. R., Ross, C. A.
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<strong>A novel, heritable, expanding CTG repeat in an intron of the SEF2-1 gene on chromosome 18q21.1.</strong>
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Hum. Molec. Genet. 6: 1855-1863, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9302263/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9302263</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9302263" 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/6.11.1855" target="_blank">Full Text</a>]
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Du, J., Aleff, R. A., Soragni, E., Kalari, K., Nie, J., Tang, X., Davila, J., Kocher, J.-P., Patel, S. V., Gottesfeld, J. M., Baratz, K. H., Wieben, E. D.
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<strong>RNA toxicity and missplicing in the common eye disease Fuchs endothelial corneal dystrophy.</strong>
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J. Biol. Chem. 290: 5979-5990, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25593321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25593321</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25593321[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=25593321" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M114.621607" target="_blank">Full Text</a>]
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Li, Y.-J., Minear, M. A., Rimmler, J., Zhao, B., Balajonda, E., Hauser, M. A., Allingham, R. R., Eghrari, A. O., Riazuddin, S. A., Katsanis, N., Gottsch, J. D., Gregory, S. G., Klintworth, G. K., Afshari, N. A.
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<strong>Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy.</strong>
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PLoS One 6: e18044, 2011. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21533127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21533127</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21533127[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=21533127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1371/journal.pone.0018044" target="_blank">Full Text</a>]
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Mootha, V. V., Gong, X., Ku, H.-C., Xing, C.
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<strong>Association and familial segregation of CTG18.1 trinucleotide repeat expansion of TCF4 gene in Fuchs' endothelial corneal dystrophy.</strong>
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Invest. Ophthal. Vis. Sci. 55: 33-42, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24255041/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24255041</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24255041[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=24255041" 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/10.1167/iovs.13-12611" target="_blank">Full Text</a>]
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Mootha, V. V., Hussain, I., Cunnusamy, K., Graham, E., Gong, X., Neelam, S., Xing, C., Kittler, R., Petroll, W. M.
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<strong>TCF4 triplet repeat expansion and nuclear RNA foci in Fuchs' endothelial corneal dystrophy.</strong>
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Invest. Ophthal. Vis. Sci. 56: 2003-2011, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25722209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25722209</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25722209[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=25722209" 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/10.1167/iovs.14-16222" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Riazuddin2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Riazuddin, S. A., McGlumphy, E. J., Yeo, W. S., Wang, J., Katsanis, N., Gottsch, J. D.
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<strong>Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus.</strong>
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Invest. Ophthal. Vis. Sci. 52: 2825-2829, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21245398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21245398</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21245398[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=21245398" 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/10.1167/iovs.10-6497" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Riazuddin2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Riazuddin, S. A., Zaghloul, N. A., Al-Saif, A., Davey, L., Diplas, B. H., Meadows, D. N., Eghrari, A. O., Minear, M. A., Li, Y.-J., Klintworth, G. K., Afshari, N., Gregory, S. G., Gottsch, J. D., Katsanis, N.
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<strong>Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p.</strong>
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Am. J. Hum. Genet. 86: 45-53, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20036349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20036349</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20036349[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=20036349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2009.12.001" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Soliman2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Soliman, A. Z., Xing, C., Radwan, S. H., Gong, X., Mootha, V. V.
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<strong>Correlation of severity of Fuchs endothelial corneal dystrophy with triplet repeat expansion in TCF4.</strong>
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JAMA Ophthal. 133: 1386-1391, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26401622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26401622</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26401622" 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/10.1001/jamaophthalmol.2015.3430" target="_blank">Full Text</a>]
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<li>
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<a id="10" class="mim-anchor"></a>
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<a id="Sundin2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sundin, O. H., Broman, K. W., Chang, H. H., Vito, E. C. L., Stark, W. J., Gottsch, J. D.
