3976 lines
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Entry
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- *602054 - T-BOX TRANSCRIPTION FACTOR 1; TBX1
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- OMIM
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<p>
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<span class="h4">*602054</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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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="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</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/602054">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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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000184058;t=ENST00000649276" 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=6899" 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=602054" 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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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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<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=ENSG00000184058;t=ENST00000649276" 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_001379200,NM_005992,NM_080646,NM_080647,XM_006724312,XM_017028926,XM_017028927" 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_001379200" 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=602054" 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=09069&isoform_id=09069_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/TBX1" 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/2735861,2735863,5174711,6175055,14289455,18104950,18104952,109138677,119623429,119623430,119623431,239740411,239740412,239740413,302313189,578837373,1034629389,1824610210,2217340077,2462585390,2462585392,2462585394" 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/O43435" 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 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=6899" 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=ENSG00000184058;t=ENST00000649276" 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=TBX1" 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=TBX1" 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+6899" 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/TBX1" 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:6899" 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/6899" 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=chr22&hgg_gene=ENST00000649276.2&hgg_start=19756703&hgg_end=19783593&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:11592" 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://medlineplus.gov/genetics/gene/tbx1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=602054[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=602054[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/TBX1/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/ENSG00000184058" 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=TBX1" 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=TBX1" 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=TBX1" 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=TBX1&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/PA36355" 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:11592" 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/FBgn0021767.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:98493" 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/TBX1#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:98493" 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/6899/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=6899" 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=WBGene00003376;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-030805-5" 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=TBX1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 767263007, 86299006<br />
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<strong>ICD10CM:</strong> D82.1, Q21.3, Q93.81<br />
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<strong>ICD9CM:</strong> 279.11, 745.2, 758.32<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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602054
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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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T-BOX TRANSCRIPTION FACTOR 1; TBX1
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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">
|
|
T-BOX 1
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TBX1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TBX1</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>
|
|
Cytogenetic location: <a href="/geneMap/22/48?start=-3&limit=10&highlight=48">22q11.21</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr22:19756703-19783593&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'})">22:19,756,703-19,783,593</a> </span>
|
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</em>
|
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</strong>
|
|
<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>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<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>
|
|
Location
|
|
</th>
|
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<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=217095,188400,187500,192430" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/22/48?start=-3&limit=10&highlight=48">
|
|
22q11.21
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Conotruncal anomaly face syndrome
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/217095"> 217095 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
DiGeorge syndrome
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/188400"> 188400 </a>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
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</span>
|
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</td>
|
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</tr>
|
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Tetralogy of Fallot
|
|
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/187500"> 187500 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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<p><a href="#4" class="mim-tip-reference" title="Chieffo, C., Garvey, N., Gong, W., Roe, B., Zhang, G., Silver, L., Emanuel, B. S., Budarf, M. L. <strong>Isolation and characterization of a gene from the DiGeorge chromosomal region homologous to the mouse Tbx1 gene.</strong> Genomics 43: 267-277, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9268629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9268629</a>] [<a href="https://doi.org/10.1006/geno.1997.4829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9268629">Chieffo et al. (1997)</a> described the identification, cloning, and characterization of the human TBX1 gene, which maps to the center of the DiGeorge syndrome (DGS; <a href="/entry/188400">188400</a>) chromosomal region on 22q11.2. TBX1 is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes are transcription factors involved in the regulation of developmental processes (see TBX2, <a href="/entry/600747">600747</a>). Human and mouse TBX1 proteins share 98% amino acid identity overall and are identical except for 2 residues within the T-box domain. Expression of human TBX1 in adult and fetal tissues, as determined by Northern blot analysis, was similar to that found in the mouse. Additionally, using 3-prime RACE, <a href="#4" class="mim-tip-reference" title="Chieffo, C., Garvey, N., Gong, W., Roe, B., Zhang, G., Silver, L., Emanuel, B. S., Budarf, M. L. <strong>Isolation and characterization of a gene from the DiGeorge chromosomal region homologous to the mouse Tbx1 gene.</strong> Genomics 43: 267-277, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9268629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9268629</a>] [<a href="https://doi.org/10.1006/geno.1997.4829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9268629">Chieffo et al. (1997)</a> demonstrated a differentially spliced message in adult skeletal muscle. Mouse Tbx1 had previously been shown to be expressed during early embryogenesis in the pharyngeal arches, pouches, and otic vesicle. Later in development, expression was seen in the vertebral column and tooth bud. Thus, the authors concluded that TBX1 is a candidate for some of the features seen in the 22q11 deletion syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9268629" 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 TBX1 gene maps within the DiGeorge syndrome region on chromosome 22q11.2 (<a href="#4" class="mim-tip-reference" title="Chieffo, C., Garvey, N., Gong, W., Roe, B., Zhang, G., Silver, L., Emanuel, B. S., Budarf, M. L. <strong>Isolation and characterization of a gene from the DiGeorge chromosomal region homologous to the mouse Tbx1 gene.</strong> Genomics 43: 267-277, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9268629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9268629</a>] [<a href="https://doi.org/10.1006/geno.1997.4829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9268629">Chieffo et al., 1997</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9268629" 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="#22" class="mim-tip-reference" title="Vitelli, F., Viola, A., Morishima, M., Pramparo, T., Baldini, A., Lindsay, E. <strong>TBX1 is required for inner ear morphogenesis.</strong> Hum. Molec. Genet. 12: 2041-2048, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12913075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12913075</a>] [<a href="https://doi.org/10.1093/hmg/ddg216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12913075">Vitelli et al. (2003)</a> showed that Tbx1 is expressed early in otocyst development in the otic epithelium and in the periotic mesenchyme. Tbx -/- mice demonstrated severe inner ear defects that prevented the formation of the cochlea and of the vestibulum at the early otocyst stage and after neurogenesis. The authors proposed a model wherein Tbx1 is required for expansion of a subpopulation of otic epithelial cells, which in turn participate in formation of the vestibular and auditory organs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12913075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Chen, T., Heller, E., Beronja, S., Oshimori, N., Stokes, N., Fuchs, E. <strong>An RNA interference screen uncovers a new molecule in stem cell self-renewal and long-term regeneration.</strong> Nature 485: 104-108, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22495305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22495305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22495305[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10940" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22495305">Chen et al. (2012)</a> used RNA-interference-based loss-of-function screening as a powerful approach to uncover transcriptional regulators that govern the self-renewal capacity and regenerative potential of stem cells. Focusing on the nuclear proteins and/or transcription factors that are enriched in stem cells compared with their progeny, <a href="#3" class="mim-tip-reference" title="Chen, T., Heller, E., Beronja, S., Oshimori, N., Stokes, N., Fuchs, E. <strong>An RNA interference screen uncovers a new molecule in stem cell self-renewal and long-term regeneration.</strong> Nature 485: 104-108, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22495305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22495305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22495305[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10940" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22495305">Chen et al. (2012)</a> screened approximately 2,000 short hairpin RNAs for their effect on long-term, not short-term, stem cell self-renewal in vitro. They identified TBX1 in this screen and, by conditionally ablating TBX1 in vivo, showed that during homeostasis, tissue regeneration occurs normally but is markedly delayed. They then devised an in vivo assay for stem cell replenishment and found that when challenged with repetitive rounds of regeneration, the TBX1-deficient stem cell niche became progressively depleted. Addressing the mechanism of TBX1 action, <a href="#3" class="mim-tip-reference" title="Chen, T., Heller, E., Beronja, S., Oshimori, N., Stokes, N., Fuchs, E. <strong>An RNA interference screen uncovers a new molecule in stem cell self-renewal and long-term regeneration.</strong> Nature 485: 104-108, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22495305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22495305</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22495305[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10940" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22495305">Chen et al. (2012)</a> discovered that TBX1 acts as an intrinsic rheostat of BMP signaling: it is a gatekeeper that governs the transition between stem cell quiescence and proliferation in hair follicles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22495305" 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>To investigate mutations in the coding sequence of TBX1, <a href="#23" class="mim-tip-reference" title="Yagi, H., Furutani, Y., Hamada, H., Sasaki, T., Asakawa, S., Minoshima, S., Ichida, F., Joo, K., Kimura, M., Imamura, S., Kamatani, N., Momma, K., Takao, A., Nakazawa, M., Shimizu, N., Matsuoka, R. <strong>Role of TBX1 in human del22q11.2 syndrome.