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Entry
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- *607407 - EARLY B-CELL FACTOR 3; EBF3
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- OMIM
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<p>
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<span class="h4">*607407</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<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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<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/607407">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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<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 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 class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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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=ENSG00000108001;t=ENST00000440978" 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=253738" 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=607407" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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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=ENSG00000108001;t=ENST00000440978" 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_001005463,NM_001375379,NM_001375380,NM_001375389,NM_001375390,NM_001375391,NM_001375392,XM_005252667,XM_005252669,XM_006717740,XM_006717741,XM_006717744,XM_011539574,XM_011539575,XM_017016027,XM_047424961" 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_001375380" 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=607407" 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://hprd.org/summary?hprd_id=16818&isoform_id=16818_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/EBF3" 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/13959320,52545713,53828926,116496955,119569544,119569545,119569546,120659896,530394802,530394806,578819198,578819200,578819206,767962338,767962341,1034567531,1769155668,1769155681,1769155798,1769156042,1769156145,1769156359,2217276479,2462518250,2462518252,2462518254,2462518256,2462518258,2462518260,2462518262,2462518264,2462518266" 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/Q9H4W6" 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=253738" 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=ENSG00000108001;t=ENST00000440978" 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=EBF3" 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=EBF3" 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+253738" 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/EBF3" 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:253738" 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/253738" 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=ENST00000440978.2&hgg_start=129835233&hgg_end=129964274&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 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/gene-dosage/HGNC:19087" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:19087" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607407[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 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=607407[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/EBF3/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/ENSG00000108001" 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=EBF3" 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=EBF3" 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=EBF3" 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=EBF3&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/PA134972607" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:19087" 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/FBgn0001319.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:894289" 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/EBF3#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:894289" 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/253738/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=253738" 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=WBGene00006743;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-070112-292" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=EBF3&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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</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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607407
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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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EARLY B-CELL FACTOR 3; EBF3
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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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COLLIER/OLF1/EBF TRANSCRIPTION FACTOR 3; COE3
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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ENHANCER hs737, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="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=EBF3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">EBF3</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/10/661?start=-3&limit=10&highlight=661">10q26.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr10:129835233-129964274&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'})">10:129,835,233-129,964,274</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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</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="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/10/661?start=-3&limit=10&highlight=661">
|
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10q26.3
|
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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">
|
|
Hypotonia, ataxia, and delayed development 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/617330"> 617330 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</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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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/607407" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/607407" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<p>The EBF3 gene encodes one of a family of highly homologous transcription factors. EBF3 is itself a downstream transcriptional target of ARX (<a href="/entry/300382">300382</a>), and is thought to be transcriptionally repressed by ARX (summary by <a href="#1" class="mim-tip-reference" title="Chao, H.-T., Davids, M., Burke, E., Pappas, J. G., Rosenfeld, J. A., McCarty, A. J., Davis, T., Wolfe, L., Toro, C., Tifft, C., Xia, F., Strong, N., and 10 others. <strong>A syndromic neurodevelopmental disorder caused by de novo variants in EBF3</strong> Am. J. Hum. Genet. 100: 128-137, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017372</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017372[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017372">Chao et al., 2017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017372" 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>The 10q26.3 region is frequently deleted in grade IV brain tumors. <a href="#6" class="mim-tip-reference" title="Zardo, G., Tiirikainen, M. I., Hong, C., Misra, A., Feuerstein, B. G., Volik, S., Collins, C. C., Lamborn, K. R., Bollen, A., Pinkel, D., Albertson, D. G., Costello, J. F. <strong>Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors.</strong> Nature Genet. 32: 453-458, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355068</a>] [<a href="https://doi.org/10.1038/ng1007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355068">Zardo et al. (2002)</a> found that a fragment from that region was aberrantly methylated and deleted in grade IV brain tumors and homozygously methylated in grade II brain tumors. They determined that the fragment maps to the 5-prime end of the EBF3 gene, which the authors called COE3. EBF3 is a COE transcription factor, which regulate neurogenesis and differentiation (see EBF1; <a href="/entry/164343">164343</a>). RT-PCR analysis detected EBF3 expression in normal adult brain, but expression was repressed in 4 glioma cell lines. <a href="#6" class="mim-tip-reference" title="Zardo, G., Tiirikainen, M. I., Hong, C., Misra, A., Feuerstein, B. G., Volik, S., Collins, C. C., Lamborn, K. R., Bollen, A., Pinkel, D., Albertson, D. G., Costello, J. F. <strong>Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors.</strong> Nature Genet. 32: 453-458, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355068</a>] [<a href="https://doi.org/10.1038/ng1007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355068">Zardo et al. (2002)</a> were able to reactivate EBF3 expression by treating cells with the demethylating agent 5-aza-2-deoxycytidine, suggesting that aberrant methylation causes silencing of EBF3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355068" 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 cellular studies, <a href="#3" class="mim-tip-reference" title="Harms, F. L., Girisha, K. M., Hardigan, A. A., Kortum, F., Shukla, A., Alawi, M., Dalal, A., Brady, L., Tarnopolsky, M., Bird, L. M., Ceulemans, S., Bebin, M., and 21 others. <strong>Mutations in EBF3 disturb transcriptional profiles and cause intellectual disability, ataxia, and facial dysmorphism.