4026 lines
318 KiB
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4026 lines
318 KiB
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Entry
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- *601893 - TRIPLE FUNCTIONAL DOMAIN; TRIO
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601893</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601893">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</div>
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</div>
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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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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000038382;t=ENST00000344204" 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=7204" 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=601893" 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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</span>
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</div>
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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=ENSG00000038382;t=ENST00000344204" 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_007118,NR_134469,XM_011514107,XM_011514108,XM_011514109,XM_011514110,XM_017009801,XM_017009802,XM_017009803,XM_047417679,XM_047417681" 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_007118" 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=601893" 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=03537&isoform_id=03537_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/TRIO" 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/3522970,3644048,27370625,33146382,40226068,45439359,47077363,62089094,119628449,119628450,119628451,119628452,119628453,194388306,257050981,767934608,767934610,767934612,767934614,1034645983,1034645988,1034645990,1403730492,2217357183,2217357189,2462604166,2462604168,2462604170,2462604172,2462604174,2462604176,2462604178,2462604180" 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/O75962" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=7204" 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=ENSG00000038382;t=ENST00000344204" 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=TRIO" 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=TRIO" 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+7204" 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/TRIO" 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:7204" 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/7204" 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=chr5&hgg_gene=ENST00000344204.9&hgg_start=14143342&hgg_end=14510204&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:12303" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:12303" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601893[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=601893[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/TRIO/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/ENSG00000038382" 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=TRIO" 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=TRIO" 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=TRIO" 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=TRIO&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/PA36982" 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:12303" 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/FBgn0024277.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:1927230" 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/TRIO#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:1927230" 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/7204/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=7204" 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=WBGene00006805;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-030616-399" 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=TRIO&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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601893
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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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TRIPLE FUNCTIONAL DOMAIN; TRIO
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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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<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=TRIO" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TRIO</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/5/58?start=-3&limit=10&highlight=58">5p15.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:14143342-14510204&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'})">5:14,143,342-14,510,204</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>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
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<a href="/clinicalSynopsis/table?mimNumber=617061,618825" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
|
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</th>
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<th>
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Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
|
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<tr>
|
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<td rowspan="2">
|
|
<span class="mim-font">
|
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<a href="/geneMap/5/58?start=-3&limit=10&highlight=58">
|
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5p15.2
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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Intellectual developmental disorder, autosomal dominant 44, with microcephaly
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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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|
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<a href="/entry/617061"> 617061 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Intellectual developmental disorder, autosomal dominant 63, with macrocephaly
|
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|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/618825"> 618825 </a>
|
|
|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/601893" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/601893" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
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</div>
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<p>The TRIO protein contains 3 functional domains: a serine/threonine kinase domain and 2 guanine nucleotide exchange factor (GEF) domains for the family of Rho-like GTPases, specific for Rac1 (<a href="/entry/602048">602048</a>) and RhoA (<a href="/entry/165390">165390</a>), respectively (<a href="#3" class="mim-tip-reference" title="Debant, A., Serra-Pages, C., Seipel, K., O'Brien, S., Tang, M., Park, S.-H., Streuli, M. <strong>The multidomain protein Trio binds the LAR transmembrane tyrosine phosphatase, contains a protein kinase domain, and has separate rac-specific and rho-specific guanine nucleotide exchange factor domains.</strong> Proc. Nat. Acad. Sci. 93: 5466-5471, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8643598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8643598</a>] [<a href="https://doi.org/10.1073/pnas.93.11.5466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8643598">Debant et al., 1996</a>). These domains suggest that this enzyme may play a key role in several signaling pathways that control cell proliferation. The TRIO gene is highly expressed in the developing brain (summary by <a href="#1" class="mim-tip-reference" title="Ba, W., Yan, Y., Reijnders, M. R. F., Schuurs-Hoeijmakers, J. H. M., Feenstra, I., Bongers, E. M. H. F., Bosch, D. G. M., De Leeuw, N., Pfundt, R., Gilissen, C., De Vries, P. F., Veltman, J. A., Hoischen, A., Mefford, H. C., Eichler, E. E., Vissers, L. E. L. M., Kasri, N. N., De Vries, B. B. A. <strong>TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.</strong> Hum. Molec. Genet. 25: 892-902, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26721934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26721934</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26721934[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/ddv618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26721934">Ba et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26721934+8643598" 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="#4" class="mim-tip-reference" title="Ferraro, F., Ma, X.-M., Sobota, J. A., Eipper, B. A., Mains, R. E. <strong>Kalirin/Trio Rho guanine nucleotide exchange factors regulate a novel step in secretory granule maturation.</strong> Molec. Biol. Cell 18: 4813-4825, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17881726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17881726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17881726[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/10.1091/mbc.e07-05-0503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17881726">Ferraro et al. (2007)</a> showed that some isoforms of kalirin (<a href="/entry/604605">604605</a>) and Trio colocalized with immature secretory granules in mouse and rat neuroendocrine cells and modulated their cargo secretion. Overexpression of their N-terminal GEF domains enhanced secretion from immature granules, depleting cells of secretory cargo in the absence of secretagogue. This response required GEF activity and was mimicked by kalirin/Trio substrates Rac1 and RhoG (<a href="/entry/179505">179505</a>). Selective pharmacologic inhibition of endogenous GEF activity decreased secretagogue-independent release of hormone precursors, causing accumulation of product peptide in mature secretory granules. <a href="#4" class="mim-tip-reference" title="Ferraro, F., Ma, X.-M., Sobota, J. A., Eipper, B. A., Mains, R. E. <strong>Kalirin/Trio Rho guanine nucleotide exchange factors regulate a novel step in secretory granule maturation.</strong> Molec. Biol. Cell 18: 4813-4825, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17881726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17881726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17881726[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/10.1091/mbc.e07-05-0503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17881726">Ferraro et al. (2007)</a> concluded that kalirin/TRIO modulation of cargo secretion from immature granules provides secretory cells with an extra layer of control over the sets of peptides released and enhances the range of physiologic responses that can be elicited. