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Entry
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- *614258 - POLYMERASE III, RNA, SUBUNIT A; POLR3A
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- OMIM
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<p>
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<span class="h4">*614258</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/614258">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000148606;t=ENST00000372371" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=11128" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=614258" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000148606;t=ENST00000372371" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_007055" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_007055" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=614258" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.proteinatlas.org/search/POLR3A" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/2460208,20159749,20159751,20159757,20159759,26996801,31417307,39725938,119575002,206729892,221043166" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/O14802" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=11128" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000148606;t=ENST00000372371" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=POLR3A" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=POLR3A" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+11128" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/POLR3A" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:11128" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/11128" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr10&hgg_gene=ENST00000372371.8&hgg_start=77975149&hgg_end=78029515&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:30074" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/polr3a" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=614258[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=614258[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/POLR3A/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000148606" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=POLR3A" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=POLR3A" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=POLR3A" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=POLR3A&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA134900426" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:30074" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0030687.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:2681836" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/POLR3A#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:2681836" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/11128/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=11128" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00004411;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050208-103" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:11128" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=POLR3A&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 238874008, 721846006<br />
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<strong>ICD10CM:</strong> G11.5<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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614258
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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POLYMERASE III, RNA, SUBUNIT A; POLR3A
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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RNA POLYMERASE III, SUBUNIT C1; RPC1<br />
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RNA POLYMERASE III, 155-KD SUBUNIT<br />
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RPC155
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=POLR3A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">POLR3A</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/10/327?start=-3&limit=10&highlight=327">10q22.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr10:77975149-78029515&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">10:77,975,149-78,029,515</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=607694,264090" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
|
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
|
<a href="/geneMap/10/327?start=-3&limit=10&highlight=327">
|
|
10q22.3
|
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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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Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism
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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/607694"> 607694 </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 recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
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Wiedemann-Rautenstrauch syndrome
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<a href="/entry/264090"> 264090 </a>
|
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|
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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 recessive">AR</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>
|
|
</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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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
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<p>POLR3A is the largest subunit of RNA polymerase III. RNA polymerase III is a DNA-directed RNA polymerase (<a href="https://enzyme.expasy.org/EC/2.7.7.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 2.7.7.6</a>) that transcribes genes encoding ribosomal 5S RNA (<a href="/entry/180420">180420</a>), tRNAs, U6 small nuclear RNA (see <a href="/entry/180692">180692</a>), mitochondrial RNA-processing RNA (RMRP; <a href="/entry/157660">157660</a>), H1 RNA (RPPH1; <a href="/entry/608513">608513</a>), Y RNAs (see <a href="/entry/601821">601821</a>), and 7SK RNA (RN7SK; <a href="/entry/606515">606515</a>) (summary by <a href="#18" class="mim-tip-reference" title="Sepehri, S., Hernandez, N. <strong>The largest subunit of human RNA polymerase III is closely related to the largest subunit of yeast and trypanosome RNA polymerase III.</strong> Genome Res. 7: 1006-1019, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9331371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9331371</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9331371[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/10.1101/gr.7.10.1006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9331371">Sepehri and Hernandez, 1997</a>). Pol III can also act as a DNA sensor and induces the expression of interferons (IFN) when stimulated by AT-rich DNA, which is present in certain viruses, including varicella zoster virus (VZV) and cytomegalovirus (CMV) (<a href="#13" class="mim-tip-reference" title="Ogunjimi, B., Zhang, S.-Y., Sorensen, K. B., Skipper, K. A., Carter-Timofte, M., Kerner, G., Luecke, S., Prabakaran, T., Cai, Y., Meester, J., Bartholomeus, E., Bolar, N. A., and 33 others. <strong>Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections.</strong> J. Clin. Invest. 127: 3543-3556, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28783042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28783042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28783042[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/10.1172/JCI92280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28783042">Ogunjimi et al., 2017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28783042+9331371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By PCR using primers based on sequences conserved in RNA polymerase III large subunits in lower organisms, followed by screening a human NTera2D1 teratocarcinoma cell cDNA library and 5-prime RACE of total HeLa cell RNA, <a href="#18" class="mim-tip-reference" title="Sepehri, S., Hernandez, N. <strong>The largest subunit of human RNA polymerase III is closely related to the largest subunit of yeast and trypanosome RNA polymerase III.</strong> Genome Res. 7: 1006-1019, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9331371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9331371</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9331371[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/10.1101/gr.7.10.1006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9331371">Sepehri and Hernandez (1997)</a> cloned POLR3A, which they called RPC155. The deduced 1,391-amino acid protein has a calculated molecular mass of 154.7 kD. It contains a zinc-binding domain, a helix-turn-helix motif, a magnesium-binding site, and 8 regions that are conserved in RNA polymerase large subunits. RPC155 shares 50% and 40% amino acid identity with the large subunits of S. cerevisiae and T. brucei RNA polymerase III, respectively, but it shares only 32% identity with the large subunit of human RNA polymerase II (POLR2A; <a href="/entry/180660">180660</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9331371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#7" class="mim-tip-reference" title="Hartz, P. A. <strong>Personal Communication.</strong> Baltimore, Md. 9/28/2011."None>Hartz (2011)</a> mapped the POLR3A gene to chromosome 10q22.3 based on an alignment of the POLR3A sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF021351" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF021351</a>) with the genomic sequence (GRCh37).</p>
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<p><a href="#18" class="mim-tip-reference" title="Sepehri, S., Hernandez, N. <strong>The largest subunit of human RNA polymerase III is closely related to the largest subunit of yeast and trypanosome RNA polymerase III.</strong> Genome Res. 7: 1006-1019, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9331371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9331371</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9331371[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/10.1101/gr.7.10.1006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9331371">Sepehri and Hernandez (1997)</a> found that in vitro transcribed and translated RPC115 showed significant RNA polymerase III activity in a nonspecific transcription assay. Depletion of RPC155 with neutralizing antibodies inhibited transcription from an RNA polymerase III promoter, but not from an RNA polymerase II promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9331371" 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>RNA polymerase II, which is responsible for protein-coding mRNA synthesis, binds many regions not actively transcribed owing to stalled polymerase activity, alternate transcription start sites, and regulated alternative splicing. However, by sequencing transcripts in mouse liver, <a href="#10" class="mim-tip-reference" title="Kutter, C., Brown, G. D., Goncalves, A., Wilson, M. D., Watt, S., Brazma, A., White, R. J., Odom, D. T. <strong>Pol III binding in six mammals shows conservation among amino acid isotypes despite divergence among tRNA genes.</strong> Nature Genet. 43: 948-955, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21873999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21873999</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21873999[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21873999">Kutter et al. (2011)</a> showed that every tRNA gene bound by RNA polymerase III was expressed. Conversely, few RNA transcripts aligned to predicted tRNA loci that were not bound by RNA polymerase III. Differential expression of tRNAs in mouse muscle, testis, and liver was determined by differential RNA polymerase III binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21873999" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Hypomyelinating Leukodystrophy 7 with or without Oligodontia and/or Hypogonadotropic Hypogonadism</em></strong></p><p>
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By narrowing the candidate disease locus followed by direct sequencing of genes in the refined 2.99-Mb interval in several families with hypomyelinating leukodystrophy-7 with or without oligodontia and/or hypogonadotropic hypogonadism (HLD7; <a href="/entry/607694">607694</a>), <a href="#4" class="mim-tip-reference" title="Bernard, G., Chouery, E., Putorti, M. L., Tetreault, M., Takanohashi, A., Carosso, G., Clement, I., Boespflug-Tanguy, O., Rodriguez, D., Delague, V., Abou Ghoch, J., Jalkh, N., Dorboz, I., Fribourg, S., Teichmann, M., Megarbane, A., Schiffmann, R., Vanderver, A., Brais, B. <strong>Mutations of POLR3A encoding a catalytic subunit of RNA polymerase pol III cause a recessive hypomyelinating leukodystrophy.</strong> Am. J. Hum. Genet. 89: 415-423, 2011. Note: Erratum: Am. J. Hum. Genet. 91: 972 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21855841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21855841</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21855841[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.2011.07.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21855841">Bernard et al. (2011)</a> identified 14 different mutations in the POLR3A gene (see, e.g., <a href="#0001">614258.0001</a>-<a href="#0005">614258.0005</a>). All mutations were in homozygous or compound heterozygous state, and no patient had 2 truncating mutations. There were 19 patients from 12 families, including those reported by <a href="#3" class="mim-tip-reference" title="Atrouni, S., Daraze, A., Tamraz, J., Cassia, A., Caillaud, C., Megarbane, A. <strong>Leukodystrophy associated with oligodontia in a large inbred family: fortuitous association or new entity?</strong> Am. J. Med. Genet. 118A: 76-81, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12605447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12605447</a>] [<a href="https://doi.org/10.1002/ajmg.a.10019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12605447">Atrouni et al. (2003)</a>, <a href="#19" class="mim-tip-reference" title="Timmons, M., Tsokos, M., Abu Asab, M., Seminara, S. B., Zirzow, G. C., Kaneski, C. R., Heiss, J. D., van der Knaap, M. S., Vanier, M. T., Schiffmann, R., Wong, K. <strong>Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia.</strong> Neurology 67: 2066-2069, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17159124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/01.wnl.0000247666.28904.35" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159124">Timmons et al. (2006)</a>, and <a href="#5" class="mim-tip-reference" title="Bernard, G., Thiffault, I., Tetreault, M., Putorti, M. L., Bouchard, I., Sylvain, M., Melancon, S., Laframboise, R., Langevin, P., Bouchard, J.-P., Vanasse, M., Vanderver, A., Sebire, G., Brais, B. <strong>Tremor-ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3-10q23.31.</strong> Neurogenetics 11: 457-464, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20640464/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20640464</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20640464[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/10.1007/s10048-010-0251-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20640464">Bernard et al. (2010)</a>. The mutations were spread throughout the gene, and there were no obvious genotype/phenotype correlations. Immunoblot analysis showed decreased levels of POLR3A protein in fibroblasts from 4 affected individuals, and decreased levels in the cortex and cerebral white matter of another patient, suggesting that loss of protein function is responsible for the disorder. <a href="#4" class="mim-tip-reference" title="Bernard, G., Chouery, E., Putorti, M. L., Tetreault, M., Takanohashi, A., Carosso, G., Clement, I., Boespflug-Tanguy, O., Rodriguez, D., Delague, V., Abou Ghoch, J., Jalkh, N., Dorboz, I., Fribourg, S., Teichmann, M., Megarbane, A., Schiffmann, R., Vanderver, A., Brais, B. <strong>Mutations of POLR3A encoding a catalytic subunit of RNA polymerase pol III cause a recessive hypomyelinating leukodystrophy.</strong> Am. J. Hum. Genet. 89: 415-423, 2011. Note: Erratum: Am. J. Hum. Genet. 91: 972 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21855841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21855841</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21855841[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.2011.07.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21855841">Bernard et al. (2011)</a> hypothesized that POLR3A mutations lead to dysregulation of RNA polymerase III and its targets, resulting in decreased expression of certain tRNAs during development and impaired protein synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17159124+20640464+12605447+21855841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Saitsu, H., Osaka, H., Sasaki, M., Takanashi, J., Hamada, K., Yamashita, A., Shibayama, H., Shiina, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Miyake, N., Doi, H., Ogata, K., Inoue, K., Matsumoto, N. <strong>Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.</strong> Am. J. Hum. Genet. 89: 644-651, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036171[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.2011.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036171">Saitsu et al. (2011)</a> reported a 17-year-old Japanese boy with HLD7 without oligodontia or hypogonadism caused by compound heterozygous mutations in the POLR3A gene (<a href="#0006">614258.0006</a> and <a href="#0007">614258.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036171" 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>Wiedemann-Rautenstrauch Syndrome</em></strong></p><p>