</strong> Am. J. Hum. Genet. 100: 117-127, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017373[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017373">Harms et al. (2017)</a> demonstrated that the EBF3 protein localized exclusively to the nucleus where it was tightly associated with chromatin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Zardo, G., Tiirikainen, M. I., Hong, C., Misra, A., Feuerstein, B. G., Volik, S., Collins, C. C., Lamborn, K. R., Bollen, A., Pinkel, D., Albertson, D. G., Costello, J. F. <strong>Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors.</strong> Nature Genet. 32: 453-458, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355068</a>] [<a href="https://doi.org/10.1038/ng1007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355068">Zardo et al. (2002)</a> stated that the EBF3 gene maps to chromosome 10q26. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355068" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 sibs with hypotonia, ataxia, and delayed development syndrome (HADDS; <a href="/entry/617330">617330</a>), <a href="#3" class="mim-tip-reference" title="Harms, F. L., Girisha, K. M., Hardigan, A. A., Kortum, F., Shukla, A., Alawi, M., Dalal, A., Brady, L., Tarnopolsky, M., Bird, L. M., Ceulemans, S., Bebin, M., and 21 others. <strong>Mutations in EBF3 disturb transcriptional profiles and cause intellectual disability, ataxia, and facial dysmorphism.</strong> Am. J. Hum. Genet. 100: 117-127, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017373[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017373">Harms et al. (2017)</a> identified a heterozygous mutation in the EBF3 gene (<a href="#0001">607407.0001</a>). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was inherited from an unaffected mother who was mosaic for the mutation. The authors reported 8 additional patients with HADDS; the variants in these patients, all of which occurred de novo (see, e.g., <a href="#0002">607407.0002</a>-<a href="#0004">607407.0004</a>), were said to have been identified through whole-exome sequencing by groups that independently submitted to GeneMatcher. There were 5 missense mutations, all of which occurred at highly conserved residues in the DNA-binding domain, and 4 frameshift, splice site, or nonsense mutations. In vitro functional expression studies showed that the mutations resulted in significantly reduced ability to activate transcription of a reporter gene. Some mutations demonstrated a dominant-negative effect, whereas others appeared to result in a loss of function. The findings showed that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017373" 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 3 unrelated children with HADDS, <a href="#1" class="mim-tip-reference" title="Chao, H.-T., Davids, M., Burke, E., Pappas, J. G., Rosenfeld, J. A., McCarty, A. J., Davis, T., Wolfe, L., Toro, C., Tifft, C., Xia, F., Strong, N., and 10 others. <strong>A syndromic neurodevelopmental disorder caused by de novo variants in EBF3</strong> Am. J. Hum. Genet. 100: 128-137, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017372</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017372[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017372">Chao et al. (2017)</a> identified de novo heterozygous missense mutations affecting the same residue in the EBF3 gene (R163Q, <a href="#0005">607407.0005</a> and R163L, <a href="#0006">607407.0006</a>). The mutations were found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that the R163Q variant resulted in complete loss of function, whereas R163L was a hypomorphic allele. Neither variant was able to rescue the embryonic lethality and defects in development of the nervous system in Drosophila with homozygous loss of the Ebf3 homolog ('knot' or 'collier'), indicating that the mutations resulted in a loss of function. <a href="#1" class="mim-tip-reference" title="Chao, H.-T., Davids, M., Burke, E., Pappas, J. G., Rosenfeld, J. A., McCarty, A. J., Davis, T., Wolfe, L., Toro, C., Tifft, C., Xia, F., Strong, N., and 10 others. <strong>A syndromic neurodevelopmental disorder caused by de novo variants in EBF3</strong> Am. J. Hum. Genet. 100: 128-137, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017372</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017372[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017372">Chao et al. (2017)</a> noted that EBF3 is transcriptionally repressed by ARX, and that gain-of-function mutations in ARX, which would suppress EBF3, cause overlapping neurodevelopmental disorders, suggesting a common transcriptional cascade pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017372" 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 8 patients from 7 unrelated families with HADDS, <a href="#5" class="mim-tip-reference" title="Sleven, H., Welsh, S. J., Yu, J., Churchill, M. E. A., Wright, C. F., Henderson, A., Horvath, R., Rankin, J., Vogt, J., Magee, A., McConnell, V., Green, A., and 11 others. <strong>De novo mutations in EBF3 cause a neurodevelopmental syndrome.</strong> Am. J. Hum. Genet. 100: 138-150, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017370[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017370">Sleven et al. (2017)</a> identified heterozygous mutations in the EBF3 gene (see, e.g., <a href="#0003">607407.0003</a>; <a href="#0007">607407.0007</a>-<a href="#0010">607407.0010</a>). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Mutations in 6 patients occurred de novo; 2 affected sibs inherited a mutation from a mosaic parent. There were 3 missense mutations, 2 splice site mutations, a frameshift, and a nonsense mutation. In vitro functional studies of the missense mutations showed that they resulted in impaired EBF3 transcription function compared to wildtype. The mutant missense proteins were able to form a heterodimer with wildtype EBF3, suggesting that they may have a dominant-negative effect. However, <a href="#5" class="mim-tip-reference" title="Sleven, H., Welsh, S. J., Yu, J., Churchill, M. E. A., Wright, C. F., Henderson, A., Horvath, R., Rankin, J., Vogt, J., Magee, A., McConnell, V., Green, A., and 11 others. <strong>De novo mutations in EBF3 cause a neurodevelopmental syndrome.</strong> Am. J. Hum. Genet. 100: 138-150, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017370[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017370">Sleven et al. (2017)</a> concluded that the mechanism of action is most likely related to loss of function, leading to a reduction in transcriptional activation of EBF3 early in development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017370" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Deisseroth, C. A., Lerma, V. C., Magyar, C. L., Pfliger, J. M., Nayak, A., Bliss, N. D., LeMaire, A. W., Narayanan, V., Balak, C., Zanni, G., Valente, E. M., Bertini, E., Benke, P. J., Wangler, M. F., Chao, H. T. <strong>An integrated phenotypic and genotypic approach reveals a high-risk subtype association for EBF3 missense variants affecting the zinc finger domain.</strong> Ann. Neurol. 92: 138-153, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35340043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35340043</a>] [<a href="https://doi.org/10.1002/ana.26359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35340043">Deisseroth et al. (2022)</a> performed a genotypic assessment of 41 patients with variation affecting the EBF3 gene. Twenty-seven patients (66%) had a de novo mutation, 5 patients had an affected parent (4 mothers and 1 father), and 2 patients had affected parents with mosaicism (1 mother and 1 father). In 7 patients, inheritance was either unknown or the family opted out of testing. Among their cohort of 41 patients, 7 had noncoding EBF3 variants, 2 had 10q26 deletions (<a href="/entry/609625">609625</a>) disrupting the EBF3 locus, and 32 had coding EBF3 variants. The authors also reviewed 47 previously reported patients with an EBF3 mutation and identified 5 with noncoding variants, 5 with 10q26 deletions disrupting the EBF3 gene, and 37 with coding EBF3 variants. Overall, the majority of the EBF3 variants clustered within the N-terminal DNA-binding domain, many of which were within 5 amino acids of the zinc finger domain, which is required for stabilizing the interaction between EBF3 and the DNA target. Nine unrelated individuals (10% of those with pathogenic EBF3 variants) affected the arginine residue at position 163 (R163Q, <a href="#0005">607407.0005</a> in 4; R163P, <a href="#0007">607407.0007</a> in 2; R163W in 2, and R163L, <a href="#0006">607407.0006</a> in 1). Other recurrent variants included ones that affected the arginine residue at position 209 in 9 individuals, including R209W (<a href="#0001">607407.0001</a>) in 5 patients. <a href="#2" class="mim-tip-reference" title="Deisseroth, C. A., Lerma, V. C., Magyar, C. L., Pfliger, J. M., Nayak, A., Bliss, N. D., LeMaire, A. W., Narayanan, V., Balak, C., Zanni, G., Valente, E. M., Bertini, E., Benke, P. J., Wangler, M. F., Chao, H. T. <strong>An integrated phenotypic and genotypic approach reveals a high-risk subtype association for EBF3 missense variants affecting the zinc finger domain.