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17881726" 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="#5" class="mim-tip-reference" title="Liu, X., Wang, H., Eberstadt, M., Schnuchel, A., Olejniczak, E. T., Meadows, R. P., Schkeryantz, J. M., Janowick, D. A., Harlan, J. E., Harris, E. A. S., Staunton, D. E., Fesik, S. W. <strong>NMR structure and mutagenesis of the N-terminal DBl homology domain of the nucleotide exchange factor Trio.</strong> Cell 95: 269-277, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9790533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9790533</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81757-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9790533">Liu et al. (1998)</a> described the solution structure of the N-terminal Dbl homology (DH) domain of TRIO (amino acids 1227-1407) that catalyzes nucleotide exchange for Rac1. The all-alpha-helical protein has a very different structure compared to other exchange factors. Based on site-directed mutagenesis, the authors identified functionally important residues of the DH domain. They are all highly conserved and reside in close proximity on 2 alpha helices. In addition, <a href="#5" class="mim-tip-reference" title="Liu, X., Wang, H., Eberstadt, M., Schnuchel, A., Olejniczak, E. T., Meadows, R. P., Schkeryantz, J. M., Janowick, D. A., Harlan, J. E., Harris, E. A. S., Staunton, D. E., Fesik, S. W. <strong>NMR structure and mutagenesis of the N-terminal DBl homology domain of the nucleotide exchange factor Trio.</strong> Cell 95: 269-277, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9790533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9790533</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81757-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9790533">Liu et al. (1998)</a> discovered a unique capability of the pleckstrin homology (PH) domain to enhance nucleotide exchange in DH domain-containing proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9790533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By fluorescence in situ hybridization, <a href="#9" class="mim-tip-reference" title="Taviaux, S., Diriong, S., Bellanger, J.-M., Streuli, M., Debant, A. <strong>Assignment of TRIO, the trio gene (PTPRF interacting) to human chromosome bands 5p15.1-p14 by in situ hybridization.</strong> Cytogenet. Cell Genet. 76: 107-108, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9154137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9154137</a>] [<a href="https://doi.org/10.1159/000134524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9154137">Taviaux et al. (1997)</a> mapped the TRIO gene to 5p15.1-p14. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9154137" 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="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 04/03/2020."None>Stumpf (2020)</a> mapped the TRIO gene to chromosome 5p12.2 based on an alignment of the TRIO sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC017268" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC017268</a>) with the genomic sequence (GRCh38).</p>
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<p><strong><em>Autosomal Dominant Intellectual Developmental Disorder 44 with Microcephaly</em></strong></p><p>
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In 4 patients from 3 unrelated families with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; <a href="/entry/617061">617061</a>), <a href="#1" class="mim-tip-reference" title="Ba, W., Yan, Y., Reijnders, M. R. F., Schuurs-Hoeijmakers, J. H. M., Feenstra, I., Bongers, E. M. H. F., Bosch, D. G. M., De Leeuw, N., Pfundt, R., Gilissen, C., De Vries, P. F., Veltman, J. A., Hoischen, A., Mefford, H. C., Eichler, E. E., Vissers, L. E. L. M., Kasri, N. N., De Vries, B. B. A. <strong>TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.</strong> Hum. Molec. Genet. 25: 892-902, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26721934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26721934</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26721934[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/ddv618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26721934">Ba et al. (2016)</a> identified 3 different heterozygous truncating mutations in the TRIO gene (<a href="#0001">601893.0001</a>-<a href="#0003">601893.0003</a>). Two of the mutations occurred de novo. Studies of patient cells were not performed, but knockdown of the Trio gene in rat hippocampal cells resulted in an increase in dendrites and alterations in synaptic transmission, resulting in increased excitatory transmission during development (see ANIMAL MODEL). <a href="#1" class="mim-tip-reference" title="Ba, W., Yan, Y., Reijnders, M. R. F., Schuurs-Hoeijmakers, J. H. M., Feenstra, I., Bongers, E. M. H. F., Bosch, D. G. M., De Leeuw, N., Pfundt, R., Gilissen, C., De Vries, P. F., Veltman, J. A., Hoischen, A., Mefford, H. C., Eichler, E. E., Vissers, L. E. L. M., Kasri, N. N., De Vries, B. B. A. <strong>TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.</strong> Hum. Molec. Genet. 25: 892-902, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26721934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26721934</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26721934[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/ddv618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26721934">Ba et al. (2016)</a> noted that premature maturation of excitatory synapses has been observed in several models of autism spectrum disorder, which was observed in these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26721934" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By exome sequencing in 3 members of a family with MRD44, originally reported by <a href="#6" class="mim-tip-reference" title="Mercer, C. L., Keeton, B., Dennis, N. R. <strong>Familial multiple ventricular extrasystoles, short stature, craniofacial abnormalities and digital hypoplasia: a further case of Stoll syndrome?</strong> Clin. Dysmorph. 17: 91-93, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18388777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18388777</a>] [<a href="https://doi.org/10.1097/MCD.0b013e3282efefc9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18388777">Mercer et al. (2008)</a>, <a href="#7" class="mim-tip-reference" title="Pengelly, R. J., Greville-Heygate, S., Schmidt, S., Seaby, E. G., Jabalameli, M. R., Mehta, S. G. Parker, M. J., Goudie, D., Fagotto-Kaufmann, C., Mercer, C., the DDD Study, Debant, A., Ennis, S., Baralle, D. <strong>Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly.</strong> J. Med. Genet. 53: 735-742, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27418539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27418539</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-103942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27418539">Pengelly et al. (2016)</a> identified a heterozygous truncating mutation in the TRIO gene (<a href="#0004">601893.0004</a>). Exome sequencing subsequently identified de novo heterozygous missense mutations in the TRIO gene in 2 additional unrelated patients with MRD44 (<a href="#0005">601893.0005</a>-<a href="#0006">601893.0006</a>). All mutations were confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the truncating mutation and 2 of the missense mutations affecting the GEFD1 domain resulted in decreased RAC1 activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27418539+18388777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 5 unrelated patients (patients 10, 12, 14, 15, and 16) with MRD44, <a href="#2" class="mim-tip-reference" title="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> identified de novo heterozygous missense mutations at highly conserved residues in the GEFD1 domain of the TRIO gene (see, e.g., <a href="#0005">601893.0005</a> and <a href="#0011">601893.0011</a>). The mutations, which were found by exome sequencing, were not present in the gnomAD database. Immunoblot analysis of HEK293 cells transfected with the mutations showed impaired TRIO binding to RAC1 compared to wildtype. Transfection of the mutations into neuroblastoma cells caused decreased neurite outgrowth and decreased lamellipodia formation compared to controls. The findings were consistent with a loss-of-function effect. <a href="#2" class="mim-tip-reference" title="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> also identified heterozygous nonsense or frameshift mutations in 5 additional individuals with a similar disorder (see, e.g., <a href="#0012">601893.0012</a> and <a href="#0013">601893.0013</a>). Three of the mutations were demonstrated to occur de novo. Similar in vitro functional studies performed on 1 of the mutations were consistent with a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32109419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Autosomal Dominant Intellectual Developmental Disorder 63 with Macrocephaly</em></strong></p><p>
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In 9 unrelated patients with autosomal dominant intellectual developmental disorder-63 with macrocephaly (MRD63; <a href="/entry/618825">618825</a>), <a href="#2" class="mim-tip-reference" title="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> identified 5 different heterozygous missense mutations in the TRIO gene (see, e.g., <a href="#0007">601893.0007</a>-<a href="#0010">601893.0010</a>). One of the patients had previously been reported by <a href="#7" class="mim-tip-reference" title="Pengelly, R. J., Greville-Heygate, S., Schmidt, S., Seaby, E. G., Jabalameli, M. R., Mehta, S. G. Parker, M. J., Goudie, D., Fagotto-Kaufmann, C., Mercer, C., the DDD Study, Debant, A., Ennis, S., Baralle, D. <strong>Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly.</strong> J. Med. Genet. 