4781 lines
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- *608210 - EXOSTOSIN GLYCOSYLTRANSFERASE 2; EXT2
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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">*608210</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<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/608210">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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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 role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<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=ENSG00000151348;t=ENST00000533608" 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=2132" 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=608210" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="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=ENSG00000151348;t=ENST00000533608" 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_000401,NM_001178083,NM_001389628,NM_001389630,NM_207122,XM_011519950,XM_047426528,XM_047426529,XM_047426530" 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_207122" 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=608210" 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=00599&isoform_id=00599_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/EXT2" 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/1518042,1519605,1621113,2251238,3023739,14603196,46250443,46370069,119588473,119588474,119588475,119588476,119588477,189065454,221041480,296010873,296010875,767965527,1953526465,1953526485,2217281607,2217281609,2217281611,2462523555,2462523557,2462523559" 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/Q93063" 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=2132" 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=ENSG00000151348;t=ENST00000533608" 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=EXT2" 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=EXT2" 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+2132" 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/EXT2" 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:2132" 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/2132" 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=chr11&hgg_gene=ENST00000533608.7&hgg_start=44095678&hgg_end=44251962&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:3513" 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:3513" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/ext2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=608210[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=608210[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/EXT2/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/ENSG00000151348" 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=EXT2" 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=EXT2" 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=EXT2" 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="http://medgen.ua.ac.be/LOVDv.2.0/home.php?select_db=EXT2" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=EXT2&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/PA27925" 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:3513" 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/FBgn0029175.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:108050" 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/EXT2#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:108050" 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/2132/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://omia.org/OMIA001214/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2132" 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://zfin.org/ZDB-GENE-041124-3" 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">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2132" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=EXT2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
|
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1187250005<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
608210
|
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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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EXOSTOSIN GLYCOSYLTRANSFERASE 2; EXT2
|
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
|
<br />
|
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</div>
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<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
EXOSTOSIN 2
|
|
</span>
|
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</h4>
|
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</div>
|
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</div>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=EXT2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">EXT2</a></em></strong>
|
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</span>
|
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</p>
|
|
</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/11/328?start=-3&limit=10&highlight=328">11p11.2</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:44095678-44251962&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'})">11:44,095,678-44,251,962</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
|
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|
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</span>
|
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</p>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=133701,616682" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/11/328?start=-3&limit=10&highlight=328">
|
|
11p11.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Exostoses, multiple, type 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/133701"> 133701 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Seizures, scoliosis, and macrocephaly syndrome
|
|
|
|
</span>
|
|
</td>
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<div class="mim-changed mim-change"><p>The EXT2 gene encodes a glycosyltransferase involved in the synthesis of heparan sulfate proteoglycans, which are involved in multiple cellular functions (summary by <a href="#6" class="mim-tip-reference" title="Farhan, S. M. K., Wang, J., Robinson, J. F., Prasad, A. N., Rupar, C. A., Siu, V. M., FORGE Canada Consortium, Hegele, R. A. <strong>Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses.</strong> J. Med. Genet. 52: 666-675, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26246518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26246518</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26246518">Farhan et al., 2015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26246518" 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></div>