</strong> Ann. Neurol. 92: 138-153, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35340043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35340043</a>] [<a href="https://doi.org/10.1002/ana.26359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35340043">Deisseroth et al. (2022)</a> postulated that these de novo variants may be recurrent due to their position in CpG-dinucleotide islands, which are mutation hotspots. The authors performed in vivo studies in fruit flies and in vitro studies of transcriptional activation. Variants affecting the zinc finger domain were unable to restore viability in the fruit fly and impaired transcriptional activation, whereas the recurrent R209W variant, which affects the DNA-binding domain, was able to partially rescue fruit fly viability and preserved transcriptional activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35340043" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Using whole-genome sequencing data from 2,671 families with autism (516 in discovery cohort, 2,155 in replication cohort), <a href="#4" class="mim-tip-reference" title="Padhi, E. M., Hayeck, T. J., Cheng, Z., Chatterjee, S., Mannion, B. J., Byrska-Bishop, M., Willems, M., Pinson, L., Redon, S., Benech, C., Uguen, K., Audebert-Bellanger, S., and 23 others. <strong>Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism.</strong> Hum. Genomics 15: 44, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34256850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34256850</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34256850[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s40246-021-00342-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34256850">Padhi et al. (2021)</a> identified de novo variants in the hs737 enhancer (chr10:128151746-130191746, GRCh38) in 3 unrelated patients with autism. The hs737 enhancer was shown to be brain-specific and to target the EBF3 gene. In vitro assessment showed that these de novo variants reduced enhancer activity in a neuronal cell line. Patients with a de novo variant in hs737 had a shared phenotype (they were males with intact cognitive function and hypotonia or motor delay). Patients with coding de novo variants in EBF3 were more severely affected phenotypically with features of HADDS compared to patients with these noncoding variants who had autism and hypotonia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34256850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607407[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> rs779003155 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs779003155;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/rs779003155?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=rs779003155" 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=rs779003155" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 sibs (family 1, subjects 1 and 2) with hypotonia, ataxia, and delayed development syndrome (HADDS; <a href="/entry/617330">617330</a>), <a href="#3" class="mim-tip-reference" title="Harms, F. L., Girisha, K. M., Hardigan, A. A., Kortum, F., Shukla, A., Alawi, M., Dalal, A., Brady, L., Tarnopolsky, M., Bird, L. M., Ceulemans, S., Bebin, M., and 21 others. <strong>Mutations in EBF3 disturb transcriptional profiles and cause intellectual disability, ataxia, and facial dysmorphism.</strong> Am. J. Hum. Genet. 100: 117-127, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017373[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017373">Harms et al. (2017)</a> identified a heterozygous c.625C-T transition (c.625C-T, NM_001005463.2) in exon 7 of the EBF3 gene, resulting in an arg209-to-trp (R209W) substitution at a highly conserved residue in the DNA-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found to be mosaic in the unaffected mother and absent in the unaffected sibs. It was not found in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HEK293 cells showed that the mutant protein localized to the nucleus but with altered localization to the cytoplasm as well, decreased association with chromatin, and significantly decreased ability to activate transcription of a reporter gene compared to controls. Transcriptional activation was not significantly reduced when the mutation was coexpressed with the wildtype gene, arguing against a dominant-negative effect for this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Deisseroth, C. A., Lerma, V. C., Magyar, C. L., Pfliger, J. M., Nayak, A., Bliss, N. D., LeMaire, A. W., Narayanan, V., Balak, C., Zanni, G., Valente, E. M., Bertini, E., Benke, P. J., Wangler, M. F., Chao, H. T. <strong>An integrated phenotypic and genotypic approach reveals a high-risk subtype association for EBF3 missense variants affecting the zinc finger domain.</strong> Ann. Neurol. 92: 138-153, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35340043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35340043</a>] [<a href="https://doi.org/10.1002/ana.26359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35340043">Deisseroth et al. (2022)</a> performed a genotypic assessment of 41 patients with HADDS in their cohort and 47 previously reported patients. Nine unrelated individuals had variants affecting arg209, including R209W in 5 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35340043" 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">rs1057519518 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519518;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=rs1057519518" 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=rs1057519518" 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 16.5-year-old boy (subject 4) with hypotonia, ataxia, and delayed development syndrome (HADDS; <a href="/entry/617330">617330</a>), <a href="#3" class="mim-tip-reference" title="Harms, F. L., Girisha, K. M., Hardigan, A. A., Kortum, F., Shukla, A., Alawi, M., Dalal, A., Brady, L., Tarnopolsky, M., Bird, L. M., Ceulemans, S., Bebin, M., and 21 others. <strong>Mutations in EBF3 disturb transcriptional profiles and cause intellectual disability, ataxia, and facial dysmorphism.</strong> Am. J. Hum. Genet. 100: 117-127, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017373[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017373">Harms et al. (2017)</a> reported a de novo heterozygous c.196A-G transition (c.196A-G, NM_001005463.2) in exon 2 of the EBF3 gene, resulting in an asn66-to-asp (N66D) substitution at a highly conserved residue in the DNA-binding domain. The authors stated that the variant was found by whole-exome sequencing by groups that independently submitted to GeneMatcher. The mutation was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HEK293 cells showed that the mutant protein localized to the nucleus but with additional altered localization in the cytoplasm, decreased association with chromatin, and significantly decreased ability to activate transcription of a reporter gene compared to controls. Transcriptional activation was also reduced when the mutation was coexpressed with the wildtype gene, supporting a possible dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 2.7-year-old girl (subject 6) with hypotonia, ataxia, and delayed development syndrome (HADDS; <a href="/entry/617330">617330</a>), <a href="#3" class="mim-tip-reference" title="Harms, F. L., Girisha, K. M., Hardigan, A. A., Kortum, F., Shukla, A., Alawi, M., Dalal, A., Brady, L., Tarnopolsky, M., Bird, L. M., Ceulemans, S., Bebin, M., and 21 others. <strong>Mutations in EBF3 disturb transcriptional profiles and cause intellectual disability, ataxia, and facial dysmorphism.</strong> Am. J. Hum. Genet. 100: 117-127, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017373[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017373">Harms et al. (2017)</a> reported a de novo heterozygous c.530C-T transition (c.530C-T, NM_001005463.2) in exon 6 of the EBF3 gene, resulting in a pro177-to-leu (P177L) substitution at a highly conserved residue in the DNA-binding domain. The authors stated that the variant was found by whole-exome sequencing by groups that independently submitted to GeneMatcher. The mutation was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HEK293 cells showed that the mutant protein localized to the nucleus but with additional altered localization in the cytoplasm, decreased association with chromatin, and significantly decreased ability to activate transcription of a reporter gene compared to controls. Transcriptional activation was not significantly reduced when the mutation was coexpressed with the wildtype gene, arguing against a dominant-negative effect. RNA sequence analysis and chromatin immunoprecipitation studies (ChIP) of transfected neuroblastoma cell lines showed that the P177L mutation was associated with decreased transcription of genes involved in neuron- and signaling-related pathways, as well as decreased overall genome-wide DNA binding and gene-regulatory activity compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017373" 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 7-year-old boy (patient 280219) of British and Caribbean descent with HADDS, <a href="#5" class="mim-tip-reference" title="Sleven, H., Welsh, S. J., Yu, J., Churchill, M. E. A., Wright, C. F., Henderson, A., Horvath, R., Rankin, J., Vogt, J., Magee, A., McConnell, V., Green, A., and 11 others. <strong>De novo mutations in EBF3 cause a neurodevelopmental syndrome.</strong> Am. J. Hum. Genet. 100: 138-150, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017370[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017370">Sleven et al. (2017)</a> identified a de novo heterozygous P177L mutation in the EBF3 gene. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that the mutation resulted in decreased EBF3 transcription function compared to wildtype. The mutant protein was able to form a heterodimer with wildtype EBF3, suggesting that it may have a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017370" 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">rs1057519519 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519519;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=rs1057519519" 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=rs1057519519" 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=RCV000417002 OR RCV000817610 OR RCV001266398" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000417002, RCV000817610, RCV001266398" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000417002...</a>