53: 735-742, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27418539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27418539</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-103942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27418539">Pengelly et al. (2016)</a>. The mutations, which were found by exome sequencing, were confirmed to occur de novo in 8 patients; inheritance was unknown in the ninth patient. All mutations occurred at highly conserved residues in the seventh spectrin repeat, and none were present in the gnomAD database. Three mutations, found in 6 unrelated patients, affected the same residue (R1078W, R1078G, and R1078Q). Molecular modeling predicted that the mutations could cause steric hindrance and alter the structural organization of the protein or interfere with protein folding. Expression of the mutations into HEK293 cells resulted in increased RAC1 activation, as measured by increased PAK1 (<a href="/entry/602590">602590</a>) phosphorylation, compared to wildtype. Transfection of the mutations into neuroblastoma cells caused enhanced neurite outgrowth and increased lamellipodia formation compared to controls. The findings were consistent with a gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27418539+32109419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a large study of 24 individuals with confirmed, mostly de novo heterozygous TRIO mutations, <a href="#2" class="mim-tip-reference" title="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> observed a genotype/phenotype correlation involving the location and type of mutation. Patients with mutations affecting the seventh spectrin domain, which resulted in increased RAC1 activation with a gain-of-function effect, tended to have macrocephaly and moderately to severely impaired intellectual development (MRD63). In contrast, patients with mutations in the GEFD1 domain or mutations that resulted in a frameshift or truncated proteins, which resulted in a loss-of-function effect, tended to have microcephaly and mildly to moderately impaired intellectual development or less severe learning disabilities (MRD44). However, there were some exceptions; for example, 2 missense variants in the GEFD1 domain (P1461T, <a href="#0006">601893.0006</a> and P1461L), identified in patients with MRD63, showed no impairment in RAC1 activation compared to wildtype when expressed in HEK293 cells, and both resulted in increased neurite and lamellipodia formation in transfected neuroblastoma cells. Similarly, studies of a frameshift variant (Phe2473fs), predicted to result in a loss of function, showed no effect on RAC1 activation or neurite formation compared to wildtype. The authors suggested that there may be correlation between the types of mutations and their cellular expression or effects on RAC1 activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32109419" 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="#1" class="mim-tip-reference" title="Ba, W., Yan, Y., Reijnders, M. R. F., Schuurs-Hoeijmakers, J. H. M., Feenstra, I., Bongers, E. M. H. F., Bosch, D. G. M., De Leeuw, N., Pfundt, R., Gilissen, C., De Vries, P. F., Veltman, J. A., Hoischen, A., Mefford, H. C., Eichler, E. E., Vissers, L. E. L. M., Kasri, N. N., De Vries, B. B. A. <strong>TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.</strong> Hum. Molec. Genet. 25: 892-902, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26721934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26721934</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26721934[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/ddv618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26721934">Ba et al. (2016)</a> found expression of the Trio gene during rat hippocampal development. It was expressed during the early postnatal period, but rapidly decreased after postnatal day 11, suggesting a role in early neuronal development. Knockdown of Trio using shRNA in dissociated rat hippocampal neurons resulted in an increase in primary dendrites and branch points during early neuronal development, suggesting that TRIO functions normally to limit dendrite formation. Knockdown of Trio in hippocampal slices resulted in increased AMPA receptor-mediated, but not NMDA receptor-mediated, transmission compared to controls, which was shown to result from a decrease in AMPA receptor endocytosis. These changes were associated with an increase in excitatory currents. These data suggested that Trio negatively regulates hippocampal synaptic strength during development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26721934" 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="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> found that specific knockdown of the GEFD1 domain of the trio gene in X. tropicalis resulted in abnormal craniofacial development with microcephaly, as well as deformation in the forebrain structure compared to controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32109419" 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>.0001 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY</strong>
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<p>In a 10-year-old boy with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; <a href="/entry/617061">617061</a>), <a href="#1" class="mim-tip-reference" title="Ba, W., Yan, Y., Reijnders, M. R. F., Schuurs-Hoeijmakers, J. H. M., Feenstra, I., Bongers, E. M. H. F., Bosch, D. G. M., De Leeuw, N., Pfundt, R., Gilissen, C., De Vries, P. F., Veltman, J. A., Hoischen, A., Mefford, H. C., Eichler, E. E., Vissers, L. E. L. M., Kasri, N. N., De Vries, B. B. A. <strong>TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.</strong> Hum. Molec. Genet. 25: 892-902, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26721934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26721934</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26721934[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/ddv618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26721934">Ba et al. (2016)</a> identified a de novo heterozygous c.4128G-A transition (c.4128G-A, NM_007118.2) in the TRIO gene, predicted to result in a trp1376-to-ter (W1376X) substitution in the RhoGEF domain. The mutation, which was found by targeted sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26721934" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 35-year-old woman with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; <a href="/entry/617061">617061</a>), <a href="#1" class="mim-tip-reference" title="Ba, W., Yan, Y., Reijnders, M. R. F., Schuurs-Hoeijmakers, J. H. M., Feenstra, I., Bongers, E. M. H. F., Bosch, D. G. M., De Leeuw, N., Pfundt, R., Gilissen, C., De Vries, P. F., Veltman, J. A., Hoischen, A., Mefford, H. C., Eichler, E. E., Vissers, L. E. L. M., Kasri, N. N., De Vries, B. B. A. <strong>TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.</strong> Hum. Molec. Genet. 25: 892-902, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26721934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26721934</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26721934[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/ddv618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26721934">Ba et al. (2016)</a> identified a de novo heterozygous 1-bp deletion (c.3752del, NM_007118.2) in the TRIO gene, predicted to result in a frameshift and premature termination (Asp1251ValfsTer11) in 1 of the SPEC domains. The mutation, which was found by targeted sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26721934" 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">rs879255624 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255624;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=rs879255624" 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=rs879255624" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 20-year-old man with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; <a href="/entry/617061">617061</a>), <a href="#1" class="mim-tip-reference" title="Ba, W., Yan, Y., Reijnders, M. R. F., Schuurs-Hoeijmakers, J. H. M., Feenstra, I., Bongers, E. M. H. F., Bosch, D. G. M., De Leeuw, N., Pfundt, R., Gilissen, C., De Vries, P. F., Veltman, J. A., Hoischen, A., Mefford, H. C., Eichler, E. E., Vissers, L. E. L. M., Kasri, N. N., De Vries, B. B. A. <strong>TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.</strong> Hum. Molec. Genet. 25: 892-902, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26721934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26721934</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26721934[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/ddv618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26721934">Ba et al. (2016)</a> identified a heterozygous c.649A-T transversion (c.649A-T, NM_007118.2) in the TRIO gene, resulting in an arg217-to-ter (R217X) substitution in the N terminus. The mutation was inherited from his similarly affected father. The mutation, which was found by targeted sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26721934" 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">rs879255625 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255625;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=rs879255625" 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=rs879255625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 members of a family with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; <a href="/entry/617061">617061</a>), originally reported by <a href="#6" class="mim-tip-reference" title="Mercer, C. L., Keeton, B., Dennis, N. R. <strong>Familial multiple ventricular extrasystoles, short stature, craniofacial abnormalities and digital hypoplasia: a further case of Stoll syndrome?</strong> Clin. Dysmorph. 17: 91-93, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18388777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18388777</a>] [<a href="https://doi.org/10.1097/MCD.0b013e3282efefc9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18388777">Mercer et al. (2008)</a>, <a href="#7" class="mim-tip-reference" title="Pengelly, R. J., Greville-Heygate, S., Schmidt, S., Seaby, E. G., Jabalameli, M. R., Mehta, S. G. Parker, M. J., Goudie, D., Fagotto-Kaufmann, C., Mercer, C., the DDD Study, Debant, A., Ennis, S., Baralle, D. <strong>Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly.</strong> J. Med. Genet. 53: 735-742, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27418539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27418539</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-103942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27418539">Pengelly et al. (2016)</a> identified a heterozygous 1-bp deletion (c.4466delA, NM_007118) in exon 30 of the TRIO gene, resulting in a frameshift and premature termination (Gln1489ArgfsTer11) in the GEFD1 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was predicted to result in nonsense-mediated mRNA decay. One of the patients also had a pathogenic variant in the KCNJ2 gene (<a href="/entry/600681">600681</a>), which may have been responsible for ectopic ventricular beats. In vitro functional expression studies in HEK293 cells showed that the mutation strongly reduced Rac1 (<a href="/entry/602048">602048</a>) activation compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27418539+18388777" 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">rs879255626 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255626;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=rs879255626" 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=rs879255626" 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=RCV000239597 OR RCV001545744 OR RCV004547623" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000239597, RCV001545744, RCV004547623" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000239597...</a>