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In a female infant with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>), <a href="#8" class="mim-tip-reference" title="Jay, A. M., Conway, R. L., Thiffault, I., Saunders, C., Farrow, E., Adams, J., Toriello, H. V. <strong>Neonatal progeroid syndrome associated with biallelic truncating variants in POLR3A.</strong> Am. J. Med. Genet. 170A: 3343-3346, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27612211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27612211</a>] [<a href="https://doi.org/10.1002/ajmg.a.37960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27612211">Jay et al. (2016)</a> identified compound heterozygosity for a splice site (<a href="#0002">614258.0002</a>) and a nonsense mutation (R873X; <a href="#0008">614258.0008</a>) in the POLR3A gene. The mutations segregated with disease in the family and were not found in controls or public variant databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27612211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a> studied 15 patients from 12 families with WDRTS and identified compound heterozygous POLR3A variants in affected individuals from 8 families (see, e.g., <a href="#0002">614258.0002</a>, <a href="#0004">614258.0004</a>, and <a href="#0009">614258.0009</a>-<a href="#0016">614258.0016</a>). Monoallelic variants were detected in the 4 remaining patients, but lack of genetic material precluded further analyses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30323018" 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 7 unrelated patients with WDRTS, <a href="#20" class="mim-tip-reference" title="Wambach, J. A., Wegner, D. J., Patni, N., Kircher, M., Willing, M. C., Baldridge, D., Xing, C., Agarwal, A. K., Schrier Vergano, S. A., Patel, C., Grange, D. K., Kenney, A., Najaf, T., Nickerson, D. A., Bamshad, M. J., Cole, F. S., Garg, A. <strong>Bi-allelic POLR3A loss-of-function variants cause autosomal-recessive Wiedemann-Rautenstrauch syndrome.</strong> Am. J. Hum. Genet. 103: 968-975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30414627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30414627</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30414627[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.2018.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30414627">Wambach et al. (2018)</a> identified compound heterozygosity for mutations in the POLR3A gene (see, e.g., <a href="#0004">614258.0004</a>, <a href="#0010">614258.0010</a>, <a href="#0014">614258.0014</a>, <a href="#0015">614258.0015</a>, <a href="#0017">614258.0017</a>, and <a href="#0018">614258.0018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30414627" 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>Somatic Mutation</em></strong></p><p>
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In scleroderma (<a href="/entry/181750">181750</a>), patients make antibodies to a limited group of autoantigens, including RPC1, encoded by the POLR3A gene. As patients with scleroderma and antibodies against RPC1 are at increased risk for cancer, <a href="#9" class="mim-tip-reference" title="Joseph, C. G., Darrah, E., Shah, A. A., Skora, A. D., Casciola-Rosen, L. A., Wigley, F. M., Boin, F., Fava, A., Thoburn, C., Kinde, I., Jiao, Y., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., Rosen, A. <strong>Association of the autoimmune disease scleroderma with an immunologic response to cancer.</strong> Science 343: 152-157, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24310608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24310608</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24310608[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1246886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24310608">Joseph et al. (2014)</a> hypothesized that the 'foreign' antigens in this autoimmune disease are encoded by somatically mutated genes in the patients' incipient cancers. Studying cancers from scleroderma patients, <a href="#9" class="mim-tip-reference" title="Joseph, C. G., Darrah, E., Shah, A. A., Skora, A. D., Casciola-Rosen, L. A., Wigley, F. M., Boin, F., Fava, A., Thoburn, C., Kinde, I., Jiao, Y., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., Rosen, A. <strong>Association of the autoimmune disease scleroderma with an immunologic response to cancer.</strong> Science 343: 152-157, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24310608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24310608</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24310608[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1246886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24310608">Joseph et al. (2014)</a> found genetic alterations of the POLR3A locus in 6 of 8 patients with antibodies to RPC1, but not in 8 patients without antibodies to RPC1. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations triggered cellular immunity and cross-reactive humoral immune responses. <a href="#9" class="mim-tip-reference" title="Joseph, C. G., Darrah, E., Shah, A. A., Skora, A. D., Casciola-Rosen, L. A., Wigley, F. M., Boin, F., Fava, A., Thoburn, C., Kinde, I., Jiao, Y., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., Rosen, A. <strong>Association of the autoimmune disease scleroderma with an immunologic response to cancer.</strong> Science 343: 152-157, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24310608/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24310608</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24310608[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1246886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24310608">Joseph et al. (2014)</a> concluded that these results offered insight into the pathogenesis of scleroderma and provided support for the idea that acquired immunity helps to control naturally occurring cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24310608" 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>Susceptibility To Severe Varicella Infection</em></strong></p><p>
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In a 5-year-old Belgian boy (P2) with a severe varicella zoster virus (VZV) infection manifest as cerebellitis with ataxia and nystagmus, <a href="#13" class="mim-tip-reference" title="Ogunjimi, B., Zhang, S.-Y., Sorensen, K. B., Skipper, K. A., Carter-Timofte, M., Kerner, G., Luecke, S., Prabakaran, T., Cai, Y., Meester, J., Bartholomeus, E., Bolar, N. A., and 33 others. <strong>Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections.</strong> J. Clin. Invest. 127: 3543-3556, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28783042/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28783042</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28783042[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/10.1172/JCI92280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28783042">Ogunjimi et al. (2017)</a> identified a heterozygous missense variant (M307V) in the POLR3A gene. Two additional unrelated children with severe VZV manifest as pneumonitis (P3) and encephalitis (P4) were found to carry heterozygous missense variants in both the POLR3A and POLR3C (<a href="/entry/617454">617454</a>) genes, consistent with digenic inheritance. P3 carried a heterozygous Q707R variant in the POLR3A gene and an R438G variant in the POLR3C gene, and P4 carried an R437Q variant in the POLR3A gene and an R84Q variant in the POLR3C gene. Segregation studies were consistent with incomplete penetrance. Patient peripheral blood cells showed variably impaired interferon production when exposed to AT-rich DNA or VZV, as well as variably impaired control of VZV viral replication. The authors suggested that the variants may lead to functional defects in the Pol III DNA sensing system and impaired ability to convert AT-rich DNA into the immunostimulatory RNA pathogen-associated molecular pattern (PAMP). The patients were part of a cohort of 21 children with severe VZV infection who underwent whole-exome sequencing; the variants were confirmed by Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28783042" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=614258[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267608670 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608670;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267608670?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608670" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267608670" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 5 affected members of 3 French Canadian families with hypomyelinating leukodystrophy-7 (HLD7; <a href="/entry/607694">607694</a>), <a href="#4" class="mim-tip-reference" title="Bernard, G., Chouery, E., Putorti, M. L., Tetreault, M., Takanohashi, A., Carosso, G., Clement, I., Boespflug-Tanguy, O., Rodriguez, D., Delague, V., Abou Ghoch, J., Jalkh, N., Dorboz, I., Fribourg, S., Teichmann, M., Megarbane, A., Schiffmann, R., Vanderver, A., Brais, B. <strong>Mutations of POLR3A encoding a catalytic subunit of RNA polymerase pol III cause a recessive hypomyelinating leukodystrophy.</strong> Am. J. Hum. Genet. 89: 415-423, 2011. Note: Erratum: Am. J. Hum. Genet. 91: 972 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21855841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21855841</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21855841[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.2011.07.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21855841">Bernard et al. (2011)</a> identified a homozygous 2015G-A transition in the POLR3A gene, resulting in a gly672-to-glu (G672E) substitution. The mutation was not found in more than 250 control chromosomes. The families were originally reported by <a href="#5" class="mim-tip-reference" title="Bernard, G., Thiffault, I., Tetreault, M., Putorti, M. L., Bouchard, I., Sylvain, M., Melancon, S., Laframboise, R., Langevin, P., Bouchard, J.-P., Vanasse, M., Vanderver, A., Sebire, G., Brais, B. <strong>Tremor-ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3-10q23.31.</strong> Neurogenetics 11: 457-464, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20640464/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20640464</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20640464[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/10.1007/s10048-010-0251-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20640464">Bernard et al. (2010)</a> as having a disorder termed 'tremor-ataxia with central hypomyelination (TACH).' All had mild cognitive regression, upper motor neuron signs, tremor, and cerebellar signs. Two also had hypodontia, 2 others also had hypogonadotropic hypogonadism, and the fifth had neither of these additional features. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20640464+21855841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267608677 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608677;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267608677?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267608677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000024140 OR RCV000224081 OR RCV000754389" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024140, RCV000224081, RCV000754389" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024140...</a>
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<p>In affected members of a consanguineous Syrian family (family X) with hypomyelinating leukodystrophy-7 (HLD7; <a href="/entry/607694">607694</a>), originally reported by <a href="#3" class="mim-tip-reference" title="Atrouni, S., Daraze, A., Tamraz, J., Cassia, A., Caillaud, C., Megarbane, A. <strong>Leukodystrophy associated with oligodontia in a large inbred family: fortuitous association or new entity?</strong> Am. J. Med. Genet. 118A: 76-81, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12605447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12605447</a>] [<a href="https://doi.org/10.1002/ajmg.a.10019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12605447">Atrouni et al. (2003)</a>, <a href="#4" class="mim-tip-reference" title="Bernard, G., Chouery, E., Putorti, M. L., Tetreault, M., Takanohashi, A., Carosso, G., Clement, I., Boespflug-Tanguy, O., Rodriguez, D., Delague, V., Abou Ghoch, J., Jalkh, N., Dorboz, I., Fribourg, S., Teichmann, M., Megarbane, A., Schiffmann, R., Vanderver, A., Brais, B. <strong>Mutations of POLR3A encoding a catalytic subunit of RNA polymerase pol III cause a recessive hypomyelinating leukodystrophy.</strong> Am. J. Hum. Genet. 89: 415-423, 2011. Note: Erratum: Am. J. Hum. Genet. 91: 972 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21855841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21855841</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21855841[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.2011.07.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21855841">Bernard et al. (2011)</a> identified homozygosity for a c.2003+18G-A transition (c.2003+18G-A, NM_007055.3) in intron 14 of the POLR3A gene, resulting in the retention of 19 nucleotides from intron 14, the addition of 6 amino acids to the protein, and a premature stop codon at position 650 (referred to by the authors as Tyr637CysfsTer650). The mutation was not found in more than 250 control chromosomes. All had cognitive regression, upper motor neuron signs, cerebellar signs, and hypodontia, but none had hypogonadotropic hypogonadism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12605447+21855841" 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 female infant who died at age 7 months with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>), <a href="#8" class="mim-tip-reference" title="Jay, A. M., Conway, R. L., Thiffault, I., Saunders, C., Farrow, E., Adams, J., Toriello, H. V. <strong>Neonatal progeroid syndrome associated with biallelic truncating variants in POLR3A.</strong> Am. J. Med. Genet. 170A: 3343-3346, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27612211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27612211</a>] [<a href="https://doi.org/10.1002/ajmg.a.37960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27612211">Jay et al. (2016)</a> identified compound heterozygosity for a c.1909+18G-A mutation in intron 14 of the POLR3A gene, which was predicted to create a cryptic donor site, and a c.2617C-T transition in exon 20, resulting in an arg873-to-ter (R873X; <a href="#0008">614258.0008</a>) substitution. Her unaffected parents were each heterozygous for 1 of the mutations. The authors stated that the splice site mutation was not found in the Exome Variant Server or dbSNP databases, and the nonsense mutation was not reported in the ExAC database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27612211" 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 girl who died at age 10 years with WDRTS (WRS001), originally reported by <a href="#14" class="mim-tip-reference" title="Paolacci, S., Bertola, D., Franco, J., Mohammed, S., Tartaglia, M., Wollnik, B., Hennekam, R. C. <strong>Wiedemann-Rautenstrauch syndrome: a phenotype analysis.</strong> Am. J. Med. Genet. 173A: 1763-1772, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28447407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28447407</a>] [<a href="https://doi.org/10.1002/ajmg.a.38246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28447407">Paolacci et al. (2017)</a>, <a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a> identified compound heterozygosity for the c.1909+18G-A mutation (c.1909+18G-A, chr10.79769277, GRCh37) in POLR3A and a c.3206G-A transition, resulting in an arg1069-to-gln (R1069Q; <a href="#0009">614258.0009</a>) substitution at a highly conserved residue. The missense variant was present at very low frequency (0.002%) in the gnomAD database, whereas the splicing mutation was not found in gnomAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28447407+30323018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 LEUKODYSTROPHY, HYPOMYELINATING, 7, WITH OLIGODONTIA AND HYPOGONADOTROPIC HYPOGONADISM</strong>