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<p>In a 2-year-old boy (subject 7) with hypotonia, ataxia, and delayed development syndrome (HADDS; <a href="/entry/617330">617330</a>), <a href="#3" class="mim-tip-reference" title="Harms, F. L., Girisha, K. M., Hardigan, A. A., Kortum, F., Shukla, A., Alawi, M., Dalal, A., Brady, L., Tarnopolsky, M., Bird, L. M., Ceulemans, S., Bebin, M., and 21 others. <strong>Mutations in EBF3 disturb transcriptional profiles and cause intellectual disability, ataxia, and facial dysmorphism.</strong> Am. J. Hum. Genet. 100: 117-127, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017373[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017373">Harms et al. (2017)</a> reported a de novo heterozygous c.422A-G transition (c.422A-G, NM_001005463.2) in exon 5 of the EBF3 gene, resulting in a tyr141-to-cys (Y141C) substitution at a highly conserved residue in the DNA-binding domain. The authors stated that the variant was found by whole-exome sequencing by groups that independently submitted to GeneMatcher. The mutation was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HEK293 cells showed that the mutant protein localized to the nucleus but with additional altered localization in the cytoplasm, decreased association with chromatin, and significantly decreased ability to activate transcription of a reporter gene compared to controls. Transcriptional activation was also reduced when the mutation was coexpressed with the wildtype gene, suggesting a possible dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017373" 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">rs1057519389 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519389;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=rs1057519389" 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=rs1057519389" 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=RCV000416944 OR RCV000417073 OR RCV000622833 OR RCV000663416 OR RCV001804994" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000416944, RCV000417073, RCV000622833, RCV000663416, RCV001804994" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000416944...</a>
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<p>In 2 unrelated children, one of Chinese/Japanese descent and the other of African American descent, with hypotonia, ataxia, and delayed development syndrome (HADDS; <a href="/entry/617330">617330</a>), <a href="#1" class="mim-tip-reference" title="Chao, H.-T., Davids, M., Burke, E., Pappas, J. G., Rosenfeld, J. A., McCarty, A. J., Davis, T., Wolfe, L., Toro, C., Tifft, C., Xia, F., Strong, N., and 10 others. <strong>A syndromic neurodevelopmental disorder caused by de novo variants in EBF3</strong> Am. J. Hum. Genet. 100: 128-137, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017372</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017372[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017372">Chao et al. (2017)</a> identified a de novo heterozygous c.488G-A transition (c.488G-A, NM_001005463.2) in the EBF3 gene, resulting in an arg163-to-gln (R163Q) substitution at a conserved residue in the DNA-binding domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing in both patients, was not found in the ExAC database. In vitro functional expression studies showed that the mutant protein had very poor induction of transcriptional activity similar to null background levels, consistent with a loss of function. Expression of the R163Q mutation was unable to rescue the embryonic lethality and defects in development of the nervous system in Drosophila with homozygous loss of the Ebf3 homolog ('knot' or 'collier'), indicating that the R163Q mutation results in a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017372" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Deisseroth, C. A., Lerma, V. C., Magyar, C. L., Pfliger, J. M., Nayak, A., Bliss, N. D., LeMaire, A. W., Narayanan, V., Balak, C., Zanni, G., Valente, E. M., Bertini, E., Benke, P. J., Wangler, M. F., Chao, H. T. <strong>An integrated phenotypic and genotypic approach reveals a high-risk subtype association for EBF3 missense variants affecting the zinc finger domain.</strong> Ann. Neurol. 92: 138-153, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35340043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35340043</a>] [<a href="https://doi.org/10.1002/ana.26359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35340043">Deisseroth et al. (2022)</a> performed a genotypic assessment of 41 patients in their cohort with HADDS and 47 previously reported patients. Nine unrelated individuals (10% of those with pathogenic EBF3 variants) had variants affecting arg163, including R163Q in 4 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35340043" 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 HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT 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">rs1057519389 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519389;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=rs1057519389" 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=rs1057519389" 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=RCV000416975 OR RCV000417075 OR RCV000493860" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000416975, RCV000417075, RCV000493860" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000416975...</a>
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<p>In a 3-year-old girl of European descent with hypotonia, ataxia, and delayed development syndrome (HADDS; <a href="/entry/617330">617330</a>), <a href="#1" class="mim-tip-reference" title="Chao, H.-T., Davids, M., Burke, E., Pappas, J. G., Rosenfeld, J. A., McCarty, A. J., Davis, T., Wolfe, L., Toro, C., Tifft, C., Xia, F., Strong, N., and 10 others. <strong>A syndromic neurodevelopmental disorder caused by de novo variants in EBF3</strong> Am. J. Hum. Genet. 100: 128-137, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017372</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017372[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017372">Chao et al. (2017)</a> identified a de novo heterozygous c.488G-T transversion (c.488G-T, NM_001005463.2) in the EBF3 gene, resulting in an arg163-to-leu (R163L) substitution at a conserved residue in the DNA-binding domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. In vitro functional expression studies showed that the mutant protein had decreased induction of transcriptional activity compared to wildtype, consistent with it being a hypomorphic allele. Expression of the R163L mutation was unable to rescue the embryonic lethality and defects in development of the nervous system in Drosophila with homozygous loss of the Ebf3 homolog ('knot' or 'collier'), indicating that the R163L mutation results in a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017372" 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 HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT 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">rs1057519389 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519389;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=rs1057519389" 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=rs1057519389" 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=RCV000417019" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000417019" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000417019</a>