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<strong>A common locus for late-onset Fuchs corneal dystrophy maps to 18q21.2-q21.32.</strong>
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Invest. Ophthal. Vis. Sci. 47: 3919-3926, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16936105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16936105</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16936105" 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/10.1167/iovs.05-1619" target="_blank">Full Text</a>]
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</p>
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<a id="11" class="mim-anchor"></a>
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<a id="Wieben2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wieben, E. D., Aleff, R. A., Eckloff, B. W., Atkinson, E. J., Baheti, S., Middha, S., Brown, W. L., Patel, S. V., Kocher, J.-P. A., Baratz, K. H.
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<strong>Comprehensive assessment of genetic variants within TCF4 in Fuchs' endothelial corneal dystrophy.</strong>
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Invest. Ophthal. Vis. Sci. 55: 6101-6107, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25168903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25168903</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25168903[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=25168903" 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/10.1167/iovs.14-14958" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Wieben2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wieben, E. D., Aleff, R. A., Tosakulwong, N., Butz, M. L., Highsmith, W. E., Edwards, A. O., Baratz, K. H.
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<strong>A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy.</strong>
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PLoS One 7: e49083, 2012. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23185296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23185296</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23185296[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=23185296" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1371/journal.pone.0049083" target="_blank">Full Text</a>]
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</ol>
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<br />
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Jane Kelly - updated : 08/31/2016
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 7/21/2015<br>Marla J. F. O'Neill - updated : 4/25/2012<br>Jane Kelly - updated : 3/6/2012<br>Marla J. F. O'Neill - updated : 10/22/2010
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill : 2/22/2010
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/31/2016
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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carol : 07/27/2015<br>carol : 7/24/2015<br>mcolton : 7/21/2015<br>carol : 8/6/2014<br>carol : 1/7/2013<br>carol : 4/25/2012<br>terry : 4/25/2012<br>alopez : 3/6/2012<br>wwang : 10/26/2010<br>terry : 10/22/2010<br>carol : 2/23/2010
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<h3>
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<span class="mim-font">
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<strong>#</strong> 613267
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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CORNEAL DYSTROPHY, FUCHS ENDOTHELIAL, 3; FECD3
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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FCD2 LOCUS<br />
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CORNEAL DYSTROPHY, FUCHS ENDOTHELIAL, LATE-ONSET
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<p>
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<span class="mim-text-font">
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<strong>ORPHA:</strong> 98974;
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<strong>DO:</strong> 11555;
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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Location
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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<tbody>
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<td>
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<span class="mim-font">
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18q21.2
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</span>
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</td>
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<td>
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<span class="mim-font">
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Corneal dystrophy, Fuchs endothelial, 3
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</td>
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<td>
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<span class="mim-font">
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613267
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<td>