</strong> Lancet 362: 1366-1373, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14585638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14585638</a>] [<a href="https://doi.org/10.1016/s0140-6736(03)14632-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14585638">Yagi et al. (2003)</a> searched for mutations in the coding sequence of TBX1 in 13 patients from 10 families who had the 22q11.2 deletion syndrome phenotype but no detectable deletion of 22q11.2. In 2 unrelated patients, 1 with sporadic conotruncal anomaly face syndrome (<a href="/entry/217095">217095</a>)/velocardiofacial syndrome (VCFS; <a href="/entry/192430">192430</a>) and 1 with sporadic DiGeorge syndrome, and in 3 patients from a family with conotruncal anomaly face syndrome/velocardiofacial syndrome, they identified mutations in TBX1 (<a href="#0001">602054.0001</a>-<a href="#0003">602054.0003</a>). The findings of <a href="#23" class="mim-tip-reference" title="Yagi, H., Furutani, Y., Hamada, H., Sasaki, T., Asakawa, S., Minoshima, S., Ichida, F., Joo, K., Kimura, M., Imamura, S., Kamatani, N., Momma, K., Takao, A., Nakazawa, M., Shimizu, N., Matsuoka, R. <strong>Role of TBX1 in human del22q11.2 syndrome.</strong> Lancet 362: 1366-1373, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14585638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14585638</a>] [<a href="https://doi.org/10.1016/s0140-6736(03)14632-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14585638">Yagi et al. (2003)</a> indicated that TBX1 mutations are responsible for 5 major phenotypes that are components of the del22q11.2 syndrome: abnormal facies (conotruncal anomaly face), cardiac defects, thymic hypoplasia, velopharyngeal insufficiency with cleft palate, and parathyroid dysfunction with hypocalcemia; they are not responsible for typical mental retardation that is commonly seen in patients with del22q11.2 syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14585638" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Packham, E. A., Brook, J. D. <strong>T-box genes in human disorders.</strong> Hum. Molec. Genet. 12(R1): R37-R44, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668595</a>] [<a href="https://doi.org/10.1093/hmg/ddg077" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12668595">Packham and Brook (2003)</a> reviewed the human disorders that have been linked to mutations in T-box genes: Holt-Oram syndrome (HOS; <a href="/entry/142900">142900</a>), ulnar-mammary syndrome (UMS; <a href="/entry/181450">181450</a>), DiGeorge syndrome, ACTH deficiency (<a href="/entry/201400">201400</a>), and cleft palate with ankyloglossia (CPX; <a href="/entry/303400">303400</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12668595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Paylor, R., Glaser, B., Mupo, A., Ataliotis, P., Spencer, C., Sobotka, A., Sparks, C., Choi, C.-H., Oghalai, J., Curran, S., Murphy, K. C., Monks, S., Williams, N., O'Donovan, M. C., Owen, M. J., Scambler, P. J., Lindsay, E. <strong>Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome.</strong> Proc. Nat. Acad. Sci. 103: 7729-7734, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16684884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16684884</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16684884[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0600206103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16684884">Paylor et al. (2006)</a> identified a heterozygous 23-bp deletion in the TBX1 gene (<a href="#0004">602054.0004</a>) in a mother and 2 sons with velocardiofacial syndrome. The mother also had major depression (<a href="/entry/608516">608516</a>) and 1 of the sons was diagnosed with Asperger syndrome (see, e.g., <a href="/entry/608638">608638</a> and <a href="/entry/209850">209850</a>). <a href="#15" class="mim-tip-reference" title="Paylor, R., Glaser, B., Mupo, A., Ataliotis, P., Spencer, C., Sobotka, A., Sparks, C., Choi, C.-H., Oghalai, J., Curran, S., Murphy, K. C., Monks, S., Williams, N., O'Donovan, M. C., Owen, M. J., Scambler, P. J., Lindsay, E. <strong>Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome.</strong> Proc. Nat. Acad. Sci. 103: 7729-7734, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16684884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16684884</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16684884[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0600206103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16684884">Paylor et al. (2006)</a> suggested that the TBX1 gene is a candidate for psychiatric disease in patients with VCFS and DiGeorge syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16684884" 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="#24" class="mim-tip-reference" title="Zweier, C., Sticht, H., Aydin-Yaylagul, I., Campbell, C. E., Rauch, A. <strong>Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions.</strong> Am. J. Hum. Genet. 80: 510-517, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273972[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/511993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273972">Zweier et al. (2007)</a> reported a novel heterozygous missense mutation, H194Q (<a href="#0005">602054.0005</a>), in a familial case of Shprintzen velocardiofacial syndrome and showed that this and 2 previously reported missense mutations, F148Y (<a href="#0001">602054.0001</a>) and G310S (<a href="#0002">602054.0002</a>), result in gain of function, possibly through stabilization of the protein dimer DNA complex. They concluded therefore that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17273972" 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>Mice deleted for a region of chromosome 16 syntenic to human 22q11.2 (Df(16)1 mice), the region most often deleted in DiGeorge syndrome (DGS; <a href="/entry/188400">188400</a>), display a phenotype featuring cardiovascular abnormalities characteristic of the human disease (<a href="#11" class="mim-tip-reference" title="Lindsay, E. A., Botta, A., Jurecic, V., Carattini-Rivera, S., Cheah, Y.-C., Rosenblatt, H. M., Bradley, A., Baldini, A. <strong>Congenital heart disease in mice deficient for the DiGeorge syndrome region.</strong> Nature 401: 379-383, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10517636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10517636</a>] [<a href="https://doi.org/10.1038/43900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10517636">Lindsay et al., 1999</a>). Using a combination of chromosome engineering and P1 artificial chromosome transgenesis, <a href="#12" class="mim-tip-reference" title="Lindsay, E. A., Vitelli, F., Su, H., Morishima, M., Huynh, T., Pramparo, T., Jurecic, V., Ogunrinu, G., Sutherland, H. F., Scambler, P. J., Bradley, A., Baldini, A. <strong>Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice.</strong> Nature 410: 97-101, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242049</a>] [<a href="https://doi.org/10.1038/35065105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242049">Lindsay et al. (2001)</a> localized the Tbx1 gene in mouse to this region of chromosome 16. <a href="#12" class="mim-tip-reference" title="Lindsay, E. A., Vitelli, F., Su, H., Morishima, M., Huynh, T., Pramparo, T., Jurecic, V., Ogunrinu, G., Sutherland, H. F., Scambler, P. J., Bradley, A., Baldini, A. <strong>Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice.</strong> Nature 410: 97-101, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242049</a>] [<a href="https://doi.org/10.1038/35065105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242049">Lindsay et al. (2001)</a> showed that Tbx1 is required for normal development of the pharyngeal arch arteries in a gene dosage-dependent manner. Deletion of 1 copy of Tbx1 affected the development of the fourth pharyngeal arch arteries, whereas homozygous mutation severely disrupted the entire pharyngeal arch artery system. <a href="#12" class="mim-tip-reference" title="Lindsay, E. A., Vitelli, F., Su, H., Morishima, M., Huynh, T., Pramparo, T., Jurecic, V., Ogunrinu, G., Sutherland, H. F., Scambler, P. J., Bradley, A., Baldini, A. <strong>Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice.</strong> Nature 410: 97-101, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242049</a>] [<a href="https://doi.org/10.1038/35065105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242049">Lindsay et al. (2001)</a> concluded that haploinsufficiency of Tbx1 is sufficient to generate at least 1 important component of the DiGeorge syndrome phenotype in mice. Their data demonstrated the suitability of the mouse for the genetic dissection of microdeletion syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10517636+11242049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Jerome, L. A., Papaioannou, V. E. <strong>DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1.</strong> Nature Genet. 27: 286-291, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242110</a>] [<a href="https://doi.org/10.1038/85845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242110">Jerome and Papaioannou (2001)</a> investigated the potential role of the TBX1 gene in DGS/VCFS (<a href="/entry/192430">192430</a>) by producing a null mutation in mice. They found that mice heterozygous for the mutation had a high incidence of cardiac outflow tract anomalies, thus modeling one of the major abnormalities of the human syndrome. Moreover, Tbx1 -/- mice displayed a wide range of developmental anomalies encompassing almost all of the common DGS/VCFS features, including hypoplasia of thymus and parathyroid glands, cardiac outflow tract abnormalities, abnormal facial structures, abnormal vertebrae, and cleft palate. On the basis of this phenotype in mice, they proposed that TBX1 in humans is a key gene in the etiology of DGS/VCFS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242110" 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="#13" class="mim-tip-reference" title="Merscher, S., Funke, B., Epstein, J. A., Heyer, J., Puech, A., Lu, M. M., Xavier, R. J., Demay, M. B., Russell, R. G., Factor, S., Tokooya, K., St. Jore, B., and 12 others. <strong>TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome.</strong> Cell 104: 619-629, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11239417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11239417</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00247-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11239417">Merscher et al. (2001)</a> used a Cre-loxP strategy to generate mice that were hemizygous for a 1.5-Mb deletion corresponding to that on 22q11 in VCFS/DGS patients. These mice exhibited significant perinatal lethality and had conotruncal and parathyroid defects. The conotruncal defects could be partially rescued by a human BAC containing the TBX1 gene. Mice heterozygous for a null mutation in Tbx1 developed conotruncal defects. These results together with the expression patterns of TBX1 suggested a major role for the TBX1 gene in the molecular etiology of VCFS/DGS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11239417" 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="#6" class="mim-tip-reference" title="Funke, B., Epstein, J. A., Kochilas, L. K., Lu, M. M., Pandita, R. K., Liao, J., Bauerndistel, R., Schuler, T., Schorle, H., Brown, M. C., Adams, J., Morrow, B. E. <strong>Mice overexpressing genes from the 22q11 region deleted in velo-cardio-facial syndrome/DiGeorge syndrome have middle and inner ear defects.</strong> Hum. Molec. Genet. 10: 2549-2556, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11709542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11709542</a>] [<a href="https://doi.org/10.1093/hmg/10.22.2549" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11709542">Funke et al. (2001)</a> reported that mice overexpressing 4 transgenes (PNUTL1, <a href="/entry/602724">602724</a>; GP1BB, <a href="/entry/138720">138720</a>; TBX1; and WDR14, <a href="/entry/610778">610778</a>) had chronic otitis media, a hyperactive circling behavior, and sensorineural hearing loss. This was associated with middle and inner ear malformations analogous to human Mondini dysplasia, reported to occur in VCFS/DGS patients. Based upon its pattern of expression in the ear and functional studies of the gene, the authors hypothesized that Tbx1 likely plays a central role in the etiology of ear defects in these mice, and that haploinsufficiency of TBX1 may be responsible for ear disorders in VCFS/DGS patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11709542" 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="#21" class="mim-tip-reference" title="Vitelli, F., Morishima, M., Taddei, I., Lindsay, E. A., Baldini, A. <strong>Tbx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways.</strong> Hum. Molec. Genet. 11: 915-922, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11971873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11971873</a>] [<a href="https://doi.org/10.1093/hmg/11.8.915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11971873">Vitelli et al. (2002)</a> showed that Tbx1 deficiency in transgenic mice caused a number of distinct vascular and heart defects, affecting formation and growth of the pharyngeal arch arteries, growth and septation of the outflow tract of the heart, interventricular septation, and conal alignment. Comparison of phenotype and gene expression using a Tbx1-lacZ reporter allele supported a cell-autonomous function in the growth of the pharyngeal apparatus, and a cell-non-autonomous function in the growth and early remodeling of the pharyngeal arch arteries. The data did not support a direct role of neural crest cells in the pathogenesis of the Tbx1 mutant phenotype; however, these cells and the cranial nerves were misdirected. The authors hypothesized that this is due to the lack of a guidance role from the pouch endoderm, which is missing in these mutants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11971873" 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="#18" class="mim-tip-reference" title="Stalmans, I., Lambrechts, D., De Smet, F., Jansen, S., Wang, J., Maity, S., Kneer, P., von der Ohe, M., Swillen, A., Maes, C., Gewillig, M., Molin, D. G. M., and 20 others. <strong>VEGF: a modifier of the del22q11 (DiGeorge) syndrome?