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<p>In 4 patients from 2 unrelated families (families V and VIII) with hypomyelinating leukodystrophy with hypodontia and hypogonadotropic hypogonadism (HLD7; <a href="/entry/607694">607694</a>), originally reported by <a href="#19" class="mim-tip-reference" title="Timmons, M., Tsokos, M., Abu Asab, M., Seminara, S. B., Zirzow, G. C., Kaneski, C. R., Heiss, J. D., van der Knaap, M. S., Vanier, M. T., Schiffmann, R., Wong, K. <strong>Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia.</strong> Neurology 67: 2066-2069, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17159124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/01.wnl.0000247666.28904.35" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159124">Timmons et al. (2006)</a>, <a href="#4" class="mim-tip-reference" title="Bernard, G., Chouery, E., Putorti, M. L., Tetreault, M., Takanohashi, A., Carosso, G., Clement, I., Boespflug-Tanguy, O., Rodriguez, D., Delague, V., Abou Ghoch, J., Jalkh, N., Dorboz, I., Fribourg, S., Teichmann, M., Megarbane, A., Schiffmann, R., Vanderver, A., Brais, B. <strong>Mutations of POLR3A encoding a catalytic subunit of RNA polymerase pol III cause a recessive hypomyelinating leukodystrophy.</strong> Am. J. Hum. Genet. 89: 415-423, 2011. Note: Erratum: Am. J. Hum. Genet. 91: 972 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21855841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21855841</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21855841[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.2011.07.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21855841">Bernard et al. (2011)</a> identified compound heterozygosity for 2 mutations in the POLR3A gene: a c.2554A-G transition (c.2554A-G, NM_007055.3) resulting in a met852-to-val (M852V) substitution, and a G-to-A transition in intron 19 (c.2617-1G-A; <a href="#0004">614258.0004</a>), predicted to remove an acceptor site, lead to the use of a cryptic acceptor site located in exon 20, and cause a premature stop codon at position 878 (referred to by the authors as Arg873AlafsTer878). All had cognitive regression, abnormal eye movements, upper motor neuron signs, cerebellar signs, hypodontia, and hypogonadotropic hypogonadism. <a href="#4" class="mim-tip-reference" title="Bernard, G., Chouery, E., Putorti, M. L., Tetreault, M., Takanohashi, A., Carosso, G., Clement, I., Boespflug-Tanguy, O., Rodriguez, D., Delague, V., Abou Ghoch, J., Jalkh, N., Dorboz, I., Fribourg, S., Teichmann, M., Megarbane, A., Schiffmann, R., Vanderver, A., Brais, B. <strong>Mutations of POLR3A encoding a catalytic subunit of RNA polymerase pol III cause a recessive hypomyelinating leukodystrophy.</strong> Am. J. Hum. Genet. 89: 415-423, 2011. Note: Erratum: Am. J. Hum. Genet. 91: 972 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21855841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21855841</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21855841[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.2011.07.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21855841">Bernard et al. (2011)</a> also found that a patient (individual 18 of family XI) with leukodystrophy and oligodontia was compound heterozygous for M852V and a 418C-T transition in the POLR3A gene, resulting in an arg140-to-ter (R140X; <a href="#0005">614258.0005</a>) substitution. None of the mutations was found in more than 250 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17159124+21855841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs181087667 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs181087667;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs181087667?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs181087667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs181087667" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the splice site mutation in the POLR3A gene (c.2617-1G-A, NM_007055.3), predicted to result in use of a cryptic acceptor site and premature termination (Arg873AlafsTer878), that was found in compound heterozygous state in patients with hypomyelinating leukodystrophy with hypodontia and hypogonadotropic hypogonadism (HLD7; <a href="/entry/607964">607964</a>) by <a href="#4" class="mim-tip-reference" title="Bernard, G., Chouery, E., Putorti, M. L., Tetreault, M., Takanohashi, A., Carosso, G., Clement, I., Boespflug-Tanguy, O., Rodriguez, D., Delague, V., Abou Ghoch, J., Jalkh, N., Dorboz, I., Fribourg, S., Teichmann, M., Megarbane, A., Schiffmann, R., Vanderver, A., Brais, B. <strong>Mutations of POLR3A encoding a catalytic subunit of RNA polymerase pol III cause a recessive hypomyelinating leukodystrophy.</strong> Am. J. Hum. Genet. 89: 415-423, 2011. Note: Erratum: Am. J. Hum. Genet. 91: 972 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21855841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21855841</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21855841[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.2011.07.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21855841">Bernard et al. (2011)</a>, see <a href="#0003">614258.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21855841" 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 discussion of the c.2617-1G-A splice site mutation (c.2617-1G-A, chr10.79753126) in the POLR3A gene, which was also found in compound heterozygous state in a 21-year-old woman (WRS005) with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>) by <a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a>, see <a href="#0010">614258.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30323018" 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 discussion of the c.2617-1G-A splice site mutation (c.2617-1G-A, NM_007055.3) in POLR3A, which was found in compound heterozygosity in a 21-year-old woman (subject 6) with WDRTS by <a href="#20" class="mim-tip-reference" title="Wambach, J. A., Wegner, D. J., Patni, N., Kircher, M., Willing, M. C., Baldridge, D., Xing, C., Agarwal, A. K., Schrier Vergano, S. A., Patel, C., Grange, D. K., Kenney, A., Najaf, T., Nickerson, D. A., Bamshad, M. J., Cole, F. S., Garg, A. <strong>Bi-allelic POLR3A loss-of-function variants cause autosomal-recessive Wiedemann-Rautenstrauch syndrome.</strong> Am. J. Hum. Genet. 103: 968-975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30414627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30414627</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30414627[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.2018.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30414627">Wambach et al. (2018)</a>, see <a href="#0010">614258.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30414627" 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>For discussion of the arg140-to-ter (R140X) mutation in the POLR3A gene, resulting from a c.418C-T transition (c.418C-T, NM_007055.3) that was found in compound heterozygous state in a patient with leukodystrophy and oligodontia (HLD7; <a href="/entry/607964">607964</a>) by <a href="#4" class="mim-tip-reference" title="Bernard, G., Chouery, E., Putorti, M. L., Tetreault, M., Takanohashi, A., Carosso, G., Clement, I., Boespflug-Tanguy, O., Rodriguez, D., Delague, V., Abou Ghoch, J., Jalkh, N., Dorboz, I., Fribourg, S., Teichmann, M., Megarbane, A., Schiffmann, R., Vanderver, A., Brais, B. <strong>Mutations of POLR3A encoding a catalytic subunit of RNA polymerase pol III cause a recessive hypomyelinating leukodystrophy.</strong> Am. J. Hum. Genet. 89: 415-423, 2011. Note: Erratum: Am. J. Hum. Genet. 91: 972 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21855841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21855841</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21855841[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.2011.07.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21855841">Bernard et al. (2011)</a>, see <a href="#0003">614258.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21855841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 LEUKODYSTROPHY, HYPOMYELINATING, 7, WITHOUT OLIGODONTIA OR HYPOGONADOTROPIC HYPOGONADISM</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267608681 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608681;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267608681" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 17-year-old Japanese boy (individual 4) with hypomyelinating leukodystrophy-7 (HLD7; <a href="/entry/607694">607694</a>), <a href="#17" class="mim-tip-reference" title="Saitsu, H., Osaka, H., Sasaki, M., Takanashi, J., Hamada, K., Yamashita, A., Shibayama, H., Shiina, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Miyake, N., Doi, H., Ogata, K., Inoue, K., Matsumoto, N. <strong>Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.</strong> Am. J. Hum. Genet. 89: 644-651, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036171[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.2011.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036171">Saitsu et al. (2011)</a> identified compound heterozygosity for 2 mutations in the POLR3A gene: a paternally inherited c.2690T-A transversion (c.2690T-A, NM_007055.3) in exon 20, resulting in an ile897-to-asn (I897N) substitution, and a maternally inherited c.3013C-T transition in exon 23, resulting in an arg1005-to-cys (R1005C; <a href="#0007">614258.0007</a>) substitution. Structural modeling using the homologous yeast pol II subunit suggested that the mutations would disturb subunit interaction, leading to loss of pol III function. Neither mutation was found in 540 Japanese control chromosomes. The patient showed normal development until age 4, when mild tremors were noted. He later developed cerebellar signs, including expressive ataxic speech, intention tremor, poor finger-to-nose test, dysdiadochokinesis, dysmetria, and wide-based ataxic gait. He also showed intellectual disability with an IQ of 57. Other features included severe myopia and unilateral sensorineural deafness. The motor deterioration was progressive, and he became wheelchair-bound around age 14 years. Brain MRI showed a hypoplastic corpus callosum, cerebellar atrophy, and white matter lesions in the basal ganglia. He did not have hypodontia or hypogonadism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 LEUKODYSTROPHY, HYPOMYELINATING, 7, WITHOUT OLIGODONTIA OR HYPOGONADOTROPIC HYPOGONADISM</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267608682 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608682;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267608682?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267608682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267608682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000024145 OR RCV001824118 OR RCV001852565 OR RCV003488349" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000024145, RCV001824118, RCV001852565, RCV003488349" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000024145...</a>
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<p>For discussion of the arg1005-to-cys (R1005C) mutation in the POLR3A gene, resulting from a c.3013C-T transition (c.3013C-T, NM_007055.3) that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-7 (HLD7; <a href="/entry/607694">607694</a>) by <a href="#17" class="mim-tip-reference" title="Saitsu, H., Osaka, H., Sasaki, M., Takanashi, J., Hamada, K., Yamashita, A., Shibayama, H., Shiina, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Miyake, N., Doi, H., Ogata, K., Inoue, K., Matsumoto, N. <strong>Mutations in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.</strong> Am. J. Hum. Genet. 89: 644-651, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22036171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22036171</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22036171[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.2011.10.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22036171">Saitsu et al. (2011)</a>, see <a href="#0006">614258.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22036171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs148932047 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs148932047;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs148932047?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs148932047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs148932047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000224488 OR RCV000755662 OR RCV002516224 OR RCV004532823" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000224488, RCV000755662, RCV002516224, RCV004532823" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000224488...</a>
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<p>For discussion of the c.2617C-T transition in exon 20 of the POLR3A gene, resulting in an arg873-to-ter (R873X) substitution, that was found in compound heterozygous state in a female infant with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>) by <a href="#8" class="mim-tip-reference" title="Jay, A. M., Conway, R. L., Thiffault, I., Saunders, C., Farrow, E., Adams, J., Toriello, H. V. <strong>Neonatal progeroid syndrome associated with biallelic truncating variants in POLR3A.</strong> Am. J. Med. Genet. 170A: 3343-3346, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27612211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27612211</a>] [<a href="https://doi.org/10.1002/ajmg.a.37960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27612211">Jay et al. (2016)</a>, see <a href="#0002">614258.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27612211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs778985686 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs778985686;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs778985686?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs778985686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs778985686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the c.3206G-A transition (c.3206G-A, chr10.79744964, GRCh37) in the POLR3A gene, resulting in an arg1069-to-gln (R1069Q) substitution, that was found in compound heterozygous state in a patient with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>) by <a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a>, see <a href="#0002">614258.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30323018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1564613755 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1564613755;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1564613755" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1564613755" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs191875469 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs191875469;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs191875469?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs191875469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs191875469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000514925 OR RCV000754381 OR RCV000754390 OR RCV000755664 OR RCV000988394 OR RCV001249723 OR RCV001814996 OR RCV002448556 OR RCV002506245 OR RCV002528232 OR RCV003313969 OR RCV003403205 OR RCV003736873 OR RCV003993993 OR RCV004698500" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000514925, RCV000754381, RCV000754390, RCV000755664, RCV000988394, RCV001249723, RCV001814996, RCV002448556, RCV002506245, RCV002528232, RCV003313969, RCV003403205, RCV003736873, RCV003993993, RCV004698500" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000514925...</a>