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<p>In a 13-year-old boy of British descent (patient 272588) with hypotonia, ataxia, and delayed development syndrome (HADDS; <a href="/entry/617330">617330</a>), <a href="#5" class="mim-tip-reference" title="Sleven, H., Welsh, S. J., Yu, J., Churchill, M. E. A., Wright, C. F., Henderson, A., Horvath, R., Rankin, J., Vogt, J., Magee, A., McConnell, V., Green, A., and 11 others. <strong>De novo mutations in EBF3 cause a neurodevelopmental syndrome.</strong> Am. J. Hum. Genet. 100: 138-150, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017370[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017370">Sleven et al. (2017)</a> identified a de novo heterozygous c.488G-C transversion (c.488G-C, NM_001005463.2) in exon 6 of the EBF3 gene, resulting in an arg163-to-pro (R163P) substitution at a conserved residue in the DNA-binding domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP and Exome Variant Server databases; it was not found in the ExAC database. In vitro functional expression studies showed that the mutation ablated EBF3 transcription function. The mutant protein was able to form a heterodimer with wildtype EBF3, suggesting that it may have a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017370" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000416948 OR RCV003324747" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000416948, RCV003324747" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000416948...</a>
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<p>In an Irish girl (patient 262955) with hypotonia, ataxia, and delayed development syndrome (HADDS; <a href="/entry/617330">617330</a>), <a href="#5" class="mim-tip-reference" title="Sleven, H., Welsh, S. J., Yu, J., Churchill, M. E. A., Wright, C. F., Henderson, A., Horvath, R., Rankin, J., Vogt, J., Magee, A., McConnell, V., Green, A., and 11 others. <strong>De novo mutations in EBF3 cause a neurodevelopmental syndrome.</strong> Am. J. Hum. Genet. 100: 138-150, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017370[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017370">Sleven et al. (2017)</a> identified a de novo heterozygous c.579G-T transversion (c.579G-T, NM_001005463.2) in exon 7 of the EBF3 gene, resulting in a lys193-to-asn (K193N) substitution at a conserved residue in the DNA-binding domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP and Exome Variant Server databases; it was not found in the ExAC database. In vitro functional expression studies showed that the mutation resulted in decreased EBF3 transcription function compared to wildtype. The mutant protein was able to form a heterodimer with wildtype EBF3, suggesting that it may have a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017370" 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>.0009 HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT 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">rs1057519521 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519521;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=rs1057519521" 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=rs1057519521" 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=RCV000416978 OR RCV001003596" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000416978, RCV001003596" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000416978...</a>
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<p>In an 8-year-old girl (patient 263361) of English descent with hypotonia, ataxia, and delayed development syndrome (HADDS; <a href="/entry/617330">617330</a>), <a href="#5" class="mim-tip-reference" title="Sleven, H., Welsh, S. J., Yu, J., Churchill, M. E. A., Wright, C. F., Henderson, A., Horvath, R., Rankin, J., Vogt, J., Magee, A., McConnell, V., Green, A., and 11 others. <strong>De novo mutations in EBF3 cause a neurodevelopmental syndrome.</strong> Am. J. Hum. Genet. 100: 138-150, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017370[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017370">Sleven et al. (2017)</a> identified a de novo heterozygous 4-bp deletion (c.280_283del, NM_001005463.2) in exon 2 of the EBF3 gene, resulting in a frameshift and premature termination (Glu94LysfsTer37). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP and Exome Variant Server databases; it was not found in the ExAC database. The mutation was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017370" 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">rs1057519522 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519522;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=rs1057519522" 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=rs1057519522" 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=RCV000417012 OR RCV000495975 OR RCV000505244" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000417012, RCV000495975, RCV000505244" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000417012...</a>
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<p>In 2 sibs of Indian descent (patients 67-1 and 67-4) with hypotonia, ataxia, and delayed development syndrome (HADDS; <a href="/entry/617330">617330</a>), <a href="#5" class="mim-tip-reference" title="Sleven, H., Welsh, S. J., Yu, J., Churchill, M. E. A., Wright, C. F., Henderson, A., Horvath, R., Rankin, J., Vogt, J., Magee, A., McConnell, V., Green, A., and 11 others. <strong>De novo mutations in EBF3 cause a neurodevelopmental syndrome.</strong> Am. J. Hum. Genet. 100: 138-150, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017370[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.11.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28017370">Sleven et al. (2017)</a> identified a heterozygous c.616C-T transition (c.616C-T, NM_001005463.2) in exon 7 of the EBF3 gene, resulting in an arg206-to-ter (R206X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP and Exome Variant Server databases; it was not found in the ExAC database. The mutation was predicted to result in haploinsufficiency. Evidence suggested parental germline mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28017370" 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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Chao, H.-T., Davids, M., Burke, E., Pappas, J. G., Rosenfeld, J. A., McCarty, A. J., Davis, T., Wolfe, L., Toro, C., Tifft, C., Xia, F., Strong, N., and 10 others.
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<strong>A syndromic neurodevelopmental disorder caused by de novo variants in EBF3</strong>
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Am. J. Hum. Genet. 100: 128-137, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017372</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017372[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=28017372" 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.2016.11.018" target="_blank">Full Text</a>]
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Deisseroth, C. A., Lerma, V. C., Magyar, C. L., Pfliger, J. M., Nayak, A., Bliss, N. D., LeMaire, A. W., Narayanan, V., Balak, C., Zanni, G., Valente, E. M., Bertini, E., Benke, P. J., Wangler, M. F., Chao, H. T.
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<strong>An integrated phenotypic and genotypic approach reveals a high-risk subtype association for EBF3 missense variants affecting the zinc finger domain.</strong>
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Ann. Neurol. 92: 138-153, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35340043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35340043</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35340043" 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/ana.26359" target="_blank">Full Text</a>]
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Harms, F. L., Girisha, K. M., Hardigan, A. A., Kortum, F., Shukla, A., Alawi, M., Dalal, A., Brady, L., Tarnopolsky, M., Bird, L. M., Ceulemans, S., Bebin, M., and 21 others.
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<strong>Mutations in EBF3 disturb transcriptional profiles and cause intellectual disability, ataxia, and facial dysmorphism.</strong>
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Am. J. Hum. Genet. 100: 117-127, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017373</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017373[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=28017373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Padhi, E. M., Hayeck, T. J., Cheng, Z., Chatterjee, S., Mannion, B. J., Byrska-Bishop, M., Willems, M., Pinson, L., Redon, S., Benech, C., Uguen, K., Audebert-Bellanger, S., and 23 others.
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<strong>Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism.</strong>
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Hum. Genomics 15: 44, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34256850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34256850</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34256850[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=34256850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Sleven, H., Welsh, S. J., Yu, J., Churchill, M. E. A., Wright, C. F., Henderson, A., Horvath, R., Rankin, J., Vogt, J., Magee, A., McConnell, V., Green, A., and 11 others.
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<strong>De novo mutations in EBF3 cause a neurodevelopmental syndrome.</strong>
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Am. J. Hum. Genet. 100: 138-150, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28017370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28017370</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28017370[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=28017370" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Zardo, G., Tiirikainen, M. I., Hong, C., Misra, A., Feuerstein, B. G., Volik, S., Collins, C. C., Lamborn, K. R., Bollen, A., Pinkel, D., Albertson, D. G., Costello, J. F.