</strong> Nature Med. 9: 173-182, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12539040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12539040</a>] [<a href="https://doi.org/10.1038/nm819" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12539040">Stalmans et al. (2003)</a> reported that absence of the 164-amino acid isoform of Vegf (Vegf164; see <a href="/entry/192240">192240</a>), the only one that binds neuropilin-1 (NRP1; <a href="/entry/602069">602069</a>), causes birth defects in mice reminiscent of those found in patients with deletion of 22q11. The close correlation of birth and vascular defects indicated that vascular dysgenesis may pathogenetically contribute to the birth defects. Vegf interacted with Tbx1, as Tbx1 expression was reduced in Vegf164-deficient embryos and knocked-down Vegf levels enhanced the pharyngeal arch artery defects induced by Tbx1 knockdown in zebrafish. Moreover, initial evidence suggested that a VEGF promoter haplotype was associated with an increased risk for cardiovascular birth defects in del22q11 individuals. <a href="#18" class="mim-tip-reference" title="Stalmans, I., Lambrechts, D., De Smet, F., Jansen, S., Wang, J., Maity, S., Kneer, P., von der Ohe, M., Swillen, A., Maes, C., Gewillig, M., Molin, D. G. M., and 20 others. <strong>VEGF: a modifier of the del22q11 (DiGeorge) syndrome?</strong> Nature Med. 9: 173-182, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12539040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12539040</a>] [<a href="https://doi.org/10.1038/nm819" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12539040">Stalmans et al. (2003)</a> concluded that genetic data in mouse, fish, and human indicated that VEGF is a modifier of cardiovascular birth defects in the del22q11 syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12539040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Guris, D. L., Duester, G., Papaioannou, V. E., Imamoto, A. <strong>Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome.</strong> Dev. Cell 10: 81-92, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16399080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16399080</a>] [<a href="https://doi.org/10.1016/j.devcel.2005.12.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16399080">Guris et al. (2006)</a> found that compound heterozygosity for null alleles of the mouse Crkl (<a href="/entry/602007">602007</a>) and Tbx1 genes recapitulated thymic, parathyroid, and cardiovascular defects characteristic of DGS at a penetrance far greater than that generated by heterozygosity of Crkl or Tbx1 alone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16399080" 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="Baldini, A. <strong>DiGeorge syndrome: the use of model organisms to dissect complex genetics.</strong> Hum. Molec. Genet. 11: 2363-2369, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12351571/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12351571</a>] [<a href="https://doi.org/10.1093/hmg/11.20.2363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12351571">Baldini (2002)</a> reviewed the molecular basis of DiGeorge syndrome, with special emphasis on mouse models and the role of TBX1 in development of the pharyngeal arches. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12351571" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Paylor, R., McIlwain, K. L., McAninch, R., Nellis, A., Yuva-Paylor, L. A., Baldini, A., Lindsay, E. A. <strong>Mice deleted for the DiGeorge/velocardiofacial syndrome region show abnormal sensorimotor gating and learning and memory impairments.</strong> Hum. Molec. Genet. 10: 2645-2650, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11726551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11726551</a>] [<a href="https://doi.org/10.1093/hmg/10.23.2645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11726551">Paylor et al. (2001)</a> showed that Df1/+ mice have deficits in learning, memory, and sensorimotor gating, as measured by prepulse inhibition (PPI) of the startle response. Decreased PPI is associated with several psychiatric and behavioral disorders, including schizophrenia (<a href="/entry/181500">181500</a>) and Asperger syndrome (see, e.g., <a href="/entry/608638">608638</a> and <a href="/entry/209850">209850</a>). By detailed mapping of Df1/+ mice, <a href="#15" class="mim-tip-reference" title="Paylor, R., Glaser, B., Mupo, A., Ataliotis, P., Spencer, C., Sobotka, A., Sparks, C., Choi, C.-H., Oghalai, J., Curran, S., Murphy, K. C., Monks, S., Williams, N., O'Donovan, M. C., Owen, M. J., Scambler, P. J., Lindsay, E. <strong>Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome.</strong> Proc. Nat. Acad. Sci. 103: 7729-7734, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16684884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16684884</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16684884[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0600206103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16684884">Paylor et al. (2006)</a> found that the PPI deficit was due to haploinsufficiency of 2 adjacent genes, Tbx1 and Gnb1l. Mutation in either gene was sufficient to cause reduced PPI. <a href="#15" class="mim-tip-reference" title="Paylor, R., Glaser, B., Mupo, A., Ataliotis, P., Spencer, C., Sobotka, A., Sparks, C., Choi, C.-H., Oghalai, J., Curran, S., Murphy, K. C., Monks, S., Williams, N., O'Donovan, M. C., Owen, M. J., Scambler, P. J., Lindsay, E. <strong>Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome.</strong> Proc. Nat. Acad. Sci. 103: 7729-7734, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16684884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16684884</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16684884[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0600206103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16684884">Paylor et al. (2006)</a> suggested that the Tbx1 gene may be a candidate for psychiatric disease in patients with DiGeorge syndrome or velocardiofacial syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16684884+11726551" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Liao, J., Kochilas, L., Nowotschin, S., Arnold, J. S., Aggarwal, V. S., Epstein, J. A., Brown, M. C., Adams, J., Morrow, B. E. <strong>Full spectrum of malformations in velo-cardio-facial syndrome/DiGeorge syndrome mouse models by altering Tbx1 dosage.</strong> Hum. Molec. Genet. 13: 1577-1585, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15190012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15190012</a>] [<a href="https://doi.org/10.1093/hmg/ddh176" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15190012">Liao et al. (2004)</a> reported that mice hemizygous for a null allele of Tbx1 had mild malformations, while homozygotes had severe malformations in the affected structures. Neither pattern of malformation precisely modeled VCFS or DGS. Furthermore, bacterial artificial chromosome (BAC) transgenic mice overexpressing human TBX1 and 3 other transgenes had similar malformations to VCFS/DGS patients. By employing genetic complementation studies, the authors demonstrated that altered TBX1 dosage, rather than overexpression of the other transgenes, was responsible for most of the defects in the BAC transgenic mice. Furthermore, the full spectrum of VCFS/DGS malformations was elicited in a TBX1 dose-dependent manner, thus providing a molecular basis for the pathogenesis and varied expressivity of the syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15190012" 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="#9" class="mim-tip-reference" title="Kelly, R. G., Jerome-Majewska, L. A., Papaioannou, V. E. <strong>The del22q11.2 candidate gene Tbx1 regulates branchiomeric myogenesis.</strong> Hum. Molec. Genet. 13: 2829-2840, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15385444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15385444</a>] [<a href="https://doi.org/10.1093/hmg/ddh304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15385444">Kelly et al. (2004)</a> showed that branchiomeric muscle development was severely perturbed in Tbx1 mutant mice. In the absence of Tbx1, the myogenic determination genes Myf5 (<a href="/entry/159990">159990</a>) and MyoD (<a href="/entry/159970">159970</a>) failed to be normally activated in pharyngeal mesoderm. Unspecified precursor cells expressing genes encoding the transcriptional repressors capsulin (TCF21; <a href="/entry/603306">603306</a>) and MyoR (MSC; <a href="/entry/603628">603628</a>) were present in the mandibular arch of Tbx1 mutant embryos. Sporadic activation of Myf5 and MyoD in these precursor cells resulted in the random presence or absence of hypoplastic mandibular arch-derived muscles at later developmental stages. Tbx1 was also required for normal expression of Tlx1 (<a href="/entry/186770">186770</a>) and Fgf10 (<a href="/entry/602115">602115</a>) in pharyngeal mesoderm, in addition to correct neural crest cell patterning in the mandibular arch. <a href="#9" class="mim-tip-reference" title="Kelly, R. G., Jerome-Majewska, L. A., Papaioannou, V. E. <strong>The del22q11.2 candidate gene Tbx1 regulates branchiomeric myogenesis.</strong> Hum. Molec. Genet. 13: 2829-2840, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15385444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15385444</a>] [<a href="https://doi.org/10.1093/hmg/ddh304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15385444">Kelly et al. (2004)</a> concluded that Tbx1 regulates the onset of branchiomeric myogenesis and controls normal mandibular arch development, including robust transcriptional activation of myogenic determination genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15385444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Arnold, J. S., Braunstein, E. M., Ohyama, T., Groves, A. K., Adams, J. C., Brown, M. C., Morrow, B. E. <strong>Tissue-specific roles of Tbx1 in the development of the outer, middle and inner ear, defective in 22q11DS patients.</strong> Hum. Molec. Genet. 15: 1629-1639, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16600992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16600992</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16600992[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddl084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16600992">Arnold et al. (2006)</a> found that mice with conditional deletion of Tbx1 in the otic vesicle, which derives from the ectoderm, and in the pharyngeal pouch, which derives from the endoderm, caused an ear phenotype identical to that of homozygous Tbx1-null mutants. Tbx1-ablation specific to the pharyngeal pouch endoderm caused absence of the auditory tube, middle, and outer ears because of failed expansion of the first pharyngeal pouch. Tbx1-ablation specific to the otic vesicle resulted in failure to form inner ear sensory organs as well as expansion of the cochleovestibular ganglion, but outer and middle ear formation remained unaffected. Thus, Tbx1 in the otic vesicle has cell-autonomous roles in patterning the inner ear, and expression of Tbx1 in the periotic mesenchyme cannot rescue these inner ear defects. <a href="#1" class="mim-tip-reference" title="Arnold, J. S., Braunstein, E. M., Ohyama, T., Groves, A. K., Adams, J. C., Brown, M. C., Morrow, B. E. <strong>Tissue-specific roles of Tbx1 in the development of the outer, middle and inner ear, defective in 22q11DS patients.</strong> Hum. Molec. Genet. 15: 1629-1639, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16600992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16600992</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16600992[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddl084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16600992">Arnold et al. (2006)</a> concluded that Tbx1 has tissue-specific roles during ear development and suggested that Tbx1 may contribute to middle and inner ear malformations in DGS patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16600992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Theveniau-Ruissy, M., Dandonneau, M., Mesbah, K., Ghez, O., Mattei, M.-G., Miquerol, L., Kelly, R. G. <strong>The del22q11.2 candidate gene Tbx1 controls regional outflow tract identity and coronary artery patterning.</strong> Circ. Res. 103: 142-148, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18583714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18583714</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.108.172189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18583714">Theveniau-Ruissy et al. (2008)</a> noted that mice heterozygous for a Tbx1-null allele display a high frequency of fourth aortic arch artery defects, and that absence of Tbx1 leads to underproliferation of the second heart field, hypoplasia of the distal outflow tract, and a common ventricular outlet. Restoration of Tbx1 expression in the second heart field is sufficient to rescue outflow tract development in a Tbx1 mutant background. <a href="#20" class="mim-tip-reference" title="Theveniau-Ruissy, M., Dandonneau, M., Mesbah, K., Ghez, O., Mattei, M.-G., Miquerol, L., Kelly, R. G. <strong>The del22q11.2 candidate gene Tbx1 controls regional outflow tract identity and coronary artery patterning.</strong> Circ. Res. 103: 142-148, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18583714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18583714</a>] [<a href="https://doi.org/10.1161/CIRCRESAHA.108.172189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18583714">Theveniau-Ruissy et al. (2008)</a> found that a myocardial subdomain normally associated with the base of the pulmonary trunk was reduced and malpositioned in embryonic Tbx1 mutant mouse hearts. The defect was associated with highly anomalous coronary artery trajectories, revealing a critical role for Tbx1 in the regulation of regional outflow tract identity and implicating the second heart field in coronary artery patterning. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18583714" 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="#5" class="mim-tip-reference" title="Choi, M., Klingensmith, J. <strong>Chordin is a modifier of Tbx1 for the craniofacial malformations of 22q11 deletion syndrome phenotypes in mouse.</strong> PLos Genet. 5: e1000395, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19247433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19247433</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19247433[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1000395" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19247433">Choi and Klingensmith (2009)</a> demonstrated that chordin (CHRD; <a href="/entry/603475">603475</a>) is a modifier of the observed craniofacial anomalies of Tbx1 mutations in mice. The Tbx1-null mouse phenotype is similar to the Chrd-null mouse phenotype, which includes dysmorphic ears, absence of the thymus, persistent truncus arteriosus, and cleft palate. However, penetrance of the Chrd-null phenotype is highly dependent on genetic background. In an inbred Chrd-null mouse strain with full penetrance, the authors found that a splice site mutation in the Tbx1 gene was a modifier influencing phenotypic expression. Chrd-null mice without the Tbx1 mutation had a low penetrance of mandibular hypoplasia, but no cardiac or thoracic organ malformations. The hypomorphic Tbx1 allele resulted in defects resembling 22q11 deletion syndrome, but with a low penetrance of craniofacial malformations, unless Chrd was also mutant. Expression studies suggested that Chrd has a role in promoting Tbx1 expression. The findings suggested that chordin is a modifier of the craniofacial anomalies of Tbx1 mutations, demonstrating the existence of a second-site modifier for a specific subset of the phenotypes associated with 22q11 deletion syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19247433" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<p>In a sporadic case of conotruncal anomaly face syndrome (<a href="/entry/217095">217095</a>)/velocardiofacial syndrome (<a href="/entry/192430">192430</a>), <a href="#23" class="mim-tip-reference" title="Yagi, H., Furutani, Y., Hamada, H., Sasaki, T., Asakawa, S., Minoshima, S., Ichida, F., Joo, K., Kimura, M., Imamura, S., Kamatani, N., Momma, K., Takao, A., Nakazawa, M., Shimizu, N., Matsuoka, R. <strong>Role of TBX1 in human del22q11.2 syndrome.</strong> Lancet 362: 1366-1373, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14585638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14585638</a>] [<a href="https://doi.org/10.1016/s0140-6736(03)14632-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14585638">Yagi et al. (2003)</a> identified a 443T-A transversion in the TBX1 gene, predicted to result in a phe148-to-tyr (F148Y) substitution. The patient had typical conotruncal anomaly face and velopharyngeal insufficiency, tetralogy of Fallot, pulmonary atresia, atrial septal defect, and major aorticopulmonary collateral artery. She did not have typical mental retardation that is commonly seen in patients with del22q11.2 syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14585638" 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="#24" class="mim-tip-reference" title="Zweier, C., Sticht, H., Aydin-Yaylagul, I., Campbell, C. E., Rauch, A. <strong>Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions.</strong> Am. J. Hum. Genet. 80: 510-517, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273972[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/511993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273972">Zweier et al. (2007)</a> concluded that the F148Y missense mutation like other cause gain of function, probably through similar effects on TBX1 structure that result in an increased dimer stability and/or DNA-binding affinity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17273972" 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=RCV000008000 OR RCV000618981 OR RCV000828677" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008000, RCV000618981, RCV000828677" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008000...</a>
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<p>In a sporadic case of DiGeorge syndrome (<a href="/entry/188400">188400</a>), <a href="#23" class="mim-tip-reference" title="Yagi, H., Furutani, Y., Hamada, H., Sasaki, T., Asakawa, S., Minoshima, S., Ichida, F., Joo, K., Kimura, M., Imamura, S., Kamatani, N., Momma, K., Takao, A., Nakazawa, M., Shimizu, N., Matsuoka, R. <strong>Role of TBX1 in human del22q11.2 syndrome.</strong> Lancet 362: 1366-1373, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14585638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14585638</a>] [<a href="https://doi.org/10.1016/s0140-6736(03)14632-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14585638">Yagi et al. (2003)</a> identified a heterozygous 928G-A transition in the TBX1 gene, predicted to result in a gly310-to-ser (G310S) substitution. The patient had typical conotruncal anomaly face and velopharyngeal insufficiency, interrupted aortic arch (type B), and perimembranous-type ventricular septal defect with pulmonary hypertension, absent thymus, parathyroid dysfunction, and deafness. He did not have mental retardation and was in a regular class of a junior high school. Thus the patient had all 5 major phenotypes of the 22q11.2 deletion syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14585638" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 CONOTRUNCAL ANOMALY FACE SYNDROME/VELOCARDIOFACIAL 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">rs1601294362 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1601294362;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=rs1601294362" 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=rs1601294362" 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=RCV001815166" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001815166" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001815166</a>
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<p>In a mother and her son and daughter with conotruncal anomaly face syndrome (<a href="/entry/217095">217095</a>)/velocardiofacial syndrome (<a href="/entry/192430">192430</a>) and normal intelligence, <a href="#23" class="mim-tip-reference" title="Yagi, H., Furutani, Y., Hamada, H., Sasaki, T., Asakawa, S., Minoshima, S., Ichida, F., Joo, K., Kimura, M., Imamura, S., Kamatani, N., Momma, K., Takao, A., Nakazawa, M., Shimizu, N., Matsuoka, R. <strong>Role of TBX1 in human del22q11.2 syndrome.</strong> Lancet 362: 1366-1373, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14585638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14585638</a>] [<a href="https://doi.org/10.1016/s0140-6736(03)14632-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14585638">Yagi et al. (2003)</a> identified a heterozygous 1-bp deletion, 1223delC, in the TBX1 gene. The deletion occurred at codon 408 and caused a frameshift leading to a stop codon after 51 codons. This truncated TBX1 protein remained as the DNA binding motif but did not have the C-terminal region, including the putative activator and repressor domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14585638" 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="#19" class="mim-tip-reference" title="Stoller, J. Z., Epstein, J. A. <strong>Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation.</strong> Hum. Molec. Genet. 14: 885-892, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703190</a>] [<a href="https://doi.org/10.1093/hmg/ddi081" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15703190">Stoller and Epstein (2005)</a> identified a previously unrecognized nuclear localization signal (NLS) at the C terminus of Tbx1 that is deleted by the 1223delC mutation, thus explaining the mechanism of disease in DiGeorge syndrome patients with this mutation. The NLS is conserved across species among T-box family members, including T (<a href="/entry/601397">601397</a>) and TBX10 (<a href="/entry/604648">604648</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15703190" 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=RCV000008002" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008002" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008002</a>
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<p>In a mother and 2 sons with velocardiofacial syndrome (<a href="/entry/192430">192430</a>), <a href="#15" class="mim-tip-reference" title="Paylor, R., Glaser, B., Mupo, A., Ataliotis, P., Spencer, C., Sobotka, A., Sparks, C., Choi, C.-H., Oghalai, J., Curran, S., Murphy, K. C., Monks, S., Williams, N., O'Donovan, M. C., Owen, M. J., Scambler, P. J., Lindsay, E. <strong>Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome.</strong> Proc. Nat. Acad. Sci. 103: 7729-7734, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16684884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16684884</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16684884[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0600206103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16684884">Paylor et al. (2006)</a> identified a heterozygous 23-bp deletion in the TBX1 gene (1320-1342del23), resulting in a frameshift and extension of the protein from 504 to 616 amino acids. The mother had major depression (<a href="/entry/608516">608516</a>) and 1 of the sons was diagnosed with Asperger syndrome (see, e.g., <a href="/entry/608638">608638</a> and <a href="/entry/209850">209850</a>). <a href="#15" class="mim-tip-reference" title="Paylor, R., Glaser, B., Mupo, A., Ataliotis, P., Spencer, C., Sobotka, A., Sparks, C., Choi, C.-H., Oghalai, J., Curran, S., Murphy, K. C., Monks, S., Williams, N., O'Donovan, M. C., Owen, M. J., Scambler, P. J., Lindsay, E. <strong>Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome.</strong> Proc. Nat. Acad. Sci. 103: 7729-7734, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16684884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16684884</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16684884[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0600206103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16684884">Paylor et al. (2006)</a> suggested that the TBX1 gene is a candidate for psychiatric disease in patients with VCFS and DiGeorge syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16684884" 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">rs74315522 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74315522;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=rs74315522" 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=rs74315522" 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=RCV000008003" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008003" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008003</a>
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<p>In a familial case of Shprintzen velocardiofacial syndrome (<a href="/entry/192430">192430</a>), <a href="#24" class="mim-tip-reference" title="Zweier, C., Sticht, H., Aydin-Yaylagul, I., Campbell, C. E., Rauch, A. <strong>Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions.</strong> Am. J. Hum. Genet. 80: 510-517, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273972[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/511993" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17273972">Zweier et al. (2007)</a> described the third missense mutation and the fifth overall mutation in TBX1. Their observations expanded the associated phenotype to include short stature and, possibly, developmental delay. They provided the first evidence that TBX1 missense mutations can alter the transcriptional activity of the TBX1 protein. They concluded that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17273972" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs746335599 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs746335599;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/rs746335599?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=rs746335599" 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=rs746335599" 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=RCV000599046 OR RCV002310991 OR RCV002532692" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000599046, RCV002310991, RCV002532692" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000599046...</a>
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<p>In a Turkish patient with tetralogy of Fallot (<a href="/entry/187500">187500</a>), <a href="#17" class="mim-tip-reference" title="Rauch, R., Hofbeck, M., Zweier, C., Koch, A., Zink, S., Trautmann, U., Hoyer, J., Kaulitz, R., Singer, H., Rauch, A. <strong>Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot.</strong> J. Med. Genet. 47: 321-331, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19948535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19948535</a>] [<a href="https://doi.org/10.1136/jmg.2009.070391" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19948535">Rauch et al. (2010)</a> identified a heterozygous 30-bp duplication (1399_1428dup30) in exon 9c of the TBX1 gene. She had facial asymmetry, scoliosis, absent pulmonary vein, isolated left pulmonary artery, ventricular septal defect, and normal cognitive development. She did not have the facial gestalt of 22q11.2 deletion syndrome. The insertion was shown to result in the expansion of a polyalanine tract, which caused decreased transcriptional activity and cytoplasmic aggregation of the protein in cellular studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19948535" 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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Arnold, J. S., Braunstein, E. M., Ohyama, T., Groves, A. K., Adams, J. C., Brown, M. C., Morrow, B. E.