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<span class="mim-font">
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Autosomal dominant
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</td>
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<td>
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<span class="mim-font">
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3
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<td>
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<span class="mim-font">
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TCF4
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</td>
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<td>
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<span class="mim-font">
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602272
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that Fuchs endothelial corneal dystrophy-3 (FECD3) is caused by heterozygous intronic trinucleotide repeat expansion (CTG)n in the TCF4 gene (602272) on chromosome 18q21.</p>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Late-onset Fuchs endothelial corneal dystrophy (FECD) is a degenerative disorder affecting roughly 4% of the population older than 40 years. It is distinguished from other corneal disorders by the progressive formation of guttae, which are microscopic refractile excrescences of the Descemet membrane, a collagen-rich basal lamina secreted by the corneal endothelium. From onset, it usually takes 2 decades for FECD to impair endothelial cell function seriously, leading to stromal edema and impaired vision (Sundin et al., 2006). </p><p>For a discussion of genetic heterogeneity of Fuchs endothelial corneal dystrophy, see FECD1 (136800).</p>
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<br />
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</div>
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<h4>
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<span class="mim-font">
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<strong>Nomenclature</strong>
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<span class="mim-text-font">
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<p>The late-onset form of Fuchs endothelial corneal dystrophy mapping to chromosome 18q21.2-q21.32 is referred to in OMIM as FECD3. Some references in the literature (e.g., Riazuddin et al., 2010) have used the designation 'FCD2 locus' to refer to the genetic locus for FECD on chromosome 18. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>Sundin et al. (2006) performed linkage analysis in 43 affected and 33 unaffected individuals from 3 large late-onset FECD families and obtained the highest 2-point lod score for each family at D18S1129 on chromosome 18q21.2-q21.3 (3.41, 2.89, and 2.45, respectively), with a combined 2-point lod score of 7.70. Multipoint analysis yielded a maximum lod score of 5.94 at D18S1129 for a dominant mendelian trait exhibiting 85% penetrance and 15% phenocopy rate. The disease-associated haplotype of 1 of the kindreds defined a 7-Mb critical interval from D18S487 to D18S1134. Noting the incomplete penetrance and high phenocopy rate, Sundin et al. (2006) suggested that the origin of FECD in these 3 families was complex and might depend on other genetic loci or environmental factors. </p><p>Baratz et al. (2010) performed a genomewide association study in 130 patients with FECD and 260 age- and sex-matched controls and found association to a region on chromosome 18q spanning the gene encoding transcription factor-4 (TCF4; 602272), with replication in 150 independent patients. The most significant association was found with rs613872 in intron 3 of the TCF4 gene on 18q21.1 (combined p = 2.3 x 10(-26)). The odds of having FECD increased by a factor of 30 for persons with 2 copies of the disease variant and discriminated between cases and controls with about 76% accuracy. The authors noted that many SNPs across the TCF4 locus were associated with FECD, and stepwise regression analysis implicated 4 SNPs as being independently associated with FECD. Baratz et al. (2010) concluded that genetic variation across the TCF4 locus might explain the linkage signal with FECD previously observed on chromosome 18q21. </p><p>Riazuddin et al. (2011) examined the association of the TCF4 intronic variant rs613872 in their cohort of 170 patients with late-onset Fuchs corneal dystrophy and 180 age-matched controls. They found that the risk allele, G, of rs613872 was significantly associated with late-onset FECD (odds ratio, 4.2; p = 4.28 x 10(-15)) and was present in male and female affected persons without any sex bias, replicating the findings of Baratz et al. (2010), although no apparent correlation with the severity of the disease phenotype was found. Riazuddin et al. (2011) found that the risk allele did not cosegregate with the disease phenotype in any of the 3 FCD2-linked families. The authors also did not identify any pathogenic variants within the coding region of TCF4. Riazuddin et al. (2011) concluded that