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<strong>Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors.</strong>
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Nature Genet. 32: 453-458, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355068</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355068" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1007" target="_blank">Full Text</a>]
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Sonja A. Rasmussen - updated : 01/24/2024
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<span class="mim-text-font">
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Sonja A. Rasmussen - updated : 02/23/2023<br>Cassandra L. Kniffin - updated : 02/01/2017
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<a id="creationDate" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 12/9/2002
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<span class="mim-text-font">
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carol : 01/24/2024
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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carol : 02/23/2023<br>ckniffin : 08/14/2017<br>carol : 02/13/2017<br>carol : 02/08/2017<br>carol : 02/08/2017<br>carol : 02/07/2017<br>ckniffin : 02/01/2017<br>alopez : 12/19/2002<br>mgross : 12/9/2002
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<h3>
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<span class="mim-font">
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<strong>*</strong> 607407
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<h3>
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<span class="mim-font">
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EARLY B-CELL FACTOR 3; EBF3
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</h3>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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COLLIER/OLF1/EBF TRANSCRIPTION FACTOR 3; COE3
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<span class="h3 mim-font">
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ENHANCER hs737, INCLUDED
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: EBF3</em></strong>
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</span>
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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: 10q26.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 10:129,835,233-129,964,274 </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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</span>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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Location
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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<tbody>
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<td rowspan="1">
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<span class="mim-font">
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10q26.3
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<span class="mim-font">
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Hypotonia, ataxia, and delayed development 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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617330
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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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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The EBF3 gene encodes one of a family of highly homologous transcription factors. EBF3 is itself a downstream transcriptional target of ARX (300382), and is thought to be transcriptionally repressed by ARX (summary by Chao et al., 2017). </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>The 10q26.3 region is frequently deleted in grade IV brain tumors. Zardo et al. (2002) found that a fragment from that region was aberrantly methylated and deleted in grade IV brain tumors and homozygously methylated in grade II brain tumors. They determined that the fragment maps to the 5-prime end of the EBF3 gene, which the authors called COE3. EBF3 is a COE transcription factor, which regulate neurogenesis and differentiation (see EBF1; 164343). RT-PCR analysis detected EBF3 expression in normal adult brain, but expression was repressed in 4 glioma cell lines. Zardo et al. (2002) were able to reactivate EBF3 expression by treating cells with the demethylating agent 5-aza-2-deoxycytidine, suggesting that aberrant methylation causes silencing of EBF3. </p><p>In cellular studies, Harms et al. (2017) demonstrated that the EBF3 protein localized exclusively to the nucleus where it was tightly associated with chromatin. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Zardo et al. (2002) stated that the EBF3 gene maps to chromosome 10q26. </p>
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</span>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 2 sibs with hypotonia, ataxia, and delayed development syndrome (HADDS; 617330), Harms et al. (2017) identified a heterozygous mutation in the EBF3 gene (607407.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was inherited from an unaffected mother who was mosaic for the mutation. The authors reported 8 additional patients with HADDS; the variants in these patients, all of which occurred de novo (see, e.g., 607407.0002-607407.0004), were said to have been identified through whole-exome sequencing by groups that independently submitted to GeneMatcher. There were 5 missense mutations, all of which occurred at highly conserved residues in the DNA-binding domain, and 4 frameshift, splice site, or nonsense mutations. In vitro functional expression studies showed that the mutations resulted in significantly reduced ability to activate transcription of a reporter gene. Some mutations demonstrated a dominant-negative effect, whereas others appeared to result in a loss of function. The findings showed that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay. </p><p>In 3 unrelated children with HADDS, Chao et al. (2017) identified de novo heterozygous missense mutations affecting the same residue in the EBF3 gene (R163Q, 607407.0005 and R163L, 607407.0006). The mutations were found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that the R163Q variant resulted in complete loss of function, whereas R163L was a hypomorphic allele. Neither variant was able to rescue the embryonic lethality and defects in development of the nervous system in Drosophila with homozygous loss of the Ebf3 homolog ('knot' or 'collier'), indicating that the mutations resulted in a loss of function. Chao et al. (2017) noted that EBF3 is transcriptionally repressed by ARX, and that gain-of-function mutations in ARX, which would suppress EBF3, cause overlapping neurodevelopmental disorders, suggesting a common transcriptional cascade pathway. </p><p>In 8 patients from 7 unrelated families with HADDS, Sleven et al. (2017) identified heterozygous mutations in the EBF3 gene (see, e.g., 607407.0003; 607407.0007-607407.0010). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Mutations in 6 patients occurred de novo; 2 affected sibs inherited a mutation from a mosaic parent. There were 3 missense mutations, 2 splice site mutations, a frameshift, and a nonsense mutation. In vitro functional studies of the missense mutations showed that they resulted in impaired EBF3 transcription function compared to wildtype. The mutant missense proteins were able to form a heterodimer with wildtype EBF3, suggesting that they may have a dominant-negative effect. However, Sleven et al. (2017) concluded that the mechanism of action is most likely related to loss of function, leading to a reduction in transcriptional activation of EBF3 early in development. </p><p>Deisseroth et al. (2022) performed a genotypic assessment of 41 patients with variation affecting the EBF3 gene. Twenty-seven patients (66%) had a de novo mutation, 5 patients had an affected parent (4 mothers and 1 father), and 2 patients had affected parents with mosaicism (1 mother and 1 father). In 7 patients, inheritance was either unknown or the family opted out of testing. Among their cohort of 41 patients, 7 had noncoding EBF3 variants, 2 had 10q26 deletions (609625) disrupting the EBF3 locus, and 32 had coding EBF3 variants. The authors also reviewed 47 previously reported patients with an EBF3 mutation and identified 5 with noncoding variants, 5 with 10q26 deletions disrupting the EBF3 gene, and 37 with coding EBF3 variants. Overall, the majority of the EBF3 variants clustered within the N-terminal DNA-binding domain, many of which were within 5 amino acids of the zinc finger domain, which is required for stabilizing the interaction between EBF3 and the DNA target. Nine unrelated individuals (10% of those with pathogenic EBF3 variants) affected the arginine residue at position 163 (R163Q, 607407.0005 in 4; R163P, 607407.0007 in 2; R163W in 2, and R163L, 607407.0006 in 1). Other recurrent variants included ones that affected the arginine residue at position 209 in 9 individuals, including R209W (607407.0001) in 5 patients. Deisseroth et al. (2022) postulated that these de novo variants may be recurrent due to their position in CpG-dinucleotide islands, which are mutation hotspots. The authors performed in vivo studies in fruit flies and in vitro studies of transcriptional activation. Variants affecting the zinc finger domain were unable to restore viability in the fruit fly and impaired transcriptional activation, whereas the recurrent R209W variant, which affects the DNA-binding domain, was able to partially rescue fruit fly viability and preserved transcriptional activation. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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|