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<strong>Tissue-specific roles of Tbx1 in the development of the outer, middle and inner ear, defective in 22q11DS patients.</strong>
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Hum. Molec. Genet. 15: 1629-1639, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19948535/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19948535</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19948535" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2009.070391" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Stalmans2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stalmans, I., Lambrechts, D., De Smet, F., Jansen, S., Wang, J., Maity, S., Kneer, P., von der Ohe, M., Swillen, A., Maes, C., Gewillig, M., Molin, D. G. M., and 20 others.
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|
<strong>VEGF: a modifier of the del22q11 (DiGeorge) syndrome?</strong>
|
|
Nature Med. 9: 173-182, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12539040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12539040</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12539040" 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/nm819" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Stoller2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stoller, J. Z., Epstein, J. A.
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|
<strong>Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation.</strong>
|
|
Hum. Molec. Genet. 14: 885-892, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15703190/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15703190</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15703190" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi081" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Theveniau-Ruissy2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Theveniau-Ruissy, M., Dandonneau, M., Mesbah, K., Ghez, O., Mattei, M.-G., Miquerol, L., Kelly, R. G.
|
|
<strong>The del22q11.2 candidate gene Tbx1 controls regional outflow tract identity and coronary artery patterning.</strong>
|
|
Circ. Res. 103: 142-148, 2008.
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|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18583714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18583714</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18583714" 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/10.1161/CIRCRESAHA.108.172189" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Vitelli2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vitelli, F., Morishima, M., Taddei, I., Lindsay, E. A., Baldini, A.
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<strong>Tbx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways.</strong>
|
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Hum. Molec. Genet. 11: 915-922, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11971873/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11971873</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11971873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/11.8.915" target="_blank">Full Text</a>]
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Vitelli2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vitelli, F., Viola, A., Morishima, M., Pramparo, T., Baldini, A., Lindsay, E.
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<strong>TBX1 is required for inner ear morphogenesis.</strong>
|
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Hum. Molec. Genet. 12: 2041-2048, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12913075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12913075</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12913075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg216" target="_blank">Full Text</a>]
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<a id="23" class="mim-anchor"></a>
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<a id="Yagi2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yagi, H., Furutani, Y., Hamada, H., Sasaki, T., Asakawa, S., Minoshima, S., Ichida, F., Joo, K., Kimura, M., Imamura, S., Kamatani, N., Momma, K., Takao, A., Nakazawa, M., Shimizu, N., Matsuoka, R.
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<strong>Role of TBX1 in human del22q11.2 syndrome.</strong>
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Lancet 362: 1366-1373, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14585638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14585638</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14585638" 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/s0140-6736(03)14632-6" target="_blank">Full Text</a>]
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</div>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Zweier2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zweier, C., Sticht, H., Aydin-Yaylagul, I., Campbell, C. E., Rauch, A.
|
|
<strong>Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions.</strong>
|
|
Am. J. Hum. Genet. 80: 510-517, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17273972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17273972</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17273972[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=17273972" 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/10.1086/511993" target="_blank">Full Text</a>]
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</p>
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</div>
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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>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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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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Ada Hamosh - updated : 9/20/2012
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 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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Cassandra L. Kniffin - updated : 8/16/2010<br>Cassandra L. Kniffin - updated : 6/3/2010<br>Cassandra L. Kniffin - updated : 6/5/2009<br>Patricia A. Hartz - updated : 4/15/2009<br>George E. Tiller - updated : 4/29/2008<br>George E. Tiller - updated : 5/22/2007<br>Victor A. McKusick - updated : 2/8/2007<br>George E. Tiller - updated : 1/16/2007<br>Cassandra L. Kniffin - updated : 6/1/2006<br>Patricia A. Hartz - updated : 2/16/2006<br>George E. Tiller - updated : 6/6/2005<br>George E. Tiller - updated : 3/2/2005<br>Victor A. McKusick - updated : 12/23/2003<br>George E. Tiller - updated : 12/2/2003<br>Ada Hamosh - updated : 2/27/2003<br>George E. Tiller - updated : 12/4/2002<br>George E. Tiller - updated : 5/9/2002<br>Ada Hamosh - updated : 3/7/2001<br>Stylianos E. Antonarakis - updated : 3/6/2001<br>Victor A. McKusick - updated : 2/22/2001
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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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 : 10/15/1997
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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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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carol : 04/11/2024
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</span>
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</div>
|
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</div>
|
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 03/23/2020<br>carol : 11/11/2019<br>carol : 11/08/2019<br>alopez : 09/24/2012<br>terry : 9/20/2012<br>wwang : 8/25/2010<br>ckniffin : 8/16/2010<br>carol : 7/1/2010<br>wwang : 6/8/2010<br>ckniffin : 6/3/2010<br>wwang : 6/23/2009<br>wwang : 6/23/2009<br>wwang : 6/23/2009<br>wwang : 6/22/2009<br>ckniffin : 6/5/2009<br>mgross : 4/15/2009<br>wwang : 4/30/2008<br>terry : 4/29/2008<br>wwang : 5/30/2007<br>terry : 5/22/2007<br>alopez : 2/13/2007<br>terry : 2/8/2007<br>alopez : 1/17/2007<br>alopez : 1/17/2007<br>terry : 1/16/2007<br>wwang : 6/14/2006<br>ckniffin : 6/1/2006<br>wwang : 2/16/2006<br>alopez : 6/6/2005<br>alopez : 3/2/2005<br>carol : 2/12/2004<br>carol : 2/12/2004<br>cwells : 2/12/2004<br>cwells : 12/30/2003<br>terry : 12/23/2003<br>mgross : 12/2/2003<br>alopez : 3/14/2003<br>terry : 2/27/2003<br>cwells : 12/4/2002<br>cwells : 5/17/2002<br>cwells : 5/17/2002<br>cwells : 5/9/2002<br>alopez : 3/7/2001<br>mgross : 3/6/2001<br>mgross : 3/6/2001<br>alopez : 3/1/2001<br>alopez : 2/22/2001<br>terry : 2/22/2001<br>mark : 10/15/1997
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
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<strong>*</strong> 602054
|
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</span>
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</h3>
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</div>
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<div>
|
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<h3>
|
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<span class="mim-font">
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|
|
T-BOX TRANSCRIPTION FACTOR 1; TBX1
|
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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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<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">
|
|
T-BOX 1
|
|
</span>
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: TBX1</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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<p>
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<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 767263007, 86299006;
|
|
|
|
|
|
<strong>ICD10CM:</strong> D82.1, Q21.3, Q93.81;
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|
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|
|
<strong>ICD9CM:</strong> 279.11, 745.2, 758.32;
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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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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: 22q11.21
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 22:19,756,703-19,783,593 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</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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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
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</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
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</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
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<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
22q11.21
|
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
Conotruncal anomaly face syndrome
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
217095
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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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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</td>
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</tr>
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
DiGeorge 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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188400
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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">
|
|
3
|
|
</span>
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</td>
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</tr>
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|
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|
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<tr>
|
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<td>
|
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<span class="mim-font">
|
|
Tetralogy of Fallot
|
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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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187500
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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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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Velocardiofacial 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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192430
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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
|
|
</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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<br />