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<p>In 6 patients from 4 unrelated families with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>), <a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a> identified compound heterozygosity for 2 intronic variants, c.1909+22G-A (c.1909+22G-A, chr10.79769273, GRCh37) and c.3337-11T-C (c.3337-11T-C, chr10.79743781, GRCh37), on 1 allele of the POLR3A gene, and another mutation in POLR3A on the other allele. The patients comprised 1 (WRS002) of 2 sisters originally described by <a href="#16" class="mim-tip-reference" title="Rautenstrauch, T., Snigula, F., Krieg, T., Gay, S., Muller, P. K. <strong>Progeria: a cell culture study and clinical report of familial incidence.</strong> Europ. J. Pediat. 124: 101-111, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/319005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">319005</a>] [<a href="https://doi.org/10.1007/BF00477545" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="319005">Rautenstrauch et al. (1977)</a> (patient 'GM'), a 27-year-old Palestinian man and his 2 sibs (WRS004) who were reported by <a href="#1" class="mim-tip-reference" title="Akawi, N., Ali, B., Al Gazali, L. <strong>A progeroid syndrome with neonatal presentation and long survival maps to 19p13.3p13.2.</strong> Birth Defects Res. A Clin. Molec. Teratol. 97: 456-462, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23696134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23696134</a>] [<a href="https://doi.org/10.1002/bdra.23136" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23696134">Akawi et al. (2013)</a>, a 21-year-old woman (WRS005) previously reported by <a href="#14" class="mim-tip-reference" title="Paolacci, S., Bertola, D., Franco, J., Mohammed, S., Tartaglia, M., Wollnik, B., Hennekam, R. C. <strong>Wiedemann-Rautenstrauch syndrome: a phenotype analysis.</strong> Am. J. Med. Genet. 173A: 1763-1772, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28447407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28447407</a>] [<a href="https://doi.org/10.1002/ajmg.a.38246" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28447407">Paolacci et al. (2017)</a>, and a German patient (WRS003). Analysis of RNA from patients WRS002 and WRS004 demonstrated that the c.1909+22G-A variant had a mild effect on exon 14 splicing, causing skipping of that exon and a frameshift resulting in a premature termination codon (Pro591MetfsTer9), whereas the c.3337-11T-C variant caused skipping of exon 26, resulting in an in-frame deletion (I1113_E1143del). In patient WRS002, the second mutation was another splice site mutation (c.1048+5G-T; <a href="#0011">614258.0011</a>) in intron 7 of the POLR3A gene, causing insertion of 177 bp of intronic sequence predicted to result in a frameshift and premature termination codon (Arg353ProfsTer24). The variant was present at very low frequency (0.0004%) in the gnomAD database. In the German patient (WRS003), the second mutation was a c.2474C-G transversion in the POLR3A gene, resulting in a ser825-to-ter (S825X; <a href="#0012">614258.0012</a>) substitution that was not found in the gnomAD database. In the 3 Palestinian sibs (WRS004), the second mutation was a c.1800C-T transition (<a href="#0013">614258.0013</a>) within exon 14 of the POLR3A gene, a synonymous change that caused skipping of exon 14 with a frameshift resulting in a premature termination codon (Pro591MetfsTer9); this variant was not found in the gnomAD database. cDNA analysis showed a strong additive effect on splicing by the c.1800C-T and c.1909+22G-A mutations together, with increased skipping of exon 14 compared to c.1909+22G-A alone. In patient WRS005, the second mutation was another splice site mutation (c.2617-1G-A; <a href="#0004">614258.0004</a>), present at very low frequency (0.002%) in the gnomAD database. <a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a> noted that the Palestinian sibs' apparently unaffected father was homozygous for the mutant allele carrying the c.1909+22G-A and c.3337-11T-C variants, indicating that this allele does not cause a phenotype in homozygous state; the authors suggested that a specific mutation signature indicated by the combination of compound heterozygous mutations in POLR3A is necessary to cause WDRTS. In addition, the authors stated that the c.1909+22G-A mutation represents a relatively common variant, present at a minor allele frequency of 0.1% in the gnomAD database, and noted that it previously had been reported without the presence of the c.3337-11T-C variant on the same allele in patients with leukodystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23696134+28447407+30323018+319005" 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 20-year-old woman (subject 2) with WDRTS who was originally studied by <a href="#6" class="mim-tip-reference" title="Garg, A., Kircher, M., del Campo, M., Amato, R. S., Agarwal, A. K., University of Washington Center for Mendelian Genomics. <strong>Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome.</strong> Am. J. Med. Genet. 167A: 1796-1806, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25898808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25898808</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25898808[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.37115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25898808">Garg et al. (2015)</a> (patient NLD 1300.4), and an unrelated 21-year-old woman (subject 6) with WDRTS, <a href="#20" class="mim-tip-reference" title="Wambach, J. A., Wegner, D. J., Patni, N., Kircher, M., Willing, M. C., Baldridge, D., Xing, C., Agarwal, A. K., Schrier Vergano, S. A., Patel, C., Grange, D. K., Kenney, A., Najaf, T., Nickerson, D. A., Bamshad, M. J., Cole, F. S., Garg, A. <strong>Bi-allelic POLR3A loss-of-function variants cause autosomal-recessive Wiedemann-Rautenstrauch syndrome.</strong> Am. J. Hum. Genet. 103: 968-975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30414627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30414627</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30414627[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.2018.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30414627">Wambach et al. (2018)</a> reported compound heterozygosity for the c.3337-11T-C mutation (c.3337-11T-C, NM_007055.3) and another mutation in POLR3A: in subject 6, the second mutation was a splice site mutation (c.2617-1G-A; <a href="#0004">614258.0004</a>), and in subject 2, it was a c.2005C-T transition, resulting in an arg669-to-ter (R669X; <a href="#0017">614258.0017</a>) substitution. Analysis of RNA from subject 2 demonstrated that the c.3337-11T-C mutation caused skipping of exon 26; however, in contrast to the findings of <a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a>, <a href="#20" class="mim-tip-reference" title="Wambach, J. A., Wegner, D. J., Patni, N., Kircher, M., Willing, M. C., Baldridge, D., Xing, C., Agarwal, A. K., Schrier Vergano, S. A., Patel, C., Grange, D. K., Kenney, A., Najaf, T., Nickerson, D. A., Bamshad, M. J., Cole, F. S., Garg, A. <strong>Bi-allelic POLR3A loss-of-function variants cause autosomal-recessive Wiedemann-Rautenstrauch syndrome.</strong> Am. J. Hum. Genet. 103: 968-975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30414627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30414627</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30414627[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.2018.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30414627">Wambach et al. (2018)</a> found that the c.1909+22G-A variant (c.1909+22G-A, NM_007055.3) did not result in exon skipping. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30414627+30323018+25898808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs890755853 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs890755853;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs890755853?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs890755853" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs890755853" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000754382 OR RCV003485627" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000754382, RCV003485627" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000754382...</a>
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<p>For discussion of the splicing mutation (c.1048+5G-T, chr10.79781613, GRCh37) in intron 7 of the POLR3A gene, causing insertion of 177 bp of intronic sequence predicted to result in a frameshift and premature termination codon (Arg353ProfsTer24), that was found in compound heterozygous state in a female patient (WRS002) with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>) by <a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a>, see <a href="#0010">614258.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30323018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1564617848 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1564617848;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1564617848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1564617848" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000754383 OR RCV004800512" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000754383, RCV004800512" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000754383...</a>
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<p>For discussion of the c.2474C-G transversion (c.2474C-G, chr10.79760738, GRCh37) in the POLR3A gene, resulting in a ser825-to-ter (S825X) substitution, that was found in compound heterozygous state in a German patient (WRS003) with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>) by <a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a>, see <a href="#0010">614258.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30323018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1564620047 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1564620047;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1564620047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1564620047" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000754384" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000754384" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000754384</a>
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<p>For discussion of the c.1800C-T transition (c.1800C-T, chr10.79769404, GRCh37) in exon 14 of the POLR3A gene, resulting in a synonymous change (I600I) but shown to alter splicing and cause skipping of exon 14 with a frameshift resulting in a premature termination codon (Pro591MetfsTer9), that was found in compound heterozygous state in 3 Palestinian sibs (WRS004) with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>) by <a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a>, see <a href="#0010">614258.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30323018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1248039821 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1248039821;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1248039821?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1248039821" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1248039821" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000754386 OR RCV003488779" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000754386, RCV003488779" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000754386...</a>
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<p>In 2 unrelated patients (WRS008 and WRS009) from Colombia with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>), <a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a> identified a c.Ter18C-T transition (c.Ter18C-T, chr10.79737218, GRCh37) in the POLR3A gene in compound heterozygosity with 2 different mutations. Patient WRS008, a male infant reported by <a href="#12" class="mim-tip-reference" title="Morales, L. C., Arboleda, G., Rodriguez, Y., Forero, D. A., Ramirez, N., Yunis, J. J., Arboleda, H. <strong>Absence of lamin A/C gene mutations in four Wiedemann-Rautenstrauch syndrome patients.</strong> Am. J. Med. Genet. 149A: 2695-2699, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19938095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19938095</a>] [<a href="https://doi.org/10.1002/ajmg.a.33090" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19938095">Morales et al. (2009)</a> as patient WRS2 and who died at 1 day of life, additionally carried a c.4003G-A transition, resulting in a gly1335-to-arg (G1335R; <a href="#0016">614258.0016</a>) substitution at a highly conserved residue. Patient WRS009, a 22-year-old man reported by <a href="#2" class="mim-tip-reference" title="Arboleda, H., Arboleda, G. <strong>Follow-up study of Wiedemann-Rautenstrauch syndrome: long-term survival and comparison with Rautenstrauch's patient 'G'.</strong> Birth Defects Res. A Clin. Molec. Teratol. 73: 562-568, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16007586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16007586</a>] [<a href="https://doi.org/10.1002/bdra.20166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16007586">Arboleda and Arboleda (2005)</a>, additionally carried a c.3G-T transversion (<a href="#0015">614258.0015</a>), the effect of which on the protein was described by <a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a> as M1?. All 3 variants were present at very low frequency (0.0004%) in the gnomAD database. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19938095+30323018+16007586" 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 5-year-old boy (subject 7) with WDRTS, <a href="#20" class="mim-tip-reference" title="Wambach, J. A., Wegner, D. J., Patni, N., Kircher, M., Willing, M. C., Baldridge, D., Xing, C., Agarwal, A. K., Schrier Vergano, S. A., Patel, C., Grange, D. K., Kenney, A., Najaf, T., Nickerson, D. A., Bamshad, M. J., Cole, F. S., Garg, A. <strong>Bi-allelic POLR3A loss-of-function variants cause autosomal-recessive Wiedemann-Rautenstrauch syndrome.</strong> Am. J. Hum. Genet. 103: 968-975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30414627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30414627</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30414627[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.2018.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30414627">Wambach et al. (2018)</a> identified compound heterozygosity for the same 2 mutations identified in a 22-year-old Colombian man with WDRTS by <a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a>. <a href="#20" class="mim-tip-reference" title="Wambach, J. A., Wegner, D. J., Patni, N., Kircher, M., Willing, M. C., Baldridge, D., Xing, C., Agarwal, A. K., Schrier Vergano, S. A., Patel, C., Grange, D. K., Kenney, A., Najaf, T., Nickerson, D. A., Bamshad, M. J., Cole, F. S., Garg, A. <strong>Bi-allelic POLR3A loss-of-function variants cause autosomal-recessive Wiedemann-Rautenstrauch syndrome.</strong> Am. J. Hum. Genet. 103: 968-975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30414627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30414627</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30414627[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.2018.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30414627">Wambach et al. (2018)</a> described the effect of the initiation codon mutation on the protein as M1X. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30414627+30323018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1168641193 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1168641193;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1168641193?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1168641193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1168641193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000754387 OR RCV003485628" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000754387, RCV003485628" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000754387...</a>