Using whole-genome sequencing data from 2,671 families with autism (516 in discovery cohort, 2,155 in replication cohort), Padhi et al. (2021) identified de novo variants in the hs737 enhancer (chr10:128151746-130191746, GRCh38) in 3 unrelated patients with autism. The hs737 enhancer was shown to be brain-specific and to target the EBF3 gene. In vitro assessment showed that these de novo variants reduced enhancer activity in a neuronal cell line. Patients with a de novo variant in hs737 had a shared phenotype (they were males with intact cognitive function and hypotonia or motor delay). Patients with coding de novo variants in EBF3 were more severely affected phenotypically with features of HADDS compared to patients with these noncoding variants who had autism and hypotonia. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
|
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</span>
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<strong>10 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0001 HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT 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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EBF3, ARG209TRP
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<br />
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SNP: rs779003155,
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gnomAD: rs779003155,
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ClinVar: RCV000417009, RCV001266965, RCV001821145, RCV004797808
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sibs (family 1, subjects 1 and 2) with hypotonia, ataxia, and delayed development syndrome (HADDS; 617330), Harms et al. (2017) identified a heterozygous c.625C-T transition (c.625C-T, NM_001005463.2) in exon 7 of the EBF3 gene, resulting in an arg209-to-trp (R209W) substitution at a highly conserved residue in the DNA-binding domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found to be mosaic in the unaffected mother and absent in the unaffected sibs. It was not found in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HEK293 cells showed that the mutant protein localized to the nucleus but with altered localization to the cytoplasm as well, decreased association with chromatin, and significantly decreased ability to activate transcription of a reporter gene compared to controls. Transcriptional activation was not significantly reduced when the mutation was coexpressed with the wildtype gene, arguing against a dominant-negative effect for this mutation. </p><p>Deisseroth et al. (2022) performed a genotypic assessment of 41 patients with HADDS in their cohort and 47 previously reported patients. Nine unrelated individuals had variants affecting arg209, including R209W in 5 patients. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0002 HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT 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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EBF3, ASN66ASP
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<br />
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SNP: rs1057519518,
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ClinVar: RCV000416941, RCV001265931
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 16.5-year-old boy (subject 4) with hypotonia, ataxia, and delayed development syndrome (HADDS; 617330), Harms et al. (2017) reported a de novo heterozygous c.196A-G transition (c.196A-G, NM_001005463.2) in exon 2 of the EBF3 gene, resulting in an asn66-to-asp (N66D) substitution at a highly conserved residue in the DNA-binding domain. The authors stated that the variant was found by whole-exome sequencing by groups that independently submitted to GeneMatcher. The mutation was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HEK293 cells showed that the mutant protein localized to the nucleus but with additional altered localization in the cytoplasm, decreased association with chromatin, and significantly decreased ability to activate transcription of a reporter gene compared to controls. Transcriptional activation was also reduced when the mutation was coexpressed with the wildtype gene, supporting a possible dominant-negative effect. </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 HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT 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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EBF3, PRO177LEU
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<br />
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SNP: rs869312668,
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ClinVar: RCV000416981, RCV002269264
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 2.7-year-old girl (subject 6) with hypotonia, ataxia, and delayed development syndrome (HADDS; 617330), Harms et al. (2017) reported a de novo heterozygous c.530C-T transition (c.530C-T, NM_001005463.2) in exon 6 of the EBF3 gene, resulting in a pro177-to-leu (P177L) substitution at a highly conserved residue in the DNA-binding domain. The authors stated that the variant was found by whole-exome sequencing by groups that independently submitted to GeneMatcher. The mutation was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HEK293 cells showed that the mutant protein localized to the nucleus but with additional altered localization in the cytoplasm, decreased association with chromatin, and significantly decreased ability to activate transcription of a reporter gene compared to controls. Transcriptional activation was not significantly reduced when the mutation was coexpressed with the wildtype gene, arguing against a dominant-negative effect. RNA sequence analysis and chromatin immunoprecipitation studies (ChIP) of transfected neuroblastoma cell lines showed that the P177L mutation was associated with decreased transcription of genes involved in neuron- and signaling-related pathways, as well as decreased overall genome-wide DNA binding and gene-regulatory activity compared to wildtype. </p><p>In a 7-year-old boy (patient 280219) of British and Caribbean descent with HADDS, Sleven et al. (2017) identified a de novo heterozygous P177L mutation in the EBF3 gene. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that the mutation resulted in decreased EBF3 transcription function compared to wildtype. The mutant protein was able to form a heterodimer with wildtype EBF3, suggesting that it may have a dominant-negative effect. </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 HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT 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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EBF3, TYR141CYS
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<br />
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SNP: rs1057519519,
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ClinVar: RCV000417002, RCV000817610, RCV001266398
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 2-year-old boy (subject 7) with hypotonia, ataxia, and delayed development syndrome (HADDS; 617330), Harms et al. (2017) reported a de novo heterozygous c.422A-G transition (c.422A-G, NM_001005463.2) in exon 5 of the EBF3 gene, resulting in a tyr141-to-cys (Y141C) substitution at a highly conserved residue in the DNA-binding domain. The authors stated that the variant was found by whole-exome sequencing by groups that independently submitted to GeneMatcher. The mutation was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HEK293 cells showed that the mutant protein localized to the nucleus but with additional altered localization in the cytoplasm, decreased association with chromatin, and significantly decreased ability to activate transcription of a reporter gene compared to controls. Transcriptional activation was also reduced when the mutation was coexpressed with the wildtype gene, suggesting a possible dominant-negative effect. </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 HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT 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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EBF3, ARG163GLN
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<br />
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SNP: rs1057519389,
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ClinVar: RCV000416944, RCV000417073, RCV000622833, RCV000663416, RCV001804994
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated children, one of Chinese/Japanese descent and the other of African American descent, with hypotonia, ataxia, and delayed development syndrome (HADDS; 617330), Chao et al. (2017) identified a de novo heterozygous c.488G-A transition (c.488G-A, NM_001005463.2) in the EBF3 gene, resulting in an arg163-to-gln (R163Q) substitution at a conserved residue in the DNA-binding domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing in both patients, was not found in the ExAC database. In vitro functional expression studies showed that the mutant protein had very poor induction of transcriptional activity similar to null background levels, consistent with a loss of function. Expression of the R163Q mutation was unable to rescue the embryonic lethality and defects in development of the nervous system in Drosophila with homozygous loss of the Ebf3 homolog ('knot' or 'collier'), indicating that the R163Q mutation results in a loss of function. </p><p>Deisseroth et al. (2022) performed a genotypic assessment of 41 patients in their cohort with HADDS and 47 previously reported patients. Nine unrelated individuals (10% of those with pathogenic EBF3 variants) had variants affecting arg163, including R163Q in 4 patients. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0006 HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT 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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EBF3, ARG163LEU
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<br />
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SNP: rs1057519389,
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ClinVar: RCV000416975, RCV000417075, RCV000493860