theirs was the first independent replication of rs613872 conferring risk of late-onset FECD, and stated that their data suggested that this risk factor was likely independent of the FCD2 locus, the causality of which remained undetermined. </p><p>Li et al. (2011) reported the findings of their independent validation study for TCF4 using the largest FECD dataset to that time (450 FECD cases; 340 normal controls). Li et al. (2011) found significant association with rs613872, the target marker reported by Baratz et al. (2010), for all 3 genetic models (dominant: p = 9.33 x 10(-35); additive: p = 7.48 x 10(-30); recessive: p = 5.27 x = 10(-6)). To strengthen the association study, Li et al. (2011) also conducted a genomewide linkage scan on 64 multiplex families, composed primarily of affected sib pairs, using both parametric and nonparametric 2-point and multipoint analyses. The most significant linkage region localized to chromosome 18 from 69.94 cM to 85.28 cM, with a peak multipoint hlod = 2.5 at rs1145315 (75.58 cM) under the dominant model, mapping 1.5 Mb proximal to rs613872. Li et al. (2011) concluded that their study presented evidence to support the role of the intronic TCF4 single-nucleotide polymorphism rs613872 in late-onset FECD through both association and linkage studies. </p><p>In a 3-stage discovery/replication/validation study involving 66 patients with severe FECD and 63 individuals with normal corneas, Wieben et al. (2012) tested for association between FECD and an intronic TCG repeat in the TCF4 gene (602272.0007), designated CTG18.1 by Breschel et al. (1997). Overall, 52 (79%) of 66 FECD patients had more than 50 TGC repeats and 13 (20%) had fewer than 40 repeats, compared to 2 (3%) and 60 (95%) of 63 controls, respectively. The sensitivity and specificity of more than 50 TGC repeats for identifying FECD was 79% and 96%, respectively; Wieben et al. (2012) noted that the expanded TGC repeat was more specific for FECD cases than the previously identified SNP rs613872. </p><p>In 120 Caucasian FECD probands and 100 controls, Mootha et al. (2014) tested the association between 2 intronic polymorphisms in the TCF4 gene, rs613872 and CTG18.1, and found that the 2 polymorphisms are in linkage disequilibrium. Significant associations were found between FECD and both the rs613872 polymorphism (p = 3.1 x 10(-17)) and the expanded CTG18.1 allele (p = 6.5 x 10(-25)), as well as their haplotypes (p = 5.9 x 10(-19)). The odds ratios of each copy of the rs613872 or the expanded CTG18.1 alleles for FECD were estimated to be 9.5 and 32.3, respectively. In a study of segregation of the CTG18.1 allele, the expansion was found in 24 of 29 FECD families; it segregated with disease in 18 families, but showed incomplete penetrance in 3. </p><p>To identify markers for FECD, Wieben et al. (2014) sequenced the TCF4 gene region in 68 patients with FECD and 16 unaffected individuals. TGC expansion of greater than 50 repeats was present in 46 (68%) of 68 FECD patients and 1 (6%) of 16 controls. No variant, including TGC expansion, correlated perfectly with disease status. Wieben et al. (2014) noted that even within some families, repeat expansions occurred in both affected and unaffected individuals, including individuals over age 70 with more than 80 TGC repeats who remained unaffected. However, they stated that the CTG18.1 intronic trinucleotide repeat expansion within TCF4 was a better predictor of disease than any other variant. </p>
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<strong>Molecular Genetics</strong>
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<p>Mootha et al. (2015) studied corneal endothelial tissue samples from 8 FECD patients carrying the TCF4 CTG18.1 repeat expansion (602272.0007), all of whom had greater than 5-mm diameter confluent guttae with edema (Krachmer scale grade 6). Abundant discrete, punctate nuclear CUG-repeat RNA foci, the hallmark of toxic RNA, were observed in endothelial samples from all 8 FECD patients with the CTG18.1 expansion; however, no RNA foci were seen in endothelium from 7 individuals without the CTG18.1 expansion, including 1 FECD patient, 1 patient with corneal edema without guttae, and 5 controls. Nuclear RNA foci were also detected in 2 control endothelial samples; subsequent genotyping revealed CTG18.1 repeat expansion in both samples, and cellular polymorphism and polymegethism were seen on specular microscopy of the corneal endothelium. Noting that there was no significant difference in TCF4 expression by quantitative PCR in FECD endothelial samples with CTG18.1 expansion compared to control endothelium, Mootha et al. (2015) concluded that rather than haploinsufficiency of TCF4, toxic RNA is the primary mechanism of disease in FECD with CTG18.1 triplet repeat expansion, mediated by CUG-repeat RNA foci. </p><p>Du et al. (2015) studied corneal endothelium and fibroblasts from FECD patients and controls and determined that the CTG-CAG trinucleotide repeat expansion is transcribed into a stable sense-strand RNA, which causes the formation of CUG RNA foci in the affected tissue. There