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<p>For discussion of the c.3G-T transversion (c.3G-T, NM_007055.3) in the POLR3A gene, resulting in a Met1-to-? (M1?) substitution, that was found in compound heterozygous state in patients with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>) by <a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a> and <a href="#20" class="mim-tip-reference" title="Wambach, J. A., Wegner, D. J., Patni, N., Kircher, M., Willing, M. C., Baldridge, D., Xing, C., Agarwal, A. K., Schrier Vergano, S. A., Patel, C., Grange, D. K., Kenney, A., Najaf, T., Nickerson, D. A., Bamshad, M. J., Cole, F. S., Garg, A. <strong>Bi-allelic POLR3A loss-of-function variants cause autosomal-recessive Wiedemann-Rautenstrauch syndrome.</strong> Am. J. Hum. Genet. 103: 968-975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30414627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30414627</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30414627[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.2018.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30414627">Wambach et al. (2018)</a>, see <a href="#0014">614258.0014</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30414627+30323018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an 11-month-old girl with WDRTS (patient 11), <a href="#11" class="mim-tip-reference" title="Lessel, D., Ozel, A. B., Campbell, S. E., Saadi, A., Arlt, M. F., McSweeney, K. M., Plaiasu, V., Szakszon, K., Szollos, A., Rusu, C., Rojas, A. J., Lopez-Valdez, J., Thiele, H., Nurnberg, P., Nickerson, D. A., Bamshad, M. J., Li, J. Z., Kubisch, C., Glover, T. W., Gordon, L. B. <strong>Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations.</strong> Hum. Genet. 137: 921-939, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30450527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30450527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30450527[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/10.1007/s00439-018-1957-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30450527">Lessel et al. (2018)</a> identified heterozygosity for the c.3G-T (M1I) mutation. Although a second mutation was not detected, the authors suggested that it might be deeply intronic, a copy-number variant, balanced translocation, or possibly involve a regulatory region of POLR3A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30450527" 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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POLR3A, GLY1335ARG (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs768222183;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs768222183</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs768222183 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs768222183;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs768222183?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs768222183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs768222183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000754392 OR RCV003488781" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000754392, RCV003488781" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000754392...</a>
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<p>For discussion of the c.4003G-A transition (c.4003G-A, chr10.79739920, GRCh37) in the POLR3A gene, resulting in a gly1335-to-arg (G1335R) substitution, that was found in compound heterozygous state in a male infant (WRS008) with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>) by <a href="#15" class="mim-tip-reference" title="Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others. <strong>Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.</strong> J. Med. Genet. 55: 837-846, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30323018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30323018</a>] [<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30323018">Paolacci et al. (2018)</a>, see <a href="#0014">614258.0014</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30323018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs774007232 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs774007232;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs774007232?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs774007232" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs774007232" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000755668 OR RCV000760689 OR RCV001542770" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000755668, RCV000760689, RCV001542770" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000755668...</a>
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<p>For discussion of the c.2005C-T transition (c.2005C-T, NM_007055.3) in the POLR3A gene, resulting in an arg669-to-ter (R669X) substitution, that was found in compound heterozygous state in a 20-year-old woman (subject 2) with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>) by <a href="#20" class="mim-tip-reference" title="Wambach, J. A., Wegner, D. J., Patni, N., Kircher, M., Willing, M. C., Baldridge, D., Xing, C., Agarwal, A. K., Schrier Vergano, S. A., Patel, C., Grange, D. K., Kenney, A., Najaf, T., Nickerson, D. A., Bamshad, M. J., Cole, F. S., Garg, A. <strong>Bi-allelic POLR3A loss-of-function variants cause autosomal-recessive Wiedemann-Rautenstrauch syndrome.</strong> Am. J. Hum. Genet. 103: 968-975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30414627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30414627</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30414627[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.2018.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30414627">Wambach et al. (2018)</a>, see <a href="#0010">614258.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30414627" 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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POLR3A, IVS25, T-A, -5 (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs368905417;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs368905417</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs368905417 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs368905417;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs368905417?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs368905417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs368905417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000498819 OR RCV000755669 OR RCV001291254 OR RCV003488638" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000498819, RCV000755669, RCV001291254, RCV003488638" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000498819...</a>
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<p>In 4 unrelated children (subjects 1, 3, 4, and 5) with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>), including a 13-year-old girl (subject 3) previously studied by <a href="#6" class="mim-tip-reference" title="Garg, A., Kircher, M., del Campo, M., Amato, R. S., Agarwal, A. K., University of Washington Center for Mendelian Genomics. <strong>Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome.</strong> Am. J. Med. Genet. 167A: 1796-1806, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25898808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25898808</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25898808[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.37115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25898808">Garg et al. (2015)</a> as patient NLD 2200.4, <a href="#20" class="mim-tip-reference" title="Wambach, J. A., Wegner, D. J., Patni, N., Kircher, M., Willing, M. C., Baldridge, D., Xing, C., Agarwal, A. K., Schrier Vergano, S. A., Patel, C., Grange, D. K., Kenney, A., Najaf, T., Nickerson, D. A., Bamshad, M. J., Cole, F. S., Garg, A. <strong>Bi-allelic POLR3A loss-of-function variants cause autosomal-recessive Wiedemann-Rautenstrauch syndrome.</strong> Am. J. Hum. Genet. 103: 968-975, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30414627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30414627</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30414627[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.2018.10.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30414627">Wambach et al. (2018)</a> identified compound heterozygosity for a c.3337-5T-A transversion (c.3337-5T-A, NM_007055.3) in intron 25 of the POLR3A gene and another splice site or truncating mutation in POLR3A. The c.3337-5T-A variant was present in only 1 heterozygous individual in gnomAD (minor allele frequency, 0.000004), and analysis of RNA from subject 1 showed that the mutation causes in-frame skipping of exon 26 (Ile1113_Glu1143del). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30414627+25898808" 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 10-year-old boy (patient 1) and an unrelated 12.75-year-old girl (patient 4) with WDRTS, <a href="#11" class="mim-tip-reference" title="Lessel, D., Ozel, A. B., Campbell, S. E., Saadi, A., Arlt, M. F., McSweeney, K. M., Plaiasu, V., Szakszon, K., Szollos, A., Rusu, C., Rojas, A. J., Lopez-Valdez, J., Thiele, H., Nurnberg, P., Nickerson, D. A., Bamshad, M. J., Li, J. Z., Kubisch, C., Glover, T. W., Gordon, L. B. <strong>Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations.</strong> Hum. Genet. 137: 921-939, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30450527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30450527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30450527[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/10.1007/s00439-018-1957-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30450527">Lessel et al. (2018)</a> identified compound heterozygosity for the c.3337-5T-A splice site mutation and another mutation in the POLR3A gene: in the boy, the second mutation was a c.3337-1G-A variant (<a href="#0019">614258.0019</a>) in intron 25, predicted to abolish the splice acceptor site, whereas in the girl it was a c.760C-T transition, resulting in an arg254-to-ter (R254X; <a href="#0020">614258.0020</a>) substitution. All 3 variants were extremely rare in the dbSNP, 1000 Genomes, ExAC, and gnomAD databases, and were only present in heterozygous state in those databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30450527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1041175828 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1041175828;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1041175828" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1041175828" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the c.3337-1G-A transition in intron 25 of the POLR3A gene, predicted to abolish the splice acceptor site, that was found in compound heterozygosity in a 10-year-old boy (patient 1) with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>) by <a href="#11" class="mim-tip-reference" title="Lessel, D., Ozel, A. B., Campbell, S. E., Saadi, A., Arlt, M. F., McSweeney, K. M., Plaiasu, V., Szakszon, K., Szollos, A., Rusu, C., Rojas, A. J., Lopez-Valdez, J., Thiele, H., Nurnberg, P., Nickerson, D. A., Bamshad, M. J., Li, J. Z., Kubisch, C., Glover, T. W., Gordon, L. B. <strong>Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations.</strong> Hum. Genet. 137: 921-939, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30450527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30450527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30450527[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/10.1007/s00439-018-1957-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30450527">Lessel et al. (2018)</a>, see <a href="#0018">614258.0018</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30450527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs141659018 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs141659018;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs141659018?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs141659018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs141659018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000755671 OR RCV000994469 OR RCV001291256 OR RCV002507319 OR RCV002533777 OR RCV003330936" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000755671, RCV000994469, RCV001291256, RCV002507319, RCV002533777, RCV003330936" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000755671...</a>
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<p>For discussion of the c.760C-T transition in the POLR3A gene, resulting in an arg254-to-ter (R254X) substitution, that was found in compound heterozygosity in a 12.75-year-old girl (patient 4) with Wiedemann-Rautenstrauch syndrome (WDRTS; <a href="/entry/264090">264090</a>) by <a href="#11" class="mim-tip-reference" title="Lessel, D., Ozel, A. B., Campbell, S. E., Saadi, A., Arlt, M. F., McSweeney, K. M., Plaiasu, V., Szakszon, K., Szollos, A., Rusu, C., Rojas, A. J., Lopez-Valdez, J., Thiele, H., Nurnberg, P., Nickerson, D. A., Bamshad, M. J., Li, J. Z., Kubisch, C., Glover, T. W., Gordon, L. B. <strong>Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations.</strong> Hum. Genet. 137: 921-939, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30450527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30450527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30450527[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/10.1007/s00439-018-1957-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30450527">Lessel et al. (2018)</a>, see <a href="#0018">614258.0018</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30450527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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Akawi, N., Ali, B., Al Gazali, L.
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<strong>A progeroid syndrome with neonatal presentation and long survival maps to 19p13.3p13.2.</strong>
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Birth Defects Res. A Clin. Molec. Teratol. 97: 456-462, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23696134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23696134</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23696134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/bdra.23136" target="_blank">Full Text</a>]
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Arboleda, H., Arboleda, G.
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<strong>Follow-up study of Wiedemann-Rautenstrauch syndrome: long-term survival and comparison with Rautenstrauch's patient 'G'.</strong>
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Birth Defects Res. A Clin. Molec. Teratol. 73: 562-568, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16007586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16007586</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16007586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/bdra.20166" target="_blank">Full Text</a>]
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Atrouni, S., Daraze, A., Tamraz, J., Cassia, A., Caillaud, C., Megarbane, A.
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<strong>Leukodystrophy associated with oligodontia in a large inbred family: fortuitous association or new entity?</strong>
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Am. J. Med. Genet. 118A: 76-81, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12605447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12605447</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12605447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.10019" target="_blank">Full Text</a>]
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Bernard, G., Chouery, E., Putorti, M. L., Tetreault, M., Takanohashi, A., Carosso, G., Clement, I., Boespflug-Tanguy, O., Rodriguez, D., Delague, V., Abou Ghoch, J., Jalkh, N., Dorboz, I., Fribourg, S., Teichmann, M., Megarbane, A., Schiffmann, R., Vanderver, A., Brais, B.
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<strong>Mutations of POLR3A encoding a catalytic subunit of RNA polymerase pol III cause a recessive hypomyelinating leukodystrophy.</strong>
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Am. J. Hum. Genet. 89: 415-423, 2011. Note: Erratum: Am. J. Hum. Genet. 91: 972 only, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21855841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21855841</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21855841[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=21855841" 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.2011.07.014" target="_blank">Full Text</a>]
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Bernard, G., Thiffault, I., Tetreault, M., Putorti, M. L., Bouchard, I., Sylvain, M., Melancon, S., Laframboise, R., Langevin, P., Bouchard, J.-P., Vanasse, M., Vanderver, A., Sebire, G., Brais, B.
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<strong>Tremor-ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3-10q23.31.</strong>
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Neurogenetics 11: 457-464, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20640464/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20640464</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20640464[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=20640464" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-010-0251-8" target="_blank">Full Text</a>]
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Garg, A., Kircher, M., del Campo, M., Amato, R. S., Agarwal, A. K., University of Washington Center for Mendelian Genomics.