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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>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>Cloning and Expression</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>Chieffo et al. (1997) described the identification, cloning, and characterization of the human TBX1 gene, which maps to the center of the DiGeorge syndrome (DGS; 188400) chromosomal region on 22q11.2. TBX1 is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes are transcription factors involved in the regulation of developmental processes (see TBX2, 600747). Human and mouse TBX1 proteins share 98% amino acid identity overall and are identical except for 2 residues within the T-box domain. Expression of human TBX1 in adult and fetal tissues, as determined by Northern blot analysis, was similar to that found in the mouse. Additionally, using 3-prime RACE, Chieffo et al. (1997) demonstrated a differentially spliced message in adult skeletal muscle. Mouse Tbx1 had previously been shown to be expressed during early embryogenesis in the pharyngeal arches, pouches, and otic vesicle. Later in development, expression was seen in the vertebral column and tooth bud. Thus, the authors concluded that TBX1 is a candidate for some of the features seen in the 22q11 deletion syndrome. </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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<h4>
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<span class="mim-font">
|
|
<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>The TBX1 gene maps within the DiGeorge syndrome region on chromosome 22q11.2 (Chieffo et al., 1997). </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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<h4>
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<span class="mim-font">
|
|
<strong>Gene Function</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>Vitelli et al. (2003) showed that Tbx1 is expressed early in otocyst development in the otic epithelium and in the periotic mesenchyme. Tbx -/- mice demonstrated severe inner ear defects that prevented the formation of the cochlea and of the vestibulum at the early otocyst stage and after neurogenesis. The authors proposed a model wherein Tbx1 is required for expansion of a subpopulation of otic epithelial cells, which in turn participate in formation of the vestibular and auditory organs. </p><p>Chen et al. (2012) used RNA-interference-based loss-of-function screening as a powerful approach to uncover transcriptional regulators that govern the self-renewal capacity and regenerative potential of stem cells. Focusing on the nuclear proteins and/or transcription factors that are enriched in stem cells compared with their progeny, Chen et al. (2012) screened approximately 2,000 short hairpin RNAs for their effect on long-term, not short-term, stem cell self-renewal in vitro. They identified TBX1 in this screen and, by conditionally ablating TBX1 in vivo, showed that during homeostasis, tissue regeneration occurs normally but is markedly delayed. They then devised an in vivo assay for stem cell replenishment and found that when challenged with repetitive rounds of regeneration, the TBX1-deficient stem cell niche became progressively depleted. Addressing the mechanism of TBX1 action, Chen et al. (2012) discovered that TBX1 acts as an intrinsic rheostat of BMP signaling: it is a gatekeeper that governs the transition between stem cell quiescence and proliferation in hair follicles. </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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<h4>
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<span class="mim-font">
|
|
<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>To investigate mutations in the coding sequence of TBX1, Yagi et al. (2003) searched for mutations in the coding sequence of TBX1 in 13 patients from 10 families who had the 22q11.2 deletion syndrome phenotype but no detectable deletion of 22q11.2. In 2 unrelated patients, 1 with sporadic conotruncal anomaly face syndrome (217095)/velocardiofacial syndrome (VCFS; 192430) and 1 with sporadic DiGeorge syndrome, and in 3 patients from a family with conotruncal anomaly face syndrome/velocardiofacial syndrome, they identified mutations in TBX1 (602054.0001-602054.0003). The findings of Yagi et al. (2003) indicated that TBX1 mutations are responsible for 5 major phenotypes that are components of the del22q11.2 syndrome: abnormal facies (conotruncal anomaly face), cardiac defects, thymic hypoplasia, velopharyngeal insufficiency with cleft palate, and parathyroid dysfunction with hypocalcemia; they are not responsible for typical mental retardation that is commonly seen in patients with del22q11.2 syndrome. </p><p>Packham and Brook (2003) reviewed the human disorders that have been linked to mutations in T-box genes: Holt-Oram syndrome (HOS; 142900), ulnar-mammary syndrome (UMS; 181450), DiGeorge syndrome, ACTH deficiency (201400), and cleft palate with ankyloglossia (CPX; 303400). </p><p>Paylor et al. (2006) identified a heterozygous 23-bp deletion in the TBX1 gene (602054.0004) in a mother and 2 sons with velocardiofacial syndrome. The mother also had major depression (608516) and 1 of the sons was diagnosed with Asperger syndrome (see, e.g., 608638 and 209850). Paylor et al. (2006) suggested that the TBX1 gene is a candidate for psychiatric disease in patients with VCFS and DiGeorge syndrome. </p><p>Zweier et al. (2007) reported a novel heterozygous missense mutation, H194Q (602054.0005), in a familial case of Shprintzen velocardiofacial syndrome and showed that this and 2 previously reported missense mutations, F148Y (602054.0001) and G310S (602054.0002), result in gain of function, possibly through stabilization of the protein dimer DNA complex. They concluded therefore that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions. </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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<h4>
|
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<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
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|
<p>Mice deleted for a region of chromosome 16 syntenic to human 22q11.2 (Df(16)1 mice), the region most often deleted in DiGeorge syndrome (DGS; 188400), display a phenotype featuring cardiovascular abnormalities characteristic of the human disease (Lindsay et al., 1999). Using a combination of chromosome engineering and P1 artificial chromosome transgenesis, Lindsay et al. (2001) localized the Tbx1 gene in mouse to this region of chromosome 16. Lindsay et al. (2001) showed that Tbx1 is required for normal development of the pharyngeal arch arteries in a gene dosage-dependent manner. Deletion of 1 copy of Tbx1 affected the development of the fourth pharyngeal arch arteries, whereas homozygous mutation severely disrupted the entire pharyngeal arch artery system. Lindsay et al. (2001) concluded that haploinsufficiency of Tbx1 is sufficient to generate at least 1 important component of the DiGeorge syndrome phenotype in mice. Their data demonstrated the suitability of the mouse for the genetic dissection of microdeletion syndromes. </p><p>Jerome and Papaioannou (2001) investigated the potential role of the TBX1 gene in DGS/VCFS (192430) by producing a null mutation in mice. They found that mice heterozygous for the mutation had a high incidence of cardiac outflow tract anomalies, thus modeling one of the major abnormalities of the human syndrome. Moreover, Tbx1 -/- mice displayed a wide range of developmental anomalies encompassing almost all of the common DGS/VCFS features, including hypoplasia of thymus and parathyroid glands, cardiac outflow tract abnormalities, abnormal facial structures, abnormal vertebrae, and cleft palate. On the basis of this phenotype in mice, they proposed that TBX1 in humans is a key gene in the etiology of DGS/VCFS. </p><p>Merscher et al. (2001) used a Cre-loxP strategy to generate mice that were hemizygous for a 1.5-Mb deletion corresponding to that on 22q11 in VCFS/DGS patients. These mice exhibited significant perinatal lethality and had conotruncal and parathyroid defects. The conotruncal defects could be partially rescued by a human BAC containing the TBX1 gene. Mice heterozygous for a null mutation in Tbx1 developed conotruncal defects. These results together with the expression patterns of TBX1 suggested a major role for the TBX1 gene in the molecular etiology of VCFS/DGS. </p><p>Funke et al. (2001) reported that mice overexpressing 4 transgenes (PNUTL1, 602724; GP1BB, 138720; TBX1; and WDR14, 610778) had chronic otitis media, a hyperactive circling behavior, and sensorineural hearing loss. This was associated with middle and inner ear malformations analogous to human Mondini dysplasia, reported to occur in VCFS/DGS patients. Based upon its pattern of expression in the ear and functional studies of the gene, the authors hypothesized that Tbx1 likely plays a central role in the etiology of ear defects in these mice, and that haploinsufficiency of TBX1 may be responsible for ear disorders in VCFS/DGS patients. </p><p>Vitelli et al. (2002) showed that Tbx1 deficiency in transgenic mice caused a number of distinct vascular and heart defects, affecting formation and growth of the pharyngeal arch arteries, growth and septation of the outflow tract of the heart, interventricular septation, and conal alignment. Comparison of phenotype and gene expression using a Tbx1-lacZ reporter allele supported a cell-autonomous function in the growth of the pharyngeal apparatus, and a cell-non-autonomous function in the growth and early remodeling of the pharyngeal arch arteries. The data did not support a direct role of neural crest cells in the pathogenesis of the Tbx1 mutant phenotype; however, these cells and the cranial nerves were misdirected. The authors hypothesized that this is due to the lack of a guidance role from the pouch endoderm, which is missing in these mutants. </p><p>Stalmans et al. (2003) reported that absence of the 164-amino acid isoform of Vegf (Vegf164; see 192240), the only one that binds neuropilin-1 (NRP1; 602069), causes birth defects in mice reminiscent of those found in patients with deletion of 22q11. The close correlation of birth and vascular defects indicated that vascular dysgenesis may pathogenetically contribute to the birth defects. Vegf interacted with Tbx1, as Tbx1 expression was reduced in Vegf164-deficient embryos and knocked-down Vegf levels enhanced the pharyngeal arch artery defects induced by Tbx1 knockdown in zebrafish. Moreover, initial evidence suggested that a VEGF promoter haplotype was associated with an increased risk for cardiovascular birth defects in del22q11 individuals. Stalmans et al. (2003) concluded that genetic data in mouse, fish, and human indicated that VEGF is a modifier of cardiovascular birth defects in the del22q11 syndrome. </p><p>Guris et al. (2006) found that compound heterozygosity for null alleles of the mouse Crkl (602007) and Tbx1 genes recapitulated thymic, parathyroid, and cardiovascular defects characteristic of DGS at a penetrance far greater than that generated by heterozygosity of Crkl or Tbx1 alone. </p><p>Baldini (2002) reviewed the molecular basis of DiGeorge syndrome, with special emphasis on mouse models and the role of TBX1 in development of the pharyngeal arches. </p><p>Paylor et al. (2001) showed that Df1/+ mice have deficits in learning, memory, and sensorimotor gating, as measured by prepulse inhibition (PPI) of the startle response. Decreased PPI is associated with several psychiatric and behavioral disorders, including schizophrenia (181500) and Asperger syndrome (see, e.g., 608638 and 209850). By detailed mapping of Df1/+ mice, Paylor et al. (2006) found that the PPI deficit was due to haploinsufficiency of 2 adjacent genes, Tbx1 and Gnb1l. Mutation in either gene was sufficient to cause reduced PPI. Paylor et al. (2006) suggested that the Tbx1 gene may be a candidate for psychiatric disease in patients with DiGeorge syndrome or velocardiofacial syndrome. </p><p>Liao et al. (2004) reported that mice hemizygous for a null allele of Tbx1 had mild malformations, while homozygotes had severe malformations in the affected structures. Neither pattern of malformation precisely modeled VCFS or DGS. Furthermore, bacterial artificial chromosome (BAC) transgenic mice overexpressing human TBX1 and 3 other transgenes had similar malformations to VCFS/DGS patients. By employing genetic complementation studies, the authors demonstrated that altered TBX1 dosage, rather than overexpression of the other transgenes, was responsible for most of the defects in the BAC transgenic mice. Furthermore, the full spectrum of VCFS/DGS malformations was elicited in a TBX1 dose-dependent manner, thus providing a molecular basis for the pathogenesis and varied expressivity of the syndrome. </p><p>Kelly et al. (2004) showed that branchiomeric muscle development was severely perturbed in Tbx1 mutant mice. In the absence of Tbx1, the myogenic determination genes Myf5 (159990) and MyoD (159970) failed to be normally activated in pharyngeal mesoderm. Unspecified precursor cells expressing genes encoding the transcriptional repressors capsulin (TCF21; 603306) and MyoR (MSC; 603628) were present in the mandibular arch of Tbx1 mutant embryos. Sporadic activation of Myf5 and MyoD in these precursor cells resulted in the random presence or absence of hypoplastic mandibular arch-derived muscles at later developmental stages. Tbx1 