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 3-year-old girl of European descent with hypotonia, ataxia, and delayed development syndrome (HADDS; 617330), Chao et al. (2017) identified a de novo heterozygous c.488G-T transversion (c.488G-T, NM_001005463.2) in the EBF3 gene, resulting in an arg163-to-leu (R163L) substitution at a conserved residue in the DNA-binding domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. In vitro functional expression studies showed that the mutant protein had decreased induction of transcriptional activity compared to wildtype, consistent with it being a hypomorphic allele. Expression of the R163L mutation was unable to rescue the embryonic lethality and defects in development of the nervous system in Drosophila with homozygous loss of the Ebf3 homolog ('knot' or 'collier'), indicating that the R163L mutation results in a loss of function. </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>.0007 HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT 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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EBF3, ARG163PRO
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<br />
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SNP: rs1057519389,
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ClinVar: RCV000417019
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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 13-year-old boy of British descent (patient 272588) with hypotonia, ataxia, and delayed development syndrome (HADDS; 617330), Sleven et al. (2017) identified a de novo heterozygous c.488G-C transversion (c.488G-C, NM_001005463.2) in exon 6 of the EBF3 gene, resulting in an arg163-to-pro (R163P) substitution at a conserved residue in the DNA-binding domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP and Exome Variant Server databases; it was not found in the ExAC database. In vitro functional expression studies showed that the mutation ablated EBF3 transcription function. The mutant protein was able to form a heterodimer with wildtype EBF3, suggesting that it may have a dominant-negative effect. </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>.0008 HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
|
|
EBF3, LYS193ASN
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<br />
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SNP: rs1057519520,
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|
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|
|
ClinVar: RCV000416948, RCV003324747
|
|
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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>In an Irish girl (patient 262955) with hypotonia, ataxia, and delayed development syndrome (HADDS; 617330), Sleven et al. (2017) identified a de novo heterozygous c.579G-T transversion (c.579G-T, NM_001005463.2) in exon 7 of the EBF3 gene, resulting in a lys193-to-asn (K193N) substitution at a conserved residue in the DNA-binding domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP and Exome Variant Server databases; it was not found in the ExAC database. In vitro functional expression studies showed that the mutation resulted in decreased EBF3 transcription function compared to wildtype. The mutant protein was able to form a heterodimer with wildtype EBF3, suggesting that it may have a dominant-negative effect. </p>
|
|
</span>
|
|
</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>.0009 HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
EBF3, 4-BP DEL, NT280
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057519521,
|
|
|
|
|
|
|
|
ClinVar: RCV000416978, RCV001003596
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 8-year-old girl (patient 263361) of English descent with hypotonia, ataxia, and delayed development syndrome (HADDS; 617330), Sleven et al. (2017) identified a de novo heterozygous 4-bp deletion (c.280_283del, NM_001005463.2) in exon 2 of the EBF3 gene, resulting in a frameshift and premature termination (Glu94LysfsTer37). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP and Exome Variant Server databases; it was not found in the ExAC database. The mutation was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
EBF3, ARG206TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1057519522,
|
|
|
|
|
|
|
|
ClinVar: RCV000417012, RCV000495975, RCV000505244
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs of Indian descent (patients 67-1 and 67-4) with hypotonia, ataxia, and delayed development syndrome (HADDS; 617330), Sleven et al. (2017) identified a heterozygous c.616C-T transition (c.616C-T, NM_001005463.2) in exon 7 of the EBF3 gene, resulting in an arg206-to-ter (R206X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP and Exome Variant Server databases; it was not found in the ExAC database. The mutation was predicted to result in haploinsufficiency. Evidence suggested parental germline mosaicism. </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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Chao, H.-T., Davids, M., Burke, E., Pappas, J. G., Rosenfeld, J. A., McCarty, A. J., Davis, T., Wolfe, L., Toro, C., Tifft, C., Xia, F., Strong, N., and 10 others.
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|
<strong>A syndromic neurodevelopmental disorder caused by de novo variants in EBF3</strong>
|
|
Am. J. Hum. Genet. 100: 128-137, 2017.
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[PubMed: 28017372]
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[Full Text: https://doi.org/10.1016/j.ajhg.2016.11.018]
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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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Deisseroth, C. A., Lerma, V. C., Magyar, C. L., Pfliger, J. M., Nayak, A., Bliss, N. D., LeMaire, A. W., Narayanan, V., Balak, C., Zanni, G., Valente, E. M., Bertini, E., Benke, P. J., Wangler, M. F., Chao, H. T.
|
|
<strong>An integrated phenotypic and genotypic approach reveals a high-risk subtype association for EBF3 missense variants affecting the zinc finger domain.</strong>
|
|
Ann. Neurol. 92: 138-153, 2022.
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[PubMed: 35340043]
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[Full Text: https://doi.org/10.1002/ana.26359]
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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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Harms, F. L., Girisha, K. M., Hardigan, A. A., Kortum, F., Shukla, A., Alawi, M., Dalal, A., Brady, L., Tarnopolsky, M., Bird, L. M., Ceulemans, S., Bebin, M., and 21 others.
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<strong>Mutations in EBF3 disturb transcriptional profiles and cause intellectual disability, ataxia, and facial dysmorphism.</strong>
|
|
Am. J. Hum. Genet. 100: 117-127, 2017.
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[PubMed: 28017373]
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[Full Text: https://doi.org/10.1016/j.ajhg.2016.11.012]
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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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Padhi, E. M., Hayeck, T. J., Cheng, Z., Chatterjee, S., Mannion, B. J., Byrska-Bishop, M., Willems, M., Pinson, L., Redon, S., Benech, C., Uguen, K., Audebert-Bellanger, S., and 23 others.
|
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<strong>Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism.</strong>
|
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Hum. Genomics 15: 44, 2021.
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[PubMed: 34256850]
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[Full Text: https://doi.org/10.1186/s40246-021-00342-3]
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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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Sleven, H., Welsh, S. J., Yu, J., Churchill, M. E. A., Wright, C. F., Henderson, A., Horvath, R., Rankin, J., Vogt, J., Magee, A., McConnell, V., Green, A., and 11 others.
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<strong>De novo mutations in EBF3 cause a neurodevelopmental syndrome.</strong>
|
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Am. J. Hum. Genet. 100: 138-150, 2017.
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[PubMed: 28017370]
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[Full Text: https://doi.org/10.1016/j.ajhg.2016.11.020]
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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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Zardo, G., Tiirikainen, M. I., Hong, C., Misra, A., Feuerstein, B. G., Volik, S., Collins, C. C., Lamborn, K. R., Bollen, A., Pinkel, D., Albertson, D. G., Costello, J. F.
|
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<strong>Integrated genomic and epigenomic analyses pinpoint biallelic gene inactivation in tumors.</strong>
|
|
Nature Genet. 32: 453-458, 2002.
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[PubMed: 12355068]
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[Full Text: https://doi.org/10.1038/ng1007]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Sonja A. Rasmussen - updated : 01/24/2024<br>Sonja A. Rasmussen - updated : 02/23/2023<br>Cassandra L. Kniffin - updated : 02/01/2017
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</span>
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</div>
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</div>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 12/9/2002
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</span>
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</div>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Edit History:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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carol : 01/24/2024<br>carol : 02/23/2023<br>ckniffin : 08/14/2017<br>carol : 02/13/2017<br>carol : 02/08/2017<br>carol : 02/08/2017<br>carol : 02/07/2017<br>ckniffin : 02/01/2017<br>alopez : 12/19/2002<br>mgross : 12/9/2002
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