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<strong>Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome.</strong>
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Am. J. Med. Genet. 167A: 1796-1806, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25898808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25898808</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25898808[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=25898808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.37115" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.37960" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1246886" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng.906" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-018-1957-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.33090" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI92280" target="_blank">Full Text</a>]
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<a id="Paolacci2017" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1002/ajmg.a.38246" target="_blank">Full Text</a>]
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<a id="Paolacci2018" class="mim-anchor"></a>
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Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmuller, J., Arboleda, G., Beleggia, F., and 16 others.
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[<a href="https://doi.org/10.1136/jmedgenet-2018-105528" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00477545" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2011.10.003" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1101/gr.7.10.1006" target="_blank">Full Text</a>]
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Timmons, M., Tsokos, M., Abu Asab, M., Seminara, S. B., Zirzow, G. C., Kaneski, C. R., Heiss, J. D., van der Knaap, M. S., Vanier, M. T., Schiffmann, R., Wong, K.
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[<a href="https://doi.org/10.1212/01.wnl.0000247666.28904.35" target="_blank">Full Text</a>]
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Wambach, J. A., Wegner, D. J., Patni, N., Kircher, M., Willing, M. C., Baldridge, D., Xing, C., Agarwal, A. K., Schrier Vergano, S. A., Patel, C., Grange, D. K., Kenney, A., Najaf, T., Nickerson, D. A., Bamshad, M. J., Cole, F. S., Garg, A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30414627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30414627</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30414627[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=30414627" 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.2018.10.010" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 05/19/2022
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Marla J. F. O'Neill - updated : 02/13/2019<br>Ada Hamosh - updated : 3/27/2014<br>Cassandra L. Kniffin - updated : 12/7/2011<br>Patricia A. Hartz - updated : 11/9/2011<br>Cassandra L. Kniffin - updated : 10/3/2011
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Creation Date:
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Patricia A. Hartz : 9/29/2011
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alopez : 04/02/2024
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alopez : 05/24/2022<br>ckniffin : 05/19/2022<br>carol : 02/16/2019<br>carol : 02/15/2019<br>alopez : 02/14/2019<br>alopez : 02/13/2019<br>carol : 07/27/2015<br>mcolton : 7/22/2015<br>carol : 3/4/2015<br>alopez : 3/27/2014<br>carol : 10/1/2013<br>carol : 12/8/2011<br>ckniffin : 12/7/2011<br>mgross : 11/15/2011<br>terry : 11/9/2011<br>carol : 10/4/2011<br>ckniffin : 10/4/2011<br>carol : 10/3/2011<br>carol : 10/3/2011<br>ckniffin : 10/3/2011<br>mgross : 9/29/2011
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<span class="mim-font">
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<strong>*</strong> 614258
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<h3>
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POLYMERASE III, RNA, SUBUNIT A; POLR3A
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<em>Alternative titles; symbols</em>
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RNA POLYMERASE III, SUBUNIT C1; RPC1<br />
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RNA POLYMERASE III, 155-KD SUBUNIT<br />
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RPC155
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: POLR3A</em></strong>
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<strong>SNOMEDCT:</strong> 238874008, 721846006;
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<strong>ICD10CM:</strong> G11.5;
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Cytogenetic location: 10q22.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 10:77,975,149-78,029,515 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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10q22.3
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Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism
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<span class="mim-font">
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607694
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Autosomal recessive
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3
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Wiedemann-Rautenstrauch syndrome
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264090
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>POLR3A is the largest subunit of RNA polymerase III. RNA polymerase III is a DNA-directed RNA polymerase (EC 2.7.7.6) that transcribes genes encoding ribosomal 5S RNA (180420), tRNAs, U6 small nuclear RNA (see 180692), mitochondrial RNA-processing RNA (RMRP; 157660), H1 RNA (RPPH1; 608513), Y RNAs (see 601821), and 7SK RNA (RN7SK; 606515) (summary by Sepehri and Hernandez, 1997). Pol III can also act as a DNA sensor and induces the expression of interferons (IFN) when stimulated by AT-rich DNA, which is present in certain viruses, including varicella zoster virus (VZV) and cytomegalovirus (CMV) (Ogunjimi et al., 2017). </p>
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<strong>Cloning and Expression</strong>
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<span class="mim-text-font">
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<p>By PCR using primers based on sequences conserved in RNA polymerase III large subunits in lower organisms, followed by screening a human NTera2D1 teratocarcinoma cell cDNA library and 5-prime RACE of total HeLa cell RNA, Sepehri and Hernandez (1997) cloned POLR3A, which they called RPC155. The deduced 1,391-amino acid protein has a calculated molecular mass of 154.7 kD. It contains a zinc-binding domain, a helix-turn-helix motif, a magnesium-binding site, and 8 regions that are conserved in RNA polymerase large subunits. RPC155 shares 50% and 40% amino acid identity with the large subunits of S. cerevisiae and T. brucei RNA polymerase III, respectively, but it shares only 32% identity with the large subunit of human RNA polymerase II (POLR2A; 180660). </p>
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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>Hartz (2011) mapped the POLR3A gene to chromosome 10q22.3 based on an alignment of the POLR3A sequence (GenBank AF021351) with the genomic sequence (GRCh37).</p>
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p>Sepehri and Hernandez (1997) found that in vitro transcribed and translated RPC115 showed significant RNA polymerase III activity in a nonspecific transcription assay. Depletion of RPC155 with neutralizing antibodies inhibited transcription from an RNA polymerase III promoter, but not from an RNA polymerase II promoter. </p><p>RNA polymerase II, which is responsible for protein-coding mRNA synthesis, binds many regions not actively transcribed owing to stalled polymerase activity, alternate transcription start sites, and regulated alternative splicing. However, by sequencing transcripts in mouse liver, Kutter et al. (2011) showed that every tRNA gene bound by RNA polymerase III was expressed. Conversely, few RNA transcripts aligned to predicted tRNA loci that were not bound by RNA polymerase III. Differential expression of tRNAs in mouse muscle, testis, and liver was determined by differential RNA polymerase III binding. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p><strong><em>Hypomyelinating Leukodystrophy 7 with or without Oligodontia and/or Hypogonadotropic Hypogonadism</em></strong></p><p>
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By narrowing the candidate disease locus followed by direct sequencing of genes in the refined 2.99-Mb interval in several families with hypomyelinating leukodystrophy-7 with or without oligodontia and/or hypogonadotropic hypogonadism (HLD7; 607694), Bernard et al. (2011) identified 14 different mutations in the POLR3A gene (see, e.g., 614258.0001-614258.0005). All mutations were in homozygous or compound heterozygous state, and no patient had 2 truncating mutations. There were 19 patients from 12 families, including those reported by Atrouni et al. (2003), Timmons et al. (2006), and Bernard et al. (2010). The mutations were spread throughout the gene, and there were no obvious genotype/phenotype correlations. Immunoblot analysis showed decreased levels of POLR3A protein in fibroblasts from 4 affected individuals, and decreased levels in the cortex and cerebral white matter of another patient, suggesting that loss of protein function is responsible for the disorder. Bernard et al. (2011) hypothesized that POLR3A mutations lead to dysregulation of RNA polymerase III and its targets, resulting in decreased expression of certain tRNAs during development and impaired protein synthesis. </p><p>Saitsu et al. (2011) reported a 17-year-old Japanese boy with HLD7 without oligodontia or hypogonadism caused by compound heterozygous mutations in the POLR3A gene (614258.0006 and 614258.0007). </p><p><strong><em>Wiedemann-Rautenstrauch Syndrome</em></strong></p><p>
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In a female infant with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090), Jay et al. (2016) identified compound heterozygosity for a splice site (614258.0002) and a nonsense mutation (R873X; 614258.0008) in the POLR3A gene. The mutations segregated with disease in the family and were not found in controls or public variant databases. </p><p>Paolacci et al. (2018) studied 15 patients from 12 families with WDRTS and identified compound heterozygous POLR3A variants in affected individuals from 8 families (see, e.g., 614258.0002, 614258.0004, and 614258.0009-614258.0016). Monoallelic variants were detected in the 4 remaining patients, but lack of genetic material precluded further analyses. </p><p>In 7 unrelated patients with WDRTS, Wambach et al. (2018) identified compound heterozygosity for mutations in the POLR3A gene (see, e.g., 614258.0004, 614258.0010, 614258.0014, 614258.0015, 614258.0017, and 614258.0018). </p><p><strong><em>Somatic Mutation</em></strong></p><p>
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In scleroderma (181750), patients make antibodies to a limited group of autoantigens, including RPC1, encoded by the POLR3A gene. As patients with scleroderma and antibodies against RPC1 are at increased risk for cancer, Joseph et al. (2014) hypothesized that the 'foreign' antigens in this autoimmune disease are encoded by somatically mutated genes in the patients' incipient cancers. Studying cancers from scleroderma patients, Joseph et al. (2014) found genetic alterations of the POLR3A locus in 6 of 8 patients with antibodies to RPC1, but not in 8 patients without antibodies to RPC1. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations triggered cellular immunity and cross-reactive humoral immune responses. Joseph et al. (2014) concluded that these results offered insight into the pathogenesis of scleroderma and provided support for the idea that acquired immunity helps to control naturally occurring cancers. </p><p><strong><em>Susceptibility To Severe Varicella Infection</em></strong></p><p>
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In a 5-year-old Belgian boy (P2) with a severe varicella zoster virus (VZV) infection manifest as cerebellitis with ataxia and nystagmus, Ogunjimi et al. (2017) identified a heterozygous missense variant (M307V) in the POLR3A gene. Two additional unrelated children with severe VZV manifest as pneumonitis (P3) and encephalitis (P4) were found to carry heterozygous missense variants in both the POLR3A and POLR3C (617454) genes, consistent with digenic inheritance. P3 carried a heterozygous Q707R variant in the POLR3A gene and an R438G variant in the POLR3C gene, and P4 carried an R437Q variant in the POLR3A gene and an R84Q variant in the POLR3C gene. Segregation studies were consistent with incomplete penetrance. Patient peripheral blood cells showed variably impaired interferon production when exposed to AT-rich DNA or VZV, as well as variably impaired control of VZV viral replication. The authors suggested that the variants may lead to functional defects in the Pol III DNA sensing system and impaired ability to convert AT-rich DNA into the immunostimulatory RNA pathogen-associated molecular pattern (PAMP). The patients were part of a cohort of 21 children with severe VZV infection who underwent whole-exome sequencing; the variants were confirmed by Sanger sequencing. </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>20 Selected Examples):</strong>
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</span>
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</h4>
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<p />
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<h4>
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<span class="mim-font">
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<strong>.0001 LEUKODYSTROPHY, HYPOMYELINATING, 7, WITH OR WITHOUT OLIGODONTIA AND/OR HYPOGONADOTROPIC HYPOGONADISM</strong>
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<span class="mim-text-font">
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POLR3A, GLY672GLU
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<br />
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SNP: rs267608670,
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gnomAD: rs267608670,
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ClinVar: RCV000024139, RCV004532403, RCV004579533, RCV005089313
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<span class="mim-text-font">
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<p>In 5 affected members of 3 French Canadian families with hypomyelinating leukodystrophy-7 (HLD7; 607694), Bernard et al. (2011) identified a homozygous 2015G-A transition in the POLR3A gene, resulting in a gly672-to-glu (G672E) substitution. The mutation was not found in more than 250 control chromosomes. The families were originally reported by Bernard et al. (2010) as having a disorder termed 'tremor-ataxia with central hypomyelination (TACH).' All had mild cognitive regression, upper motor neuron signs, tremor, and cerebellar signs. Two also had hypodontia, 2 others also had hypogonadotropic hypogonadism, and the fifth had neither of these additional features. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 LEUKODYSTROPHY, HYPOMYELINATING, 7, WITH OLIGODONTIA</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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WIEDEMANN-RAUTENSTRAUCH SYNDROME, INCLUDED