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<p>In a 16-year-old girl with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; <a href="/entry/617061">617061</a>), <a href="#7" class="mim-tip-reference" title="Pengelly, R. J., Greville-Heygate, S., Schmidt, S., Seaby, E. G., Jabalameli, M. R., Mehta, S. G. Parker, M. J., Goudie, D., Fagotto-Kaufmann, C., Mercer, C., the DDD Study, Debant, A., Ennis, S., Baralle, D. <strong>Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly.</strong> J. Med. Genet. 53: 735-742, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27418539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27418539</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-103942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27418539">Pengelly et al. (2016)</a> identified a de novo heterozygous c.4283G-A transition (c.4283G-A, NM_007118) in exon 28 of the TRIO gene, resulting in an arg1428-to-gln (R1428Q) substitution at a highly conserved residue in the GEFD1 domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the mutation strongly reduced Rac1 (<a href="/entry/602048">602048</a>) activation compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27418539" 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="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> identified a de novo heterozygous R1428Q mutation in the TRIO gene in an 8-year-old girl (patient 12) with MRD44. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Immunoblot analysis of HEK293 cells transfected with the mutation showed that the mutation impaired TRIO binding to RAC1 compared to wildtype. Transfection of the mutation into neuroblastoma cells caused decreased neurite outgrowth and decreased lamellipodia formation compared to controls. The findings were consistent with a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32109419" 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">rs879255627 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255627;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=rs879255627" 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=rs879255627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an 8-year-old girl with autosomal dominant mental retardation-44 with microcephaly (MRD44; <a href="/entry/617061">617061</a>), <a href="#7" class="mim-tip-reference" title="Pengelly, R. J., Greville-Heygate, S., Schmidt, S., Seaby, E. G., Jabalameli, M. R., Mehta, S. G. Parker, M. J., Goudie, D., Fagotto-Kaufmann, C., Mercer, C., the DDD Study, Debant, A., Ennis, S., Baralle, D. <strong>Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly.</strong> J. Med. Genet. 53: 735-742, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27418539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27418539</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-103942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27418539">Pengelly et al. (2016)</a> identified a de novo heterozygous c.4381C-A transversion (c.4281C-A, NM_007118) in exon 29, resulting in a pro1461-to-thr (P1461T) substitution at a highly conserved residue in the GEFD1 domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the mutation strongly reduced Rac1 (<a href="/entry/602048">602048</a>) activation compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27418539" 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="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> found that transfection of the P1461T mutation into HEK293 cells only slightly impaired RAC1 activation (nonsignificant). Transfection of the variant into neuroblastoma cells did not alter neurite length, but it slightly increased lamellipodia formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32109419" 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">rs879255628 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255628;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=rs879255628" 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=rs879255628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 9-year-old girl with autosomal dominant intellectual developmental disorder-63 with macrocephaly (MRD63; <a href="/entry/618825">618825</a>), <a href="#7" class="mim-tip-reference" title="Pengelly, R. J., Greville-Heygate, S., Schmidt, S., Seaby, E. G., Jabalameli, M. R., Mehta, S. G. Parker, M. J., Goudie, D., Fagotto-Kaufmann, C., Mercer, C., the DDD Study, Debant, A., Ennis, S., Baralle, D. <strong>Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly.</strong> J. Med. Genet. 53: 735-742, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27418539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27418539</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-103942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27418539">Pengelly et al. (2016)</a> identified a de novo heterozygous c.3239A-T transversion (c.3239A-T, NM_007118) in exon 19 of the TRIO gene, resulting in an asn1080-to-ile (N1080I) substitution in the spectrin repeat domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the mutation did not affect RAC1 (<a href="/entry/602048">602048</a>) activation, which was in contrast to the other TRIO mutations identified by <a href="#7" class="mim-tip-reference" title="Pengelly, R. J., Greville-Heygate, S., Schmidt, S., Seaby, E. G., Jabalameli, M. R., Mehta, S. G. Parker, M. J., Goudie, D., Fagotto-Kaufmann, C., Mercer, C., the DDD Study, Debant, A., Ennis, S., Baralle, D. <strong>Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly.</strong> J. Med. Genet. 53: 735-742, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27418539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27418539</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-103942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27418539">Pengelly et al. (2016)</a>. This patient had a slightly different phenotype from the other patients: she did not have microcephaly, but had plagiocephaly, absence of speech, and seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27418539" 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="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> included the patient reported by <a href="#7" class="mim-tip-reference" title="Pengelly, R. J., Greville-Heygate, S., Schmidt, S., Seaby, E. G., Jabalameli, M. R., Mehta, S. G. Parker, M. J., Goudie, D., Fagotto-Kaufmann, C., Mercer, C., the DDD Study, Debant, A., Ennis, S., Baralle, D. <strong>Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly.</strong> J. Med. Genet. 53: 735-742, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27418539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27418539</a>] [<a href="https://doi.org/10.1136/jmedgenet-2016-103942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27418539">Pengelly et al. (2016)</a> in their study (referred to as patient 9). <a href="#2" class="mim-tip-reference" title="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> found that transfection of the N1080I mutation into HEK293 cells resulted in increased RAC1 (<a href="/entry/602048">602048</a>) activation, as measured by increased PAK1 (<a href="/entry/602590">602590</a>) phosphorylation, compared to wildtype. Transfection of the mutation into neuroblastoma cells caused enhanced neurite outgrowth and increased lamellipodia formation compared to controls. The findings were consistent with a gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27418539+32109419" 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>.0008 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 63, WITH MACROCEPHALY</strong>
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<p>In 4 unrelated boys (patients 2-5) with autosomal dominant intellectual developmental disorder-63 with macrocephaly (MRD63; <a href="/entry/618825">618825</a>), <a href="#2" class="mim-tip-reference" title="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> identified a de novo heterozygous c.3232C-T transition (c.3232C-T, NM_007118) in the TRIO gene, resulting in an arg1078-to-trp (R1078W) substitution at a highly conserved residue in the seventh spectrin repeat domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Molecular modeling predicted that the mutation could cause steric hindrance and alter the structural organization of the protein or protein folding. Expression of the mutation into HEK293 cells resulted in increased RAC1 (<a href="/entry/602048">602048</a>) activation, as measured by increased PAK1 (<a href="/entry/602590">602590</a>) phosphorylation, compared to wildtype. Transfection of the mutation into neuroblastoma cells caused enhanced neurite outgrowth and increased lamellipodia formation compared to controls. The findings were consistent with a gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32109419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 63, WITH MACROCEPHALY</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">rs1554065887 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554065887;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=rs1554065887" 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=rs1554065887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 6-year-old boy (patient 6) with autosomal dominant intellectual developmental disorder-63 with macrocephaly (MRD63; <a href="/entry/618825">618825</a>), <a href="#2" class="mim-tip-reference" title="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> identified a de novo heterozygous c.3232C-G transversion (c.3232C-G, NM_007118) in the TRIO gene, resulting in an arg1078-to-gly (R1078G) substitution at a highly conserved residue in the seventh spectrin repeat domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Molecular modeling predicted that the mutation could cause steric hindrance and alter the structural organization of the protein or protein folding. Expression of the mutation into HEK293 cells resulted in increased RAC1 (<a href="/entry/602048">602048</a>) activation, as measured by increased PAK1 (<a href="/entry/602590">602590</a>) phosphorylation, compared to wildtype. Transfection of the mutation into neuroblastoma cells caused enhanced neurite outgrowth and increased lamellipodia formation compared to controls. The findings were consistent with a gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32109419" 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>.0010 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 63, WITH MACROCEPHALY</strong>