was also required for normal expression of Tlx1 (186770) and Fgf10 (602115) in pharyngeal mesoderm, in addition to correct neural crest cell patterning in the mandibular arch. Kelly et al. (2004) concluded that Tbx1 regulates the onset of branchiomeric myogenesis and controls normal mandibular arch development, including robust transcriptional activation of myogenic determination genes. </p><p>Arnold et al. (2006) found that mice with conditional deletion of Tbx1 in the otic vesicle, which derives from the ectoderm, and in the pharyngeal pouch, which derives from the endoderm, caused an ear phenotype identical to that of homozygous Tbx1-null mutants. Tbx1-ablation specific to the pharyngeal pouch endoderm caused absence of the auditory tube, middle, and outer ears because of failed expansion of the first pharyngeal pouch. Tbx1-ablation specific to the otic vesicle resulted in failure to form inner ear sensory organs as well as expansion of the cochleovestibular ganglion, but outer and middle ear formation remained unaffected. Thus, Tbx1 in the otic vesicle has cell-autonomous roles in patterning the inner ear, and expression of Tbx1 in the periotic mesenchyme cannot rescue these inner ear defects. Arnold et al. (2006) concluded that Tbx1 has tissue-specific roles during ear development and suggested that Tbx1 may contribute to middle and inner ear malformations in DGS patients. </p><p>Theveniau-Ruissy et al. (2008) noted that mice heterozygous for a Tbx1-null allele display a high frequency of fourth aortic arch artery defects, and that absence of Tbx1 leads to underproliferation of the second heart field, hypoplasia of the distal outflow tract, and a common ventricular outlet. Restoration of Tbx1 expression in the second heart field is sufficient to rescue outflow tract development in a Tbx1 mutant background. Theveniau-Ruissy et al. (2008) found that a myocardial subdomain normally associated with the base of the pulmonary trunk was reduced and malpositioned in embryonic Tbx1 mutant mouse hearts. The defect was associated with highly anomalous coronary artery trajectories, revealing a critical role for Tbx1 in the regulation of regional outflow tract identity and implicating the second heart field in coronary artery patterning. </p><p>Choi and Klingensmith (2009) demonstrated that chordin (CHRD; 603475) is a modifier of the observed craniofacial anomalies of Tbx1 mutations in mice. The Tbx1-null mouse phenotype is similar to the Chrd-null mouse phenotype, which includes dysmorphic ears, absence of the thymus, persistent truncus arteriosus, and cleft palate. However, penetrance of the Chrd-null phenotype is highly dependent on genetic background. In an inbred Chrd-null mouse strain with full penetrance, the authors found that a splice site mutation in the Tbx1 gene was a modifier influencing phenotypic expression. Chrd-null mice without the Tbx1 mutation had a low penetrance of mandibular hypoplasia, but no cardiac or thoracic organ malformations. The hypomorphic Tbx1 allele resulted in defects resembling 22q11 deletion syndrome, but with a low penetrance of craniofacial malformations, unless Chrd was also mutant. Expression studies suggested that Chrd has a role in promoting Tbx1 expression. The findings suggested that chordin is a modifier of the craniofacial anomalies of Tbx1 mutations, demonstrating the existence of a second-site modifier for a specific subset of the phenotypes associated with 22q11 deletion syndrome. </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>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>6 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
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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>.0001 CONOTRUNCAL ANOMALY FACE SYNDROME/VELOCARDIOFACIAL 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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TBX1, PHE148TYR
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<br />
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SNP: rs28939675,
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ClinVar: RCV001815165
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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 sporadic case of conotruncal anomaly face syndrome (217095)/velocardiofacial syndrome (192430), Yagi et al. (2003) identified a 443T-A transversion in the TBX1 gene, predicted to result in a phe148-to-tyr (F148Y) substitution. The patient had typical conotruncal anomaly face and velopharyngeal insufficiency, tetralogy of Fallot, pulmonary atresia, atrial septal defect, and major aorticopulmonary collateral artery. She did not have typical mental retardation that is commonly seen in patients with del22q11.2 syndrome. </p><p>Zweier et al. (2007) concluded that the F148Y missense mutation like other cause gain of function, probably through similar effects on TBX1 structure that result in an increased dimer stability and/or DNA-binding affinity. </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
|
|
</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 DIGEORGE 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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TBX1, GLY310SER
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<br />
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SNP: rs41298838,
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gnomAD: rs41298838,
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ClinVar: RCV000008000, RCV000618981, RCV000828677
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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 sporadic case of DiGeorge syndrome (188400), Yagi et al. (2003) identified a heterozygous 928G-A transition in the TBX1 gene, predicted to result in a gly310-to-ser (G310S) substitution. The patient had typical conotruncal anomaly face and velopharyngeal insufficiency, interrupted aortic arch (type B), and perimembranous-type ventricular septal defect with pulmonary hypertension, absent thymus, parathyroid dysfunction, and deafness. He did not have mental retardation and was in a regular class of a junior high school. Thus the patient had all 5 major phenotypes of the 22q11.2 deletion syndrome. </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>.0003 CONOTRUNCAL ANOMALY FACE SYNDROME/VELOCARDIOFACIAL 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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TBX1, 1-BP DEL, 1223C
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<br />
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SNP: rs1601294362,
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ClinVar: RCV001815166
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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 mother and her son and daughter with conotruncal anomaly face syndrome (217095)/velocardiofacial syndrome (192430) and normal intelligence, Yagi et al. (2003) identified a heterozygous 1-bp deletion, 1223delC, in the TBX1 gene. The deletion occurred at codon 408 and caused a frameshift leading to a stop codon after 51 codons. This truncated TBX1 protein remained as the DNA binding motif but did not have the C-terminal region, including the putative activator and repressor domains. </p><p>Stoller and Epstein (2005) identified a previously unrecognized nuclear localization signal (NLS) at the C terminus of Tbx1 that is deleted by the 1223delC mutation, thus explaining the mechanism of disease in DiGeorge syndrome patients with this mutation. The NLS is conserved across species among T-box family members, including T (601397) and TBX10 (604648). </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 VELOCARDIOFACIAL 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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TBX1, 23-BP DEL, NT1320
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<br />
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ClinVar: RCV000008002
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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 mother and 2 sons with velocardiofacial syndrome (192430), Paylor et al. (2006) identified a heterozygous 23-bp deletion in the TBX1 gene (1320-1342del23), resulting in a frameshift and extension of the protein from 504 to 616 amino acids. The mother had major depression (608516) and 1 of the sons was diagnosed with Asperger syndrome (see, e.g., 608638 and 209850). Paylor et al. (2006) suggested that the TBX1 gene is a candidate for psychiatric disease in patients with VCFS and DiGeorge syndrome. </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>.0005 VELOCARDIOFACIAL 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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TBX1, HIS194GLN
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<br />
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SNP: rs74315522,
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ClinVar: RCV000008003
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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 familial case of Shprintzen velocardiofacial syndrome (192430), Zweier et al. (2007) described the third missense mutation and the fifth overall mutation in TBX1. Their observations expanded the associated phenotype to include short stature and, possibly, developmental delay. They provided the first evidence that TBX1 missense mutations can alter the transcriptional activity of the TBX1 protein. They concluded that TBX1 gain-of-function mutations can result in the same phenotypic spectrum as haploinsufficiency caused by loss-of-function mutations or deletions. </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 TETRALOGY OF FALLOT</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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TBX1, 30-BP DUP, NT1399, ALANINE TRACT EXPANSION
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<br />
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SNP: rs746335599,
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gnomAD: rs746335599,
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ClinVar: RCV000599046, RCV002310991, RCV002532692
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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 Turkish patient with tetralogy of Fallot (187500), Rauch et al. (2010) identified a heterozygous 30-bp duplication (1399_1428dup30) in exon 9c of the TBX1 gene. She had facial asymmetry, scoliosis, absent pulmonary vein, isolated left pulmonary artery, ventricular septal defect, and normal cognitive development. She did not have the facial gestalt of 22q11.2 deletion syndrome. The insertion was shown to result in the expansion of a polyalanine tract, which caused decreased transcriptional activity and cytoplasmic aggregation of the protein in cellular studies. </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>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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Arnold, J. S., Braunstein, E. M., Ohyama, T., Groves, A. K., Adams, J. C., Brown, M. C., Morrow, B. E.
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<strong>Tissue-specific roles of Tbx1 in the development of the outer, middle and inner ear, defective in 22q11DS patients.</strong>
|
|
Hum. Molec. Genet. 15: 1629-1639, 2006.
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[PubMed: 16600992]
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[Full Text: https://doi.org/10.1093/hmg/ddl084]
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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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Baldini, A.
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<strong>DiGeorge syndrome: the use of model organisms to dissect complex genetics.</strong>
|
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Hum. Molec. Genet. 11: 2363-2369, 2002.
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[PubMed: 12351571]
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[Full Text: https://doi.org/10.1093/hmg/11.20.2363]
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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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Chen, T., Heller, E., Beronja, S., Oshimori, N., Stokes, N., Fuchs, E.
|
|
<strong>An RNA interference screen uncovers a new molecule in stem cell self-renewal and long-term regeneration.</strong>
|
|
Nature 485: 104-108, 2012.
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[PubMed: 22495305]
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[Full Text: https://doi.org/10.1038/nature10940]
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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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Chieffo, C., Garvey, N., Gong, W., Roe, B., Zhang, G., Silver, L., Emanuel, B. S., Budarf, M. L.
|
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<strong>Isolation and characterization of a gene from the DiGeorge chromosomal region homologous to the mouse Tbx1 gene.</strong>
|
|
Genomics 43: 267-277, 1997.