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<div>
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<span class="mim-text-font">
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POLR3A, IVS14, G-A, +18 ({dbSNP rs267608677})
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<br />
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SNP: rs267608677,
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gnomAD: rs267608677,
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ClinVar: RCV000024140, RCV000224081, RCV000754389
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</span>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a consanguineous Syrian family (family X) with hypomyelinating leukodystrophy-7 (HLD7; 607694), originally reported by Atrouni et al. (2003), Bernard et al. (2011) identified homozygosity for a c.2003+18G-A transition (c.2003+18G-A, NM_007055.3) in intron 14 of the POLR3A gene, resulting in the retention of 19 nucleotides from intron 14, the addition of 6 amino acids to the protein, and a premature stop codon at position 650 (referred to by the authors as Tyr637CysfsTer650). The mutation was not found in more than 250 control chromosomes. All had cognitive regression, upper motor neuron signs, cerebellar signs, and hypodontia, but none had hypogonadotropic hypogonadism. </p><p>In a female infant who died at age 7 months with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090), Jay et al. (2016) identified compound heterozygosity for a c.1909+18G-A mutation in intron 14 of the POLR3A gene, which was predicted to create a cryptic donor site, and a c.2617C-T transition in exon 20, resulting in an arg873-to-ter (R873X; 614258.0008) substitution. Her unaffected parents were each heterozygous for 1 of the mutations. The authors stated that the splice site mutation was not found in the Exome Variant Server or dbSNP databases, and the nonsense mutation was not reported in the ExAC database. </p><p>In a girl who died at age 10 years with WDRTS (WRS001), originally reported by Paolacci et al. (2017), Paolacci et al. (2018) identified compound heterozygosity for the c.1909+18G-A mutation (c.1909+18G-A, chr10.79769277, GRCh37) in POLR3A and a c.3206G-A transition, resulting in an arg1069-to-gln (R1069Q; 614258.0009) substitution at a highly conserved residue. The missense variant was present at very low frequency (0.002%) in the gnomAD database, whereas the splicing mutation was not found in gnomAD. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 LEUKODYSTROPHY, HYPOMYELINATING, 7, WITH OLIGODONTIA AND HYPOGONADOTROPIC HYPOGONADISM</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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LEUKODYSTROPHY, HYPOMYELINATING, 7, WITH OLIGODONTIA, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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POLR3A, MET852VAL
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<br />
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SNP: rs267608671,
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gnomAD: rs267608671,
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ClinVar: RCV000024141, RCV000198773, RCV000413750, RCV003488348
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 4 patients from 2 unrelated families (families V and VIII) with hypomyelinating leukodystrophy with hypodontia and hypogonadotropic hypogonadism (HLD7; 607694), originally reported by Timmons et al. (2006), Bernard et al. (2011) identified compound heterozygosity for 2 mutations in the POLR3A gene: a c.2554A-G transition (c.2554A-G, NM_007055.3) resulting in a met852-to-val (M852V) substitution, and a G-to-A transition in intron 19 (c.2617-1G-A; 614258.0004), predicted to remove an acceptor site, lead to the use of a cryptic acceptor site located in exon 20, and cause a premature stop codon at position 878 (referred to by the authors as Arg873AlafsTer878). All had cognitive regression, abnormal eye movements, upper motor neuron signs, cerebellar signs, hypodontia, and hypogonadotropic hypogonadism. Bernard et al. (2011) also found that a patient (individual 18 of family XI) with leukodystrophy and oligodontia was compound heterozygous for M852V and a 418C-T transition in the POLR3A gene, resulting in an arg140-to-ter (R140X; 614258.0005) substitution. None of the mutations was found in more than 250 control chromosomes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 LEUKODYSTROPHY, HYPOMYELINATING, 7, WITH OLIGODONTIA AND HYPOGONADOTROPIC HYPOGONADISM</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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WIEDEMANN-RAUTENSTRAUCH SYNDROME, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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POLR3A, IVS19AS, G-A, -1 ({dbSNP rs181087667})
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<br />
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SNP: rs181087667,
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gnomAD: rs181087667,
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ClinVar: RCV000024142, RCV000384524, RCV000754391, RCV002513221
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the splice site mutation in the POLR3A gene (c.2617-1G-A, NM_007055.3), predicted to result in use of a cryptic acceptor site and premature termination (Arg873AlafsTer878), that was found in compound heterozygous state in patients with hypomyelinating leukodystrophy with hypodontia and hypogonadotropic hypogonadism (HLD7; 607964) by Bernard et al. (2011), see 614258.0003. </p><p>For discussion of the c.2617-1G-A splice site mutation (c.2617-1G-A, chr10.79753126) in the POLR3A gene, which was also found in compound heterozygous state in a 21-year-old woman (WRS005) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Paolacci et al. (2018), see 614258.0010. </p><p>For discussion of the c.2617-1G-A splice site mutation (c.2617-1G-A, NM_007055.3) in POLR3A, which was found in compound heterozygosity in a 21-year-old woman (subject 6) with WDRTS by Wambach et al. (2018), see 614258.0010. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 LEUKODYSTROPHY, HYPOMYELINATING, 7, WITH OLIGODONTIA</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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POLR3A, ARG140TER
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<br />
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SNP: rs267608678,
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ClinVar: RCV000024143, RCV001268853
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the arg140-to-ter (R140X) mutation in the POLR3A gene, resulting from a c.418C-T transition (c.418C-T, NM_007055.3) that was found in compound heterozygous state in a patient with leukodystrophy and oligodontia (HLD7; 607964) by Bernard et al. (2011), see 614258.0003. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0006 LEUKODYSTROPHY, HYPOMYELINATING, 7, WITHOUT OLIGODONTIA OR HYPOGONADOTROPIC HYPOGONADISM</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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POLR3A, ILE897ASN
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<br />
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SNP: rs267608681,
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ClinVar: RCV000024144
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 17-year-old Japanese boy (individual 4) with hypomyelinating leukodystrophy-7 (HLD7; 607694), Saitsu et al. (2011) identified compound heterozygosity for 2 mutations in the POLR3A gene: a paternally inherited c.2690T-A transversion (c.2690T-A, NM_007055.3) in exon 20, resulting in an ile897-to-asn (I897N) substitution, and a maternally inherited c.3013C-T transition in exon 23, resulting in an arg1005-to-cys (R1005C; 614258.0007) substitution. Structural modeling using the homologous yeast pol II subunit suggested that the mutations would disturb subunit interaction, leading to loss of pol III function. Neither mutation was found in 540 Japanese control chromosomes. The patient showed normal development until age 4, when mild tremors were noted. He later developed cerebellar signs, including expressive ataxic speech, intention tremor, poor finger-to-nose test, dysdiadochokinesis, dysmetria, and wide-based ataxic gait. He also showed intellectual disability with an IQ of 57. Other features included severe myopia and unilateral sensorineural deafness. The motor deterioration was progressive, and he became wheelchair-bound around age 14 years. Brain MRI showed a hypoplastic corpus callosum, cerebellar atrophy, and white matter lesions in the basal ganglia. He did not have hypodontia or hypogonadism. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 LEUKODYSTROPHY, HYPOMYELINATING, 7, WITHOUT OLIGODONTIA OR HYPOGONADOTROPIC HYPOGONADISM</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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POLR3A, ARG1005CYS
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<br />
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SNP: rs267608682,
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gnomAD: rs267608682,
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|
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ClinVar: RCV000024145, RCV001824118, RCV001852565, RCV003488349
|
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|
|
</span>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>For discussion of the arg1005-to-cys (R1005C) mutation in the POLR3A gene, resulting from a c.3013C-T transition (c.3013C-T, NM_007055.3) that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-7 (HLD7; 607694) by Saitsu et al. (2011), see 614258.0006. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3A, ARG873TER
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|
|
|
<br />
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|
|
SNP: rs148932047,
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|
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|
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gnomAD: rs148932047,
|
|
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|
|
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ClinVar: RCV000224488, RCV000755662, RCV002516224, RCV004532823
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.2617C-T transition in exon 20 of the POLR3A gene, resulting in an arg873-to-ter (R873X) substitution, that was found in compound heterozygous state in a female infant with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Jay et al. (2016), see 614258.0002. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3A, ARG1069GLN ({dbSNP rs778985686})
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|
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|
|
<br />
|
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|
|
SNP: rs778985686,
|
|
|
|
|
|
gnomAD: rs778985686,
|
|
|
|
|
|
ClinVar: RCV000754380, RCV001815367, RCV003488778, RCV004820861
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.3206G-A transition (c.3206G-A, chr10.79744964, GRCh37) in the POLR3A gene, resulting in an arg1069-to-gln (R1069Q) substitution, that was found in compound heterozygous state in a patient with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Paolacci et al. (2018), see 614258.0002. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
</div>
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<div>
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|
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3A, IVS14, G-A, +22 ({dbSNP rs191875469}) AND IVS25, T-C, -11
|
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|
|
<br />
|
|
|
|
SNP: rs1564613755, rs191875469,
|
|
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|
|
|
gnomAD: rs191875469,
|
|
|
|
|
|
ClinVar: RCV000514925, RCV000754381, RCV000754390, RCV000755664, RCV000988394, RCV001249723, RCV001814996, RCV002448556, RCV002506245, RCV002528232, RCV003313969, RCV003403205, RCV003736873, RCV003993993, RCV004698500
|
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 6 patients from 4 unrelated families with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090), Paolacci et al. (2018) identified compound heterozygosity for 2 intronic variants, c.1909+22G-A (c.1909+22G-A, chr10.79769273, GRCh37) and c.3337-11T-C (c.3337-11T-C, chr10.79743781, GRCh37), on 1 allele of the POLR3A gene, and another mutation in POLR3A on the other allele. The patients comprised 1 (WRS002) of 2 sisters originally described by Rautenstrauch et al. (1977) (patient 'GM'), a 27-year-old Palestinian man and his 2 sibs (WRS004) who were reported by Akawi et al. (2013), a 21-year-old woman (WRS005) previously reported by Paolacci et al. (2017), and a German patient (WRS003). Analysis of RNA from patients WRS002 and WRS004 demonstrated that the c.1909+22G-A variant had a mild effect on exon 14 splicing, causing skipping of that exon and a frameshift resulting in a premature termination codon (Pro591MetfsTer9), whereas the c.3337-11T-C variant caused skipping of exon 26, resulting in an in-frame deletion (I1113_E1143del). In patient WRS002, the second mutation was another splice site mutation (c.1048+5G-T; 614258.0011) in intron 7 of the POLR3A gene, causing insertion of 177 bp of intronic sequence predicted to result in a frameshift and premature termination codon (Arg353ProfsTer24). The variant was present at very low frequency (0.0004%) in the gnomAD database. In the German patient (WRS003), the second mutation was a c.2474C-G transversion in the POLR3A gene, resulting in a ser825-to-ter (S825X; 614258.0012) substitution that was not found in the gnomAD database. In the 3 Palestinian sibs (WRS004), the second mutation was a c.1800C-T transition (614258.0013) within exon 14 of the POLR3A gene, a synonymous change that caused skipping of exon 14 with a frameshift resulting in a premature termination codon (Pro591MetfsTer9); this variant was not found in the gnomAD database. cDNA analysis showed a strong additive effect on splicing by the c.1800C-T and c.1909+22G-A mutations together, with increased skipping of exon 14 compared to c.1909+22G-A alone. In patient WRS005, the second mutation was another splice site mutation (c.2617-1G-A; 614258.0004), present at very low frequency (0.002%) in the gnomAD database. Paolacci et al. (2018) noted that the Palestinian sibs' apparently unaffected father was homozygous for the mutant allele carrying the c.1909+22G-A and c.3337-11T-C variants, indicating that this allele does not cause a phenotype in homozygous state; the authors suggested that a specific mutation signature indicated by the combination of compound heterozygous mutations in POLR3A is necessary to cause WDRTS. In addition, the authors stated that the c.1909+22G-A mutation represents a relatively common variant, present at a minor allele frequency of 0.1% in the gnomAD database, and noted that it previously had been reported without the presence of the c.3337-11T-C variant on the same allele in patients with leukodystrophy. </p><p>In a 20-year-old woman (subject 2) with WDRTS who was originally studied by Garg et al. (2015) (patient NLD 1300.4), and an unrelated 21-year-old woman (subject 6) with WDRTS, Wambach et al. (2018) reported compound heterozygosity for the c.3337-11T-C mutation (c.3337-11T-C, NM_007055.3) and another mutation in POLR3A: in subject 6, the second mutation was a splice site mutation (c.2617-1G-A; 614258.0004), and in subject 2, it was a c.2005C-T transition, resulting in an arg669-to-ter (R669X; 614258.0017) substitution. Analysis of RNA from subject 2 demonstrated that the c.3337-11T-C mutation caused skipping of exon 26; however, in contrast to the findings of Paolacci et al. (2018), Wambach et al. (2018) found that the c.1909+22G-A variant (c.1909+22G-A, NM_007055.3) did not result in exon skipping. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