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<p>In 2 unrelated patients (patients 7 and 8) with autosomal dominant intellectual developmental disorder-63 with macrocephaly (MRD63; <a href="/entry/618825">618825</a>), <a href="#2" class="mim-tip-reference" title="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> identified a de novo heterozygous c.3233G-A transition (c.3233G-A, NM_007118) in the TRIO gene, resulting in an arg1078-to-gln (R1078Q) substitution at a highly conserved residue in the seventh spectrin repeat domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Molecular modeling predicted that the mutation could cause steric hindrance and alter the structural organization of the protein or protein folding. Expression of the mutation into HEK293 cells resulted in increased RAC1 (<a href="/entry/602048">602048</a>) activation, as measured by increased PAK1 (<a href="/entry/602590">602590</a>) phosphorylation, compared to wildtype. Transfection of the mutation into neuroblastoma cells caused enhanced neurite outgrowth and increased lamellipodia formation compared to controls. The findings were consistent with a gain-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32109419" 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>.0011 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY</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">rs1746763024 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1746763024;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=rs1746763024" 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=rs1746763024" 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=RCV001030436" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001030436" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001030436</a>
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<p>In a 20-month-old boy (patient 10) with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; <a href="/entry/617061">617061</a>), <a href="#2" class="mim-tip-reference" title="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> identified a de novo heterozygous c.3895G-A transition (c.3895G-A, NM_007118) in the TRIO gene, predicted to result in a glu1299-to-lys (E1299K) substitution at a highly conserved residue in the GEFD1 domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Immunoblot analysis of HEK293 cells transfected with the mutation showed that the mutation impaired TRIO binding to RAC1 (<a href="/entry/602048">602048</a>) compared to wildtype. Transfection of the mutation into neuroblastoma cells caused decreased neurite outgrowth and decreased lamellipodia formation compared to controls. The findings were consistent with a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32109419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY</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">rs1554062562 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554062562;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=rs1554062562" 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=rs1554062562" 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=RCV000624516 OR RCV001030437 OR RCV001260792" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000624516, RCV001030437, RCV001260792" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000624516...</a>
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<p>In a 14-year-old girl (patient 18) with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; <a href="/entry/617061">617061</a>), <a href="#2" class="mim-tip-reference" title="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> identified a heterozygous c.2302C-T transition (c.2302C-T, NM_007118) in the TRIO gene, predicted to result in a gln768-to-ter (Q768X) substitution. The mutation was found by exome sequencing; parental DNA was not available to confirm de novo occurrence. The mutation was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency, but functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32109419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY</strong>
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TRIO, 1-BP DUP, NT6092
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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> rs752676391 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs752676391;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/rs752676391?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=rs752676391" 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=rs752676391" 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=RCV001030438 OR RCV001260798 OR RCV002252297 OR RCV002272390" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001030438, RCV001260798, RCV002252297, RCV002272390" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001030438...</a>
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<p>In a 16-year-old boy (patient 20) with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; <a href="/entry/617061">617061</a>), <a href="#2" class="mim-tip-reference" title="Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others. <strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong> Am. J. Hum. Genet. 106: 338-355, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>] [<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32109419">Barbosa et al. (2020)</a> identified a de novo heterozygous 1-bp duplication in the TRIO gene (c.6092dup, NM_007118), predicted to result in a frameshift and premature termination (Leu2031PhefsTer9). The mutation was found by exome sequencing. Immunoblot analysis of HEK293 cells transfected with the mutation showed that the mutation impaired TRIO binding to RAC1 (<a href="/entry/602048">602048</a>) compared to wildtype. However, transfection of the mutation into neuroblastoma cells showed no effect on neurite outgrowth or lamellipodia formation compared to controls. The findings were suggestive of a loss-of-function effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32109419" 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 id="1" class="mim-anchor"></a>
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Ba, W., Yan, Y., Reijnders, M. R. F., Schuurs-Hoeijmakers, J. H. M., Feenstra, I., Bongers, E. M. H. F., Bosch, D. G. M., De Leeuw, N., Pfundt, R., Gilissen, C., De Vries, P. F., Veltman, J. A., Hoischen, A., Mefford, H. C., Eichler, E. E., Vissers, L. E. L. M., Kasri, N. N., De Vries, B. B. A.
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<strong>TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.</strong>
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Hum. Molec. Genet. 25: 892-902, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26721934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26721934</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26721934[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=26721934" 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/ddv618" target="_blank">Full Text</a>]
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Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others.
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<strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong>
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Am. J. Hum. Genet. 106: 338-355, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32109419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32109419</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32109419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2020.01.018" target="_blank">Full Text</a>]
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Debant, A., Serra-Pages, C., Seipel, K., O'Brien, S., Tang, M., Park, S.-H., Streuli, M.
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<strong>The multidomain protein Trio binds the LAR transmembrane tyrosine phosphatase, contains a protein kinase domain, and has separate rac-specific and rho-specific guanine nucleotide exchange factor domains.</strong>
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Proc. Nat. Acad. Sci. 93: 5466-5471, 1996.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8643598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8643598</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8643598" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Ferraro, F., Ma, X.-M., Sobota, J. A., Eipper, B. A., Mains, R. E.
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<strong>Kalirin/Trio Rho guanine nucleotide exchange factors regulate a novel step in secretory granule maturation.</strong>
|
|
Molec. Biol. Cell 18: 4813-4825, 2007.
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|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17881726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17881726</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17881726[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=17881726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Liu, X., Wang, H., Eberstadt, M., Schnuchel, A., Olejniczak, E. T., Meadows, R. P., Schkeryantz, J. M., Janowick, D. A., Harlan, J. E., Harris, E. A. S., Staunton, D. E., Fesik, S. W.
|
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<strong>NMR structure and mutagenesis of the N-terminal DBl homology domain of the nucleotide exchange factor Trio.</strong>
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Cell 95: 269-277, 1998.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9790533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9790533</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9790533" 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/s0092-8674(00)81757-2" target="_blank">Full Text</a>]
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Mercer, C. L., Keeton, B., Dennis, N. R.
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<strong>Familial multiple ventricular extrasystoles, short stature, craniofacial abnormalities and digital hypoplasia: a further case of Stoll syndrome?</strong>
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Clin. Dysmorph. 17: 91-93, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18388777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18388777</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18388777" 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/10.1097/MCD.0b013e3282efefc9" target="_blank">Full Text</a>]
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<a id="Pengelly2016" class="mim-anchor"></a>
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Pengelly, R. J., Greville-Heygate, S., Schmidt, S., Seaby, E. G., Jabalameli, M. R., Mehta, S. G. Parker, M. J., Goudie, D., Fagotto-Kaufmann, C., Mercer, C., the DDD Study, Debant, A., Ennis, S., Baralle, D.
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<strong>Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly.</strong>
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J. Med. Genet. 53: 735-742, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27418539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27418539</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27418539" 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/jmedgenet-2016-103942" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Stumpf2020" class="mim-anchor"></a>
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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 04/03/2020.
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<a id="Taviaux1997" class="mim-anchor"></a>
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Taviaux, S., Diriong, S., Bellanger, J.-M., Streuli, M., Debant, A.