was selective abundance of poly(CUG) RNA foci in FECD corneal endothelial cells compared to fibroblasts, suggesting that TCF4 poly(CUG) transcripts predominantly accumulate in the corneal endothelium, leading to FECD pathogenesis. The authors observed colocalization of CUG RNA foci with the mRNA-splicing factor MBNL1 (606516) in patient corneal endothelial cells; they also identified 342 genes with robust expression in the corneal endothelium that exhibited differential expression of at least 1 isoform in FECD patients with the expansion compared to patients without the expansion and controls. In addition, RT-PCR results for a splicing event known to be unresponsive to changes in MBNL1 showed no difference between FECD patients and controls. Du et al. (2015) concluded that expansion of the CTG-CAG repeat in the TCF4 gene contributes to FECD through a mechanism that involves sequestration of MBNL1 in RNA foci, similar to the mechanism underlying myotonic dystrophy-1 (DM1; 160900). </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of a possible role of variation in the LOXHD1 gene in Fuchs endothelial corneal dystrophy-3, see 613072.0003.</p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>In a study of 122 white index cases of FECD, Soliman et al. (2015) found that 85 (69.7%) harbored the TCF4 triplet repeat expansion. Patients with the triplet repeat expansion had a more severe form of FECD, with clinical and surgical implications. The mean (SD) Krachmer grade was 5.61 (0.76) in the group with the repeat expansion compared with 5.11 (1.05) in the group without the expanded repeats (p = .01. Forty-seven individuals with the repeat expansion (55.3%) had undergone keratoplasty at the time of study, compared with 13 (35.1%) of those without the expansion (p = .0497). There was a positive correlation of Krachmer grade to triplet repeat number (p = .0002)) and a nominal association of the keratoplasty proportion with triplet repeat number (p = .04). The mean (SD) central corneal thickness was 605.9 (50.5) micrometers in the group with the expanded repeats compared with 581.3 (50.5) micrometers in the group without the expansion (p = .04). </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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<strong>Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy.</strong>
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Mootha, V. V., Hussain, I., Cunnusamy, K., Graham, E., Gong, X., Neelam, S., Xing, C., Kittler, R., Petroll, W. M.
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<strong>TCF4 triplet repeat expansion and nuclear RNA foci in Fuchs' endothelial corneal dystrophy.</strong>
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Riazuddin, S. A., McGlumphy, E. J., Yeo, W. S., Wang, J., Katsanis, N., Gottsch, J. D.
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<strong>Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus.</strong>
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Riazuddin, S. A., Zaghloul, N. A., Al-Saif, A., Davey, L., Diplas, B. H., Meadows, D. N., Eghrari, A. O., Minear, M. A., Li, Y.-J., Klintworth, G. K., Afshari, N., Gregory, S. G., Gottsch, J. D., Katsanis, N.
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<strong>Missense mutations in TCF8 cause late-onset Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p.</strong>
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Am. J. Hum. Genet. 86: 45-53, 2010.
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Soliman, A. Z., Xing, C., Radwan, S. H., Gong, X., Mootha, V. V.
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Sundin, O. H., Broman, K. W., Chang, H. H., Vito, E. C. L., Stark, W. J., Gottsch, J. D.
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<strong>A common locus for late-onset Fuchs corneal dystrophy maps to 18q21.2-q21.32.</strong>
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Wieben, E. D., Aleff, R. A., Eckloff, B. W., Atkinson, E. J., Baheti, S., Middha, S., Brown, W. L., Patel, S. V., Kocher, J.-P. A., Baratz, K. H.
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<strong>Comprehensive assessment of genetic variants within TCF4 in Fuchs' endothelial corneal dystrophy.</strong>
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Wieben, E. D., Aleff, R. A., Tosakulwong, N., Butz, M. L., Highsmith, W. E., Edwards, A. O., Baratz, K. H.
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<strong>A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy.</strong>
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PLoS One 7: e49083, 2012. Note: Electronic Article.
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[PubMed: 23185296]
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[Full Text: https://doi.org/10.1371/journal.pone.0049083]
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Jane Kelly - updated : 08/31/2016<br>Marla J. F. O'Neill - updated : 7/21/2015<br>Marla J. F. O'Neill - updated : 4/25/2012<br>Jane Kelly - updated : 3/6/2012<br>Marla J. F. O'Neill - updated : 10/22/2010
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