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</div>
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|
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
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POLR3A, IVS7, G-T, +5 ({dbSNP rs890755853})
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<br />
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SNP: rs890755853,
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gnomAD: rs890755853,
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|
|
ClinVar: RCV000754382, RCV003485627
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|
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|
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</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the splicing mutation (c.1048+5G-T, chr10.79781613, GRCh37) in intron 7 of the POLR3A gene, causing insertion of 177 bp of intronic sequence predicted to result in a frameshift and premature termination codon (Arg353ProfsTer24), that was found in compound heterozygous state in a female patient (WRS002) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Paolacci et al. (2018), see 614258.0010. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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POLR3A, SER825TER
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<br />
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|
SNP: rs1564617848,
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ClinVar: RCV000754383, RCV004800512
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>For discussion of the c.2474C-G transversion (c.2474C-G, chr10.79760738, GRCh37) in the POLR3A gene, resulting in a ser825-to-ter (S825X) substitution, that was found in compound heterozygous state in a German patient (WRS003) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Paolacci et al. (2018), see 614258.0010. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0013 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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POLR3A, 1800C-T
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<br />
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SNP: rs1564620047,
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ClinVar: RCV000754384
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>For discussion of the c.1800C-T transition (c.1800C-T, chr10.79769404, GRCh37) in exon 14 of the POLR3A gene, resulting in a synonymous change (I600I) but shown to alter splicing and cause skipping of exon 14 with a frameshift resulting in a premature termination codon (Pro591MetfsTer9), that was found in compound heterozygous state in 3 Palestinian sibs (WRS004) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Paolacci et al. (2018), see 614258.0010. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0014 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
|
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</span>
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|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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POLR3A, TER18C-T
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<br />
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SNP: rs1248039821,
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gnomAD: rs1248039821,
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ClinVar: RCV000754386, RCV003488779
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 unrelated patients (WRS008 and WRS009) from Colombia with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090), Paolacci et al. (2018) identified a c.Ter18C-T transition (c.Ter18C-T, chr10.79737218, GRCh37) in the POLR3A gene in compound heterozygosity with 2 different mutations. Patient WRS008, a male infant reported by Morales et al. (2009) as patient WRS2 and who died at 1 day of life, additionally carried a c.4003G-A transition, resulting in a gly1335-to-arg (G1335R; 614258.0016) substitution at a highly conserved residue. Patient WRS009, a 22-year-old man reported by Arboleda and Arboleda (2005), additionally carried a c.3G-T transversion (614258.0015), the effect of which on the protein was described by Paolacci et al. (2018) as M1?. All 3 variants were present at very low frequency (0.0004%) in the gnomAD database. </p><p>In a 5-year-old boy (subject 7) with WDRTS, Wambach et al. (2018) identified compound heterozygosity for the same 2 mutations identified in a 22-year-old Colombian man with WDRTS by Paolacci et al. (2018). Wambach et al. (2018) described the effect of the initiation codon mutation on the protein as M1X. </p>
|
|
</span>
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|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
POLR3A, MET1ILE
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<br />
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SNP: rs1168641193,
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gnomAD: rs1168641193,
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ClinVar: RCV000754387, RCV003485628
|
|
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|
|
</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.3G-T transversion (c.3G-T, NM_007055.3) in the POLR3A gene, resulting in a Met1-to-? (M1?) substitution, that was found in compound heterozygous state in patients with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Paolacci et al. (2018) and Wambach et al. (2018), see 614258.0014. </p><p>In an 11-month-old girl with WDRTS (patient 11), Lessel et al. (2018) identified heterozygosity for the c.3G-T (M1I) mutation. Although a second mutation was not detected, the authors suggested that it might be deeply intronic, a copy-number variant, balanced translocation, or possibly involve a regulatory region of POLR3A. </p>
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|
</span>
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|
</div>
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
POLR3A, GLY1335ARG ({dbSNP rs768222183})
|
|
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|
|
<br />
|
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|
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SNP: rs768222183,
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|
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|
|
|
gnomAD: rs768222183,
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|
|
|
|
|
ClinVar: RCV000754392, RCV003488781
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.4003G-A transition (c.4003G-A, chr10.79739920, GRCh37) in the POLR3A gene, resulting in a gly1335-to-arg (G1335R) substitution, that was found in compound heterozygous state in a male infant (WRS008) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Paolacci et al. (2018), see 614258.0014. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3A, ARG669TER
|
|
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|
|
|
<br />
|
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|
|
SNP: rs774007232,
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|
|
|
|
|
gnomAD: rs774007232,
|
|
|
|
|
|
ClinVar: RCV000755668, RCV000760689, RCV001542770
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.2005C-T transition (c.2005C-T, NM_007055.3) in the POLR3A gene, resulting in an arg669-to-ter (R669X) substitution, that was found in compound heterozygous state in a 20-year-old woman (subject 2) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Wambach et al. (2018), see 614258.0010. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3A, IVS25, T-A, -5 ({dbSNP rs368905417})
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs368905417,
|
|
|
|
|
|
gnomAD: rs368905417,
|
|
|
|
|
|
ClinVar: RCV000498819, RCV000755669, RCV001291254, RCV003488638
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 unrelated children (subjects 1, 3, 4, and 5) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090), including a 13-year-old girl (subject 3) previously studied by Garg et al. (2015) as patient NLD 2200.4, Wambach et al. (2018) identified compound heterozygosity for a c.3337-5T-A transversion (c.3337-5T-A, NM_007055.3) in intron 25 of the POLR3A gene and another splice site or truncating mutation in POLR3A. The c.3337-5T-A variant was present in only 1 heterozygous individual in gnomAD (minor allele frequency, 0.000004), and analysis of RNA from subject 1 showed that the mutation causes in-frame skipping of exon 26 (Ile1113_Glu1143del). </p><p>In a 10-year-old boy (patient 1) and an unrelated 12.75-year-old girl (patient 4) with WDRTS, Lessel et al. (2018) identified compound heterozygosity for the c.3337-5T-A splice site mutation and another mutation in the POLR3A gene: in the boy, the second mutation was a c.3337-1G-A variant (614258.0019) in intron 25, predicted to abolish the splice acceptor site, whereas in the girl it was a c.760C-T transition, resulting in an arg254-to-ter (R254X; 614258.0020) substitution. All 3 variants were extremely rare in the dbSNP, 1000 Genomes, ExAC, and gnomAD databases, and were only present in heterozygous state in those databases. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3A, IVS25, G-A, -1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1041175828,
|
|
|
|
|
|
|
|
ClinVar: RCV000755670, RCV001291255, RCV001784365
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.3337-1G-A transition in intron 25 of the POLR3A gene, predicted to abolish the splice acceptor site, that was found in compound heterozygosity in a 10-year-old boy (patient 1) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Lessel et al. (2018), see 614258.0018. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 WIEDEMANN-RAUTENSTRAUCH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
POLR3A, ARG254TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs141659018,
|
|
|
|
|
|
gnomAD: rs141659018,
|
|
|
|
|
|
ClinVar: RCV000755671, RCV000994469, RCV001291256, RCV002507319, RCV002533777, RCV003330936
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.760C-T transition in the POLR3A gene, resulting in an arg254-to-ter (R254X) substitution, that was found in compound heterozygosity in a 12.75-year-old girl (patient 4) with Wiedemann-Rautenstrauch syndrome (WDRTS; 264090) by Lessel et al. (2018), see 614258.0018. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Akawi, N., Ali, B., Al Gazali, L.
|
|
<strong>A progeroid syndrome with neonatal presentation and long survival maps to 19p13.3p13.2.</strong>
|
|
Birth Defects Res. A Clin. Molec. Teratol. 97: 456-462, 2013.
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|
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|
|
[PubMed: 23696134]
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[Full Text: https://doi.org/10.1002/bdra.23136]
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Arboleda, H., Arboleda, G.
|
|
<strong>Follow-up study of Wiedemann-Rautenstrauch syndrome: long-term survival and comparison with Rautenstrauch's patient 'G'.</strong>
|
|
Birth Defects Res. A Clin. Molec. Teratol. 73: 562-568, 2005.
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|
|
|
|
[PubMed: 16007586]
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|
|
[Full Text: https://doi.org/10.1002/bdra.20166]
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</p>
|
|
</li>
|
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Atrouni, S., Daraze, A., Tamraz, J., Cassia, A., Caillaud, C., Megarbane, A.
|
|
<strong>Leukodystrophy associated with oligodontia in a large inbred family: fortuitous association or new entity?</strong>
|
|
Am. J. Med. Genet. 118A: 76-81, 2003.
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|
|
[PubMed: 12605447]
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|
|
[Full Text: https://doi.org/10.1002/ajmg.a.10019]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bernard, G., Chouery, E., Putorti, M. L., Tetreault, M., Takanohashi, A., Carosso, G., Clement, I., Boespflug-Tanguy, O., Rodriguez, D., Delague, V., Abou Ghoch, J., Jalkh, N., Dorboz, I., Fribourg, S., Teichmann, M., Megarbane, A., Schiffmann, R., Vanderver, A., Brais, B.
|
|
<strong>Mutations of POLR3A encoding a catalytic subunit of RNA polymerase pol III cause a recessive hypomyelinating leukodystrophy.</strong>
|
|
Am. J. Hum. Genet. 89: 415-423, 2011. Note: Erratum: Am. J. Hum. Genet. 91: 972 only, 2012.
|
|
|
|
|
|
[PubMed: 21855841]
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|
|
[Full Text: https://doi.org/10.1016/j.ajhg.2011.07.014]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Bernard, G., Thiffault, I., Tetreault, M., Putorti, M. L., Bouchard, I., Sylvain, M., Melancon, S., Laframboise, R., Langevin, P., Bouchard, J.-P., Vanasse, M., Vanderver, A., Sebire, G., Brais, B.
|
|
<strong>Tremor-ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3-10q23.31.</strong>
|
|
Neurogenetics 11: 457-464, 2010.
|
|
|
|
|
|
[PubMed: 20640464]
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|
|
[Full Text: https://doi.org/10.1007/s10048-010-0251-8]
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Garg, A., Kircher, M., del Campo, M., Amato, R. S., Agarwal, A. K., University of Washington Center for Mendelian Genomics.
|
|
<strong>Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome.</strong>
|
|
Am. J. Med. Genet. 167A: 1796-1806, 2015.
|
|
|
|
|
|
[PubMed: 25898808]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.37115]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Hartz, P. A.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 9/28/2011.
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|
|
|
</p>
|
|
</li>
|
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Jay, A. M., Conway, R. L., Thiffault, I., Saunders, C., Farrow, E., Adams, J., Toriello, H. V.
|
|
<strong>Neonatal progeroid syndrome associated with biallelic truncating variants in POLR3A.</strong>
|
|
Am. J. Med. Genet. 170A: 3343-3346, 2016.
|
|
|
|
|
|
[PubMed: 27612211]
|
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|
|
[Full Text: https://doi.org/10.1002/ajmg.a.37960]
|
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
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