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<strong>Assignment of TRIO, the trio gene (PTPRF interacting) to human chromosome bands 5p15.1-p14 by in situ hybridization.</strong>
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Cytogenet. Cell Genet. 76: 107-108, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9154137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9154137</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9154137" 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/10.1159/000134524" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 04/03/2020
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 03/26/2020<br>Cassandra L. Kniffin - updated : 08/03/2016<br>Patricia A. Hartz - updated : 3/21/2008<br>Stylianos E. Antonarakis - updated : 11/6/1998
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/23/1997
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alopez : 04/03/2020
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<span class="mim-text-font">
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carol : 04/01/2020<br>carol : 03/31/2020<br>ckniffin : 03/26/2020<br>carol : 08/01/2017<br>carol : 10/24/2016<br>carol : 09/06/2016<br>carol : 08/09/2016<br>carol : 08/05/2016<br>ckniffin : 08/03/2016<br>carol : 02/03/2009<br>mgross : 3/26/2008<br>mgross : 3/26/2008<br>terry : 3/21/2008<br>psherman : 11/6/1998<br>psherman : 11/6/1998<br>jenny : 6/27/1997<br>mark : 6/23/1997<br>jenny : 6/23/1997
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<strong>*</strong> 601893
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<h3>
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TRIPLE FUNCTIONAL DOMAIN; TRIO
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TRIO</em></strong>
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<strong>
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<em>
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Cytogenetic location: 5p15.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 5:14,143,342-14,510,204 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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5p15.2
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<span class="mim-font">
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Intellectual developmental disorder, autosomal dominant 44, with microcephaly
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<td>
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<span class="mim-font">
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617061
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<span class="mim-font">
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Intellectual developmental disorder, autosomal dominant 63, with macrocephaly
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<td>
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<span class="mim-font">
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618825
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</div>
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<span class="mim-text-font">
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<p>The TRIO protein contains 3 functional domains: a serine/threonine kinase domain and 2 guanine nucleotide exchange factor (GEF) domains for the family of Rho-like GTPases, specific for Rac1 (602048) and RhoA (165390), respectively (Debant et al., 1996). These domains suggest that this enzyme may play a key role in several signaling pathways that control cell proliferation. The TRIO gene is highly expressed in the developing brain (summary by Ba et al., 2016). </p>
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<span class="mim-font">
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p>Ferraro et al. (2007) showed that some isoforms of kalirin (604605) and Trio colocalized with immature secretory granules in mouse and rat neuroendocrine cells and modulated their cargo secretion. Overexpression of their N-terminal GEF domains enhanced secretion from immature granules, depleting cells of secretory cargo in the absence of secretagogue. This response required GEF activity and was mimicked by kalirin/Trio substrates Rac1 and RhoG (179505). Selective pharmacologic inhibition of endogenous GEF activity decreased secretagogue-independent release of hormone precursors, causing accumulation of product peptide in mature secretory granules. Ferraro et al. (2007) concluded that kalirin/TRIO modulation of cargo secretion from immature granules provides secretory cells with an extra layer of control over the sets of peptides released and enhances the range of physiologic responses that can be elicited. </p>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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<span class="mim-text-font">
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<p>Liu et al. (1998) described the solution structure of the N-terminal Dbl homology (DH) domain of TRIO (amino acids 1227-1407) that catalyzes nucleotide exchange for Rac1. The all-alpha-helical protein has a very different structure compared to other exchange factors. Based on site-directed mutagenesis, the authors identified functionally important residues of the DH domain. They are all highly conserved and reside in close proximity on 2 alpha helices. In addition, Liu et al. (1998) discovered a unique capability of the pleckstrin homology (PH) domain to enhance nucleotide exchange in DH domain-containing proteins. </p>
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</span>
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<div>
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<br />
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</div>
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<h4>
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<span class="mim-font">
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<strong>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>By fluorescence in situ hybridization, Taviaux et al. (1997) mapped the TRIO gene to 5p15.1-p14. </p><p>Stumpf (2020) mapped the TRIO gene to chromosome 5p12.2 based on an alignment of the TRIO sequence (GenBank BC017268) with the genomic sequence (GRCh38).</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">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Autosomal Dominant Intellectual Developmental Disorder 44 with Microcephaly</em></strong></p><p>
|
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In 4 patients from 3 unrelated families with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; 617061), Ba et al. (2016) identified 3 different heterozygous truncating mutations in the TRIO gene (601893.0001-601893.0003). Two of the mutations occurred de novo. Studies of patient cells were not performed, but knockdown of the Trio gene in rat hippocampal cells resulted in an increase in dendrites and alterations in synaptic transmission, resulting in increased excitatory transmission during development (see ANIMAL MODEL). Ba et al. (2016) noted that premature maturation of excitatory synapses has been observed in several models of autism spectrum disorder, which was observed in these patients. </p><p>By exome sequencing in 3 members of a family with MRD44, originally reported by Mercer et al. (2008), Pengelly et al. (2016) identified a heterozygous truncating mutation in the TRIO gene (601893.0004). Exome sequencing subsequently identified de novo heterozygous missense mutations in the TRIO gene in 2 additional unrelated patients with MRD44 (601893.0005-601893.0006). All mutations were confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the truncating mutation and 2 of the missense mutations affecting the GEFD1 domain resulted in decreased RAC1 activation. </p><p>In 5 unrelated patients (patients 10, 12, 14, 15, and 16) with MRD44, Barbosa et al. (2020) identified de novo heterozygous missense mutations at highly conserved residues in the GEFD1 domain of the TRIO gene (see, e.g., 601893.0005 and 601893.0011). The mutations, which were found by exome sequencing, were not present in the gnomAD database. Immunoblot analysis of HEK293 cells transfected with the mutations showed impaired TRIO binding to RAC1 compared to wildtype. Transfection of the mutations into neuroblastoma cells caused decreased neurite outgrowth and decreased lamellipodia formation compared to controls. The findings were consistent with a loss-of-function effect. Barbosa et al. (2020) also identified heterozygous nonsense or frameshift mutations in 5 additional individuals with a similar disorder (see, e.g., 601893.0012 and 601893.0013). Three of the mutations were demonstrated to occur de novo. Similar in vitro functional studies performed on 1 of the mutations were consistent with a loss-of-function effect. </p><p><strong><em>Autosomal Dominant Intellectual Developmental Disorder 63 with Macrocephaly</em></strong></p><p>
|
|
In 9 unrelated patients with autosomal dominant intellectual developmental disorder-63 with macrocephaly (MRD63; 618825), Barbosa et al. (2020) identified 5 different heterozygous missense mutations in the TRIO gene (see, e.g., 601893.0007-601893.0010). One of the patients had previously been reported by Pengelly et al. (2016). The mutations, which were found by exome sequencing, were confirmed to occur de novo in 8 patients; inheritance was unknown in the ninth patient. All mutations occurred at highly conserved residues in the seventh spectrin repeat, and none were present in the gnomAD database. Three mutations, found in 6 unrelated patients, affected the same residue (R1078W, R1078G, and R1078Q). Molecular modeling predicted that the mutations could cause steric hindrance and alter the structural organization of the protein or interfere with protein folding. Expression of the mutations into HEK293 cells resulted in increased RAC1 activation, as measured by increased PAK1 (602590) phosphorylation, compared to wildtype. Transfection of the mutations into neuroblastoma cells caused enhanced neurite outgrowth and increased lamellipodia formation compared to controls. The findings were consistent with a gain-of-function effect. </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">
|
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a large study of 24 individuals with confirmed, mostly de novo heterozygous TRIO mutations, Barbosa et al. (2020) observed a genotype/phenotype correlation involving the location and type of mutation. Patients with mutations affecting the seventh spectrin domain, which resulted in increased RAC1 activation with a gain-of-function effect, tended to have macrocephaly and moderately to severely impaired intellectual development (MRD63). In contrast, patients with mutations in the GEFD1 domain or mutations that resulted in a frameshift or truncated proteins, which resulted in a loss-of-function effect, tended to have microcephaly and mildly to moderately impaired intellectual development or less severe learning disabilities (MRD44). However, there were some exceptions; for example, 2 missense variants in the GEFD1 domain (P1461T, 601893.0006 and P1461L), identified in patients with MRD63, showed no impairment in RAC1 activation compared to wildtype when expressed in HEK293 cells, and both resulted in increased neurite and lamellipodia formation in transfected neuroblastoma cells. Similarly, studies of a frameshift variant (Phe2473fs), predicted to result in a loss of function, showed no effect on RAC1 activation or neurite formation compared to wildtype. The authors suggested that there may be correlation between the types of mutations and their cellular expression or effects on RAC1 activity. </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">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ba et al. (2016) found expression of the Trio gene during rat hippocampal development. It was expressed during the early postnatal period, but rapidly decreased after postnatal day 11, suggesting a role in early neuronal development. Knockdown of Trio using shRNA in dissociated rat hippocampal neurons resulted in an increase in primary dendrites and branch points during early neuronal development, suggesting that TRIO functions normally to limit dendrite formation. Knockdown of Trio in hippocampal slices resulted in increased AMPA receptor-mediated, but not NMDA receptor-mediated, transmission compared to controls, which was shown to result from a decrease in AMPA receptor endocytosis. These changes were associated with an increase in excitatory currents. These data suggested that Trio negatively regulates hippocampal synaptic strength during development. </p><p>Barbosa et al. (2020) found that specific knockdown of the GEFD1 domain of the trio gene in X. tropicalis resulted in abnormal craniofacial development with microcephaly, as well as deformation in the forebrain structure compared to controls. </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">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>13 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY</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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TRIO, TRP1376TER