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[PubMed: 9268629]
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[Full Text: https://doi.org/10.1006/geno.1997.4829]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Choi, M., Klingensmith, J.
|
|
<strong>Chordin is a modifier of Tbx1 for the craniofacial malformations of 22q11 deletion syndrome phenotypes in mouse.</strong>
|
|
PLos Genet. 5: e1000395, 2009. Note: Electronic Article.
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[PubMed: 19247433]
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[Full Text: https://doi.org/10.1371/journal.pgen.1000395]
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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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Funke, B., Epstein, J. A., Kochilas, L. K., Lu, M. M., Pandita, R. K., Liao, J., Bauerndistel, R., Schuler, T., Schorle, H., Brown, M. C., Adams, J., Morrow, B. E.
|
|
<strong>Mice overexpressing genes from the 22q11 region deleted in velo-cardio-facial syndrome/DiGeorge syndrome have middle and inner ear defects.</strong>
|
|
Hum. Molec. Genet. 10: 2549-2556, 2001.
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[PubMed: 11709542]
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[Full Text: https://doi.org/10.1093/hmg/10.22.2549]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Guris, D. L., Duester, G., Papaioannou, V. E., Imamoto, A.
|
|
<strong>Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome.</strong>
|
|
Dev. Cell 10: 81-92, 2006.
|
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|
|
[PubMed: 16399080]
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[Full Text: https://doi.org/10.1016/j.devcel.2005.12.002]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Jerome, L. A., Papaioannou, V. E.
|
|
<strong>DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1.</strong>
|
|
Nature Genet. 27: 286-291, 2001.
|
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|
|
[PubMed: 11242110]
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[Full Text: https://doi.org/10.1038/85845]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Kelly, R. G., Jerome-Majewska, L. A., Papaioannou, V. E.
|
|
<strong>The del22q11.2 candidate gene Tbx1 regulates branchiomeric myogenesis.</strong>
|
|
Hum. Molec. Genet. 13: 2829-2840, 2004.
|
|
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|
|
[PubMed: 15385444]
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|
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[Full Text: https://doi.org/10.1093/hmg/ddh304]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Liao, J., Kochilas, L., Nowotschin, S., Arnold, J. S., Aggarwal, V. S., Epstein, J. A., Brown, M. C., Adams, J., Morrow, B. E.
|
|
<strong>Full spectrum of malformations in velo-cardio-facial syndrome/DiGeorge syndrome mouse models by altering Tbx1 dosage.</strong>
|
|
Hum. Molec. Genet. 13: 1577-1585, 2004.
|
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|
|
[PubMed: 15190012]
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|
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[Full Text: https://doi.org/10.1093/hmg/ddh176]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Lindsay, E. A., Botta, A., Jurecic, V., Carattini-Rivera, S., Cheah, Y.-C., Rosenblatt, H. M., Bradley, A., Baldini, A.
|
|
<strong>Congenital heart disease in mice deficient for the DiGeorge syndrome region.</strong>
|
|
Nature 401: 379-383, 1999.
|
|
|
|
|
|
[PubMed: 10517636]
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|
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[Full Text: https://doi.org/10.1038/43900]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Lindsay, E. A., Vitelli, F., Su, H., Morishima, M., Huynh, T., Pramparo, T., Jurecic, V., Ogunrinu, G., Sutherland, H. F., Scambler, P. J., Bradley, A., Baldini, A.
|
|
<strong>Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice.</strong>
|
|
Nature 410: 97-101, 2001.
|
|
|
|
|
|
[PubMed: 11242049]
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|
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[Full Text: https://doi.org/10.1038/35065105]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Merscher, S., Funke, B., Epstein, J. A., Heyer, J., Puech, A., Lu, M. M., Xavier, R. J., Demay, M. B., Russell, R. G., Factor, S., Tokooya, K., St. Jore, B., and 12 others.
|
|
<strong>TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome.</strong>
|
|
Cell 104: 619-629, 2001.
|
|
|
|
|
|
[PubMed: 11239417]
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|
|
[Full Text: https://doi.org/10.1016/s0092-8674(01)00247-1]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Packham, E. A., Brook, J. D.
|
|
<strong>T-box genes in human disorders.</strong>
|
|
Hum. Molec. Genet. 12(R1): R37-R44, 2003.
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[PubMed: 12668595]
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[Full Text: https://doi.org/10.1093/hmg/ddg077]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Paylor, R., Glaser, B., Mupo, A., Ataliotis, P., Spencer, C., Sobotka, A., Sparks, C., Choi, C.-H., Oghalai, J., Curran, S., Murphy, K. C., Monks, S., Williams, N., O'Donovan, M. C., Owen, M. J., Scambler, P. J., Lindsay, E.
|
|
<strong>Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 7729-7734, 2006.
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[PubMed: 16684884]
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[Full Text: https://doi.org/10.1073/pnas.0600206103]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Paylor, R., McIlwain, K. L., McAninch, R., Nellis, A., Yuva-Paylor, L. A., Baldini, A., Lindsay, E. A.
|
|
<strong>Mice deleted for the DiGeorge/velocardiofacial syndrome region show abnormal sensorimotor gating and learning and memory impairments.</strong>
|
|
Hum. Molec. Genet. 10: 2645-2650, 2001.
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|
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|
|
[PubMed: 11726551]
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[Full Text: https://doi.org/10.1093/hmg/10.23.2645]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Rauch, R., Hofbeck, M., Zweier, C., Koch, A., Zink, S., Trautmann, U., Hoyer, J., Kaulitz, R., Singer, H., Rauch, A.
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|
<strong>Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot.</strong>
|
|
J. Med. Genet. 47: 321-331, 2010.
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[PubMed: 19948535]
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[Full Text: https://doi.org/10.1136/jmg.2009.070391]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Stalmans, I., Lambrechts, D., De Smet, F., Jansen, S., Wang, J., Maity, S., Kneer, P., von der Ohe, M., Swillen, A., Maes, C., Gewillig, M., Molin, D. G. M., and 20 others.
|
|
<strong>VEGF: a modifier of the del22q11 (DiGeorge) syndrome?</strong>
|
|
Nature Med. 9: 173-182, 2003.
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|
|
[PubMed: 12539040]
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[Full Text: https://doi.org/10.1038/nm819]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Stoller, J. Z., Epstein, J. A.
|
|
<strong>Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation.</strong>
|
|
Hum. Molec. Genet. 14: 885-892, 2005.
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|
[PubMed: 15703190]
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[Full Text: https://doi.org/10.1093/hmg/ddi081]
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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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Theveniau-Ruissy, M., Dandonneau, M., Mesbah, K., Ghez, O., Mattei, M.-G., Miquerol, L., Kelly, R. G.
|
|
<strong>The del22q11.2 candidate gene Tbx1 controls regional outflow tract identity and coronary artery patterning.</strong>
|
|
Circ. Res. 103: 142-148, 2008.
|
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|
|
[PubMed: 18583714]
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[Full Text: https://doi.org/10.1161/CIRCRESAHA.108.172189]
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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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Vitelli, F., Morishima, M., Taddei, I., Lindsay, E. A., Baldini, A.
|
|
<strong>Tbx1 mutation causes multiple cardiovascular defects and disrupts neural crest and cranial nerve migratory pathways.</strong>
|
|
Hum. Molec. Genet. 11: 915-922, 2002.
|
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|
|
[PubMed: 11971873]
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[Full Text: https://doi.org/10.1093/hmg/11.8.915]
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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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Vitelli, F., Viola, A., Morishima, M., Pramparo, T., Baldini, A., Lindsay, E.
|
|
<strong>TBX1 is required for inner ear morphogenesis.</strong>
|
|
Hum. Molec. Genet. 12: 2041-2048, 2003.
|
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|
|
[PubMed: 12913075]
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[Full Text: https://doi.org/10.1093/hmg/ddg216]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Yagi, H., Furutani, Y., Hamada, H., Sasaki, T., Asakawa, S., Minoshima, S., Ichida, F., Joo, K., Kimura, M., Imamura, S., Kamatani, N., Momma, K., Takao, A., Nakazawa, M., Shimizu, N., Matsuoka, R.
|
|
<strong>Role of TBX1 in human del22q11.2 syndrome.</strong>
|
|
Lancet 362: 1366-1373, 2003.
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|
|
[PubMed: 14585638]
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[Full Text: https://doi.org/10.1016/s0140-6736(03)14632-6]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Zweier, C., Sticht, H., Aydin-Yaylagul, I., Campbell, C. E., Rauch, A.
|
|
<strong>Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions.</strong>
|
|
Am. J. Hum. Genet. 80: 510-517, 2007.
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|
[PubMed: 17273972]
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[Full Text: https://doi.org/10.1086/511993]
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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>
|
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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">
|
|
Contributors:
|
|
</span>
|
|
</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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Ada Hamosh - updated : 9/20/2012<br>Cassandra L. Kniffin - updated : 8/16/2010<br>Cassandra L. Kniffin - updated : 6/3/2010<br>Cassandra L. Kniffin - updated : 6/5/2009<br>Patricia A. Hartz - updated : 4/15/2009<br>George E. Tiller - updated : 4/29/2008<br>George E. Tiller - updated : 5/22/2007<br>Victor A. McKusick - updated : 2/8/2007<br>George E. Tiller - updated : 1/16/2007<br>Cassandra L. Kniffin - updated : 6/1/2006<br>Patricia A. Hartz - updated : 2/16/2006<br>George E. Tiller - updated : 6/6/2005<br>George E. Tiller - updated : 3/2/2005<br>Victor A. McKusick - updated : 12/23/2003<br>George E. Tiller - updated : 12/2/2003<br>Ada Hamosh - updated : 2/27/2003<br>George E. Tiller - updated : 12/4/2002<br>George E. Tiller - updated : 5/9/2002<br>Ada Hamosh - updated : 3/7/2001<br>Stylianos E. Antonarakis - updated : 3/6/2001<br>Victor A. McKusick - updated : 2/22/2001
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Victor A. McKusick : 10/15/1997
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