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<br />
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SNP: rs879255622,
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ClinVar: RCV000239538
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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 10-year-old boy with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; 617061), Ba et al. (2016) identified a de novo heterozygous c.4128G-A transition (c.4128G-A, NM_007118.2) in the TRIO gene, predicted to result in a trp1376-to-ter (W1376X) substitution in the RhoGEF domain. The mutation, which was found by targeted sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY</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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TRIO, 1-BP DEL, NT3752
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<br />
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SNP: rs879255623,
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ClinVar: RCV000239592
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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 35-year-old woman with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; 617061), Ba et al. (2016) identified a de novo heterozygous 1-bp deletion (c.3752del, NM_007118.2) in the TRIO gene, predicted to result in a frameshift and premature termination (Asp1251ValfsTer11) in 1 of the SPEC domains. The mutation, which was found by targeted sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0003 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY</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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TRIO, ARG217TER
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<br />
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SNP: rs879255624,
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ClinVar: RCV000239483
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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 20-year-old man with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; 617061), Ba et al. (2016) identified a heterozygous c.649A-T transversion (c.649A-T, NM_007118.2) in the TRIO gene, resulting in an arg217-to-ter (R217X) substitution in the N terminus. The mutation was inherited from his similarly affected father. The mutation, which was found by targeted sequencing, was not present in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY</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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TRIO, 1-BP DEL, 4466A
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<br />
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SNP: rs879255625,
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ClinVar: RCV000239545
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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 3 members of a family with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; 617061), originally reported by Mercer et al. (2008), Pengelly et al. (2016) identified a heterozygous 1-bp deletion (c.4466delA, NM_007118) in exon 30 of the TRIO gene, resulting in a frameshift and premature termination (Gln1489ArgfsTer11) in the GEFD1 domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was predicted to result in nonsense-mediated mRNA decay. One of the patients also had a pathogenic variant in the KCNJ2 gene (600681), which may have been responsible for ectopic ventricular beats. In vitro functional expression studies in HEK293 cells showed that the mutation strongly reduced Rac1 (602048) activation compared to wildtype. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRIO, ARG1428GLN
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|
|
<br />
|
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|
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SNP: rs879255626,
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|
|
ClinVar: RCV000239597, RCV001545744, RCV004547623
|
|
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|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 16-year-old girl with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; 617061), Pengelly et al. (2016) identified a de novo heterozygous c.4283G-A transition (c.4283G-A, NM_007118) in exon 28 of the TRIO gene, resulting in an arg1428-to-gln (R1428Q) substitution at a highly conserved residue in the GEFD1 domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the mutation strongly reduced Rac1 (602048) activation compared to wildtype. </p><p>Barbosa et al. (2020) identified a de novo heterozygous R1428Q mutation in the TRIO gene in an 8-year-old girl (patient 12) with MRD44. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Immunoblot analysis of HEK293 cells transfected with the mutation showed that the mutation impaired TRIO binding to RAC1 compared to wildtype. Transfection of the mutation into neuroblastoma cells caused decreased neurite outgrowth and decreased lamellipodia formation compared to controls. The findings were consistent with a loss-of-function effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRIO, PRO1461THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs879255627,
|
|
|
|
|
|
|
|
ClinVar: RCV000239509
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 8-year-old girl with autosomal dominant mental retardation-44 with microcephaly (MRD44; 617061), Pengelly et al. (2016) identified a de novo heterozygous c.4381C-A transversion (c.4281C-A, NM_007118) in exon 29, resulting in a pro1461-to-thr (P1461T) substitution at a highly conserved residue in the GEFD1 domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the mutation strongly reduced Rac1 (602048) activation compared to wildtype. </p><p>Barbosa et al. (2020) found that transfection of the P1461T mutation into HEK293 cells only slightly impaired RAC1 activation (nonsignificant). Transfection of the variant into neuroblastoma cells did not alter neurite length, but it slightly increased lamellipodia formation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 63, WITH MACROCEPHALY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRIO, ASN1080ILE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs879255628,
|
|
|
|
|
|
|
|
ClinVar: RCV000239559, RCV001030053
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 9-year-old girl with autosomal dominant intellectual developmental disorder-63 with macrocephaly (MRD63; 618825), Pengelly et al. (2016) identified a de novo heterozygous c.3239A-T transversion (c.3239A-T, NM_007118) in exon 19 of the TRIO gene, resulting in an asn1080-to-ile (N1080I) substitution in the spectrin repeat domain. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the mutation did not affect RAC1 (602048) activation, which was in contrast to the other TRIO mutations identified by Pengelly et al. (2016). This patient had a slightly different phenotype from the other patients: she did not have microcephaly, but had plagiocephaly, absence of speech, and seizures. </p><p>Barbosa et al. (2020) included the patient reported by Pengelly et al. (2016) in their study (referred to as patient 9). Barbosa et al. (2020) found that transfection of the N1080I mutation into HEK293 cells resulted in increased RAC1 (602048) activation, as measured by increased PAK1 (602590) phosphorylation, compared to wildtype. Transfection of the mutation into neuroblastoma cells caused enhanced neurite outgrowth and increased lamellipodia formation compared to controls. The findings were consistent with a gain-of-function effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 63, WITH MACROCEPHALY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRIO, ARG1078TRP
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000522592, RCV000623993, RCV000760240, RCV000995906, RCV001030433, RCV001260804, RCV004819226
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 unrelated boys (patients 2-5) with autosomal dominant intellectual developmental disorder-63 with macrocephaly (MRD63; 618825), Barbosa et al. (2020) identified a de novo heterozygous c.3232C-T transition (c.3232C-T, NM_007118) in the TRIO gene, resulting in an arg1078-to-trp (R1078W) substitution at a highly conserved residue in the seventh spectrin repeat domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Molecular modeling predicted that the mutation could cause steric hindrance and alter the structural organization of the protein or protein folding. Expression of the mutation into HEK293 cells resulted in increased RAC1 (602048) activation, as measured by increased PAK1 (602590) phosphorylation, compared to wildtype. Transfection of the mutation into neuroblastoma cells caused enhanced neurite outgrowth and increased lamellipodia formation compared to controls. The findings were consistent with a gain-of-function effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 63, WITH MACROCEPHALY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRIO, ARG1078GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1554065887,
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|
|
|
|
|
|
|
ClinVar: RCV001030434
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-year-old boy (patient 6) with autosomal dominant intellectual developmental disorder-63 with macrocephaly (MRD63; 618825), Barbosa et al. (2020) identified a de novo heterozygous c.3232C-G transversion (c.3232C-G, NM_007118) in the TRIO gene, resulting in an arg1078-to-gly (R1078G) substitution at a highly conserved residue in the seventh spectrin repeat domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Molecular modeling predicted that the mutation could cause steric hindrance and alter the structural organization of the protein or protein folding. Expression of the mutation into HEK293 cells resulted in increased RAC1 (602048) activation, as measured by increased PAK1 (602590) phosphorylation, compared to wildtype. Transfection of the mutation into neuroblastoma cells caused enhanced neurite outgrowth and increased lamellipodia formation compared to controls. The findings were consistent with a gain-of-function effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 63, WITH MACROCEPHALY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRIO, ARG1078GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1745369142,
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|
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|
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ClinVar: RCV001030435, RCV001579360, RCV002249637, RCV002552437, RCV004553564
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients (patients 7 and 8) with autosomal dominant intellectual developmental disorder-63 with macrocephaly (MRD63; 618825), Barbosa et al. (2020) identified a de novo heterozygous c.3233G-A transition (c.3233G-A, NM_007118) in the TRIO gene, resulting in an arg1078-to-gln (R1078Q) substitution at a highly conserved residue in the seventh spectrin repeat domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Molecular modeling predicted that the mutation could cause steric hindrance and alter the structural organization of the protein or protein folding. Expression of the mutation into HEK293 cells resulted in increased RAC1 (602048) activation, as measured by increased PAK1 (602590) phosphorylation, compared to wildtype. Transfection of the mutation into neuroblastoma cells caused enhanced neurite outgrowth and increased lamellipodia formation compared to controls. The findings were consistent with a gain-of-function effect. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
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|
TRIO, GLU1299LYS
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|
|
<br />
|
|
|
|
SNP: rs1746763024,
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ClinVar: RCV001030436
|
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|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 20-month-old boy (patient 10) with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; 617061), Barbosa et al. (2020) identified a de novo heterozygous c.3895G-A transition (c.3895G-A, NM_007118) in the TRIO gene, predicted to result in a glu1299-to-lys (E1299K) substitution at a highly conserved residue in the GEFD1 domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Immunoblot analysis of HEK293 cells transfected with the mutation showed that the mutation impaired TRIO binding to RAC1 (602048) compared to wildtype. Transfection of the mutation into neuroblastoma cells caused decreased neurite outgrowth and decreased lamellipodia formation compared to controls. The findings were consistent with a loss-of-function effect. </p>
|
|
</span>
|
|
</div>
|
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|
|
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<div>
|
|
<br />
|
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</div>
|
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</div>
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<span class="mim-font">
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<strong>.0012 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY</strong>
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</h4>
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<span class="mim-text-font">
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TRIO, GLN768TER
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<br />
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SNP: rs1554062562,
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ClinVar: RCV000624516, RCV001030437, RCV001260792
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<p>In a 14-year-old girl (patient 18) with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; 617061), Barbosa et al. (2020) identified a heterozygous c.2302C-T transition (c.2302C-T, NM_007118) in the TRIO gene, predicted to result in a gln768-to-ter (Q768X) substitution. The mutation was found by exome sequencing; parental DNA was not available to confirm de novo occurrence. The mutation was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency, but functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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<span class="mim-font">
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<strong>.0013 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 44, WITH MICROCEPHALY</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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TRIO, 1-BP DUP, NT6092
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<br />
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SNP: rs752676391,
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gnomAD: rs752676391,
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ClinVar: RCV001030438, RCV001260798, RCV002252297, RCV002272390
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</span>
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<span class="mim-text-font">
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<p>In a 16-year-old boy (patient 20) with autosomal dominant intellectual developmental disorder-44 with microcephaly (MRD44; 617061), Barbosa et al. (2020) identified a de novo heterozygous 1-bp duplication in the TRIO gene (c.6092dup, NM_007118), predicted to result in a frameshift and premature termination (Leu2031PhefsTer9). The mutation was found by exome sequencing. Immunoblot analysis of HEK293 cells transfected with the mutation showed that the mutation impaired TRIO binding to RAC1 (602048) compared to wildtype. However, transfection of the mutation into neuroblastoma cells showed no effect on neurite outgrowth or lamellipodia formation compared to controls. The findings were suggestive of a loss-of-function effect. </p>
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</span>
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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>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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Ba, W., Yan, Y., Reijnders, M. R. F., Schuurs-Hoeijmakers, J. H. M., Feenstra, I., Bongers, E. M. H. F., Bosch, D. G. M., De Leeuw, N., Pfundt, R., Gilissen, C., De Vries, P. F., Veltman, J. A., Hoischen, A., Mefford, H. C., Eichler, E. E., Vissers, L. E. L. M., Kasri, N. N., De Vries, B. B. A.
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<strong>TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.</strong>
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Hum. Molec. Genet. 25: 892-902, 2016.
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[PubMed: 26721934]
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[Full Text: https://doi.org/10.1093/hmg/ddv618]
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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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Barbosa, S., Greville-Heyate, S. Bonnet, M., Godwin, A., Fagotto-Kaufmann, C., Kajava, A. V., Laouteouet, D., Mawby, R., Wai, H. A., Dingemans, A. J. M., Hehir-Kwa, J., Willems, M., and 32 others.
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<strong>Opposite modulation of RAC2 by mutations in TRIO is associated with distinct, domain-specific neurodevelopmental disorders.</strong>
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Am. J. Hum. Genet. 106: 338-355, 2020.
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[PubMed: 32109419]
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[Full Text: https://doi.org/10.1016/j.ajhg.2020.01.018]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Debant, A., Serra-Pages, C., Seipel, K., O'Brien, S., Tang, M., Park, S.-H., Streuli, M.
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<strong>The multidomain protein Trio binds the LAR transmembrane tyrosine phosphatase, contains a protein kinase domain, and has separate rac-specific and rho-specific guanine nucleotide exchange factor domains.</strong>
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Proc. Nat. Acad. Sci. 93: 5466-5471, 1996.
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[PubMed: 8643598]
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[Full Text: https://doi.org/10.1073/pnas.93.11.5466]
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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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Ferraro, F., Ma, X.-M., Sobota, J. A., Eipper, B. A., Mains, R. E.
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<strong>Kalirin/Trio Rho guanine nucleotide exchange factors regulate a novel step in secretory granule maturation.</strong>
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Molec. Biol. Cell 18: 4813-4825, 2007.
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[PubMed: 17881726]
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[Full Text: https://doi.org/10.1091/mbc.e07-05-0503]
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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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Liu, X., Wang, H., Eberstadt, M., Schnuchel, A., Olejniczak, E. T., Meadows, R. P., Schkeryantz, J. M., Janowick, D. A., Harlan, J. E., Harris, E. A. S., Staunton, D. E., Fesik, S. W.
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<strong>NMR structure and mutagenesis of the N-terminal DBl homology domain of the nucleotide exchange factor Trio.</strong>
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Cell 95: 269-277, 1998.
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[PubMed: 9790533]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)81757-2]
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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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Mercer, C. L., Keeton, B., Dennis, N. R.
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<strong>Familial multiple ventricular extrasystoles, short stature, craniofacial abnormalities and digital hypoplasia: a further case of Stoll syndrome?</strong>
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Clin. Dysmorph. 17: 91-93, 2008.
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[PubMed: 18388777]
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[Full Text: https://doi.org/10.1097/MCD.0b013e3282efefc9]
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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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Pengelly, R. J., Greville-Heygate, S., Schmidt, S., Seaby, E. G., Jabalameli, M. R., Mehta, S. G. Parker, M. J., Goudie, D., Fagotto-Kaufmann, C., Mercer, C., the DDD Study, Debant, A., Ennis, S., Baralle, D.
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<strong>Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly.</strong>
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J. Med. Genet. 53: 735-742, 2016.
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[PubMed: 27418539]
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[Full Text: https://doi.org/10.1136/jmedgenet-2016-103942]
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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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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 04/03/2020.
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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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Taviaux, S., Diriong, S., Bellanger, J.-M., Streuli, M., Debant, A.
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<strong>Assignment of TRIO, the trio gene (PTPRF interacting) to human chromosome bands 5p15.1-p14 by in situ hybridization.</strong>
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Cytogenet. Cell Genet. 76: 107-108, 1997.
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[PubMed: 9154137]
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[Full Text: https://doi.org/10.1159/000134524]
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</p>
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</li>
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</ol>
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<br />
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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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Anne M. Stumpf - updated : 04/03/2020<br>Cassandra L. Kniffin - updated : 03/26/2020<br>Cassandra L. Kniffin - updated : 08/03/2016<br>Patricia A. Hartz - updated : 3/21/2008<br>Stylianos E. Antonarakis - updated : 11/6/1998
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<span class="mim-text-font">
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Victor A. McKusick : 6/23/1997
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alopez : 04/03/2020<br>carol : 04/01/2020<br>carol : 03/31/2020<br>ckniffin : 03/26/2020<br>carol : 08/01/2017<br>carol : 10/24/2016<br>carol : 09/06/2016<br>carol : 08/09/2016<br>carol : 08/05/2016<br>ckniffin : 08/03/2016<br>carol : 02/03/2009<br>mgross : 3/26/2008<br>mgross : 3/26/2008<br>terry : 3/21/2008<br>psherman : 11/6/1998<br>psherman : 11/6/1998<br>jenny : 6/27/1997<br>mark : 6/23/1997<br>jenny : 6/23/1997
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