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<p><a href="#10" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Strong, L. C., Hansen, M. F., Blanton, S. H., Wagner, M. <strong>Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8.</strong> Am. J. Hum. Genet. 56: 1125-1131, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726168</a>]" pmid="7726168">Hecht et al. (1995)</a> identified the candidate region for the gene responsible for hereditary multiple exostoses linked to chromosome 11 (<a href="/entry/133701">133701</a>) in an affected patient who also had a chondrosarcoma. By positional cloning and use of a chromosome 11-specific fetal brain cDNA library, <a href="#19" class="mim-tip-reference" title="Stickens, D., Clines, G., Burbee, D., Ramos, P., Thomas, S., Hogue, D., Hecht, J. T., Lovett, M., Evans, G. A. <strong>The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes.</strong> Nature Genet. 14: 25-32, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782816</a>] [<a href="https://doi.org/10.1038/ng0996-25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782816">Stickens et al. (1996)</a> identified the putative EXT2 gene, which was predicted to encode a 718-amino acid protein with a molecular mass of 82 kD. Both protein and DNA sequence-based algorithms detected significant similarity with the product of the EXT1 gene (<a href="/entry/608177">608177</a>), suggesting that the 2 genes are evolutionarily and functionally related. Northern blot analysis detected a major 3.5-kb mRNA transcript and a minor band of 3.7 to 4.0 kb in most tissues. <a href="#19" class="mim-tip-reference" title="Stickens, D., Clines, G., Burbee, D., Ramos, P., Thomas, S., Hogue, D., Hecht, J. T., Lovett, M., Evans, G. A. <strong>The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes.</strong> Nature Genet. 14: 25-32, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782816</a>] [<a href="https://doi.org/10.1038/ng0996-25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782816">Stickens et al. (1996)</a> suggested that the EXT2 gene may be expressed as a complex set of alternatively spliced forms. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8782816+7726168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Wuyts, W., Van Hul, W., Wauters, J., Nemtsova, M., Reyniers, E., Van Hul, E., De Boulle, K., de Vries, B. B. A., Hendrickx, J., Herrygers, I., Bossuyt, P., Balemans, W., Fransen, E., Vits, L., Coucke, P., Nowak, N. J., Shows, T. B., Mallet, L., van den Ouweland, A. M. W., McGaughran, J., Halley, D. J. J., Willems, P. J. <strong>Positional cloning of a gene involved in hereditary multiple exostoses.</strong> Hum. Molec. Genet. 5: 1547-1557, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8894688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8894688</a>] [<a href="https://doi.org/10.1093/hmg/5.10.1547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8894688">Wuyts et al. (1996)</a> constructed a contig of YAC and P1 clones covering the EXT2 candidate region on chromosome 11p12-p11. The EXT2 region had been defined in large families with multiple exostoses by linkage analysis. They also defined the candidate region through deletion analysis in families with the Potocki-Shaffer syndrome (<a href="/entry/601224">601224</a>). From the EXT2 candidate region, <a href="#24" class="mim-tip-reference" title="Wuyts, W., Van Hul, W., Wauters, J., Nemtsova, M., Reyniers, E., Van Hul, E., De Boulle, K., de Vries, B. B. A., Hendrickx, J., Herrygers, I., Bossuyt, P., Balemans, W., Fransen, E., Vits, L., Coucke, P., Nowak, N. J., Shows, T. B., Mallet, L., van den Ouweland, A. M. W., McGaughran, J., Halley, D. J. J., Willems, P. J. <strong>Positional cloning of a gene involved in hereditary multiple exostoses.</strong> Hum. Molec. Genet. 5: 1547-1557, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8894688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8894688</a>] [<a href="https://doi.org/10.1093/hmg/5.10.1547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8894688">Wuyts et al. (1996)</a> isolated a transcribed sequence with homology to EXT1. Alignment of the EXT1 and EXT2 genes at the amino acid level revealed an overall sequence identity of 30.9%. The amino acid homology is 18% in the 5-prime region and 48% in the 3-prime region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8894688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Stickens, D., Evans, G. A. <strong>Isolation and characterization of the murine homolog of the human EXT2 multiple exostoses gene.</strong> Biochem. Molec. Med. 61: 16-21, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9232192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9232192</a>] [<a href="https://doi.org/10.1006/bmme.1997.2588" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9232192">Stickens and Evans (1997)</a> isolated and characterized the mouse EXT2 gene. They found that the mouse EXT2 cDNA contains an open reading frame encoding a predicted protein of 718 amino acids. The mouse amino acid sequence is 95% identical to the human EXT2 protein. Northern blot analysis showed that the gene is expressed in early stages of embryonic development, and in situ hybridization suggested that EXT2 plays a role in limb development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9232192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Clines, G. A., Ashley, J. A., Shah, S., Lovett, M. <strong>The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and Caenorhabditis elegans.</strong> Genome Res. 7: 359-367, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9110175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9110175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9110175[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gr.7.4.359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9110175">Clines et al. (1997)</a> noted that at least 2 homologs of the human and mouse EXT2 genes were found in Caenorhabditis elegans, suggesting to the authors that the genes do not function exclusively as regulators of bone growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9110175" 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="Clines, G. A., Ashley, J. A., Shah, S., Lovett, M. <strong>The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and Caenorhabditis elegans.</strong> Genome Res. 7: 359-367, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9110175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9110175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9110175[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gr.7.4.359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9110175">Clines et al. (1997)</a> found that the EXT2 gene contains 14 exons, plus 2 alternative exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9110175" 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 positional cloning, <a href="#19" class="mim-tip-reference" title="Stickens, D., Clines, G., Burbee, D., Ramos, P., Thomas, S., Hogue, D., Hecht, J. T., Lovett, M., Evans, G. A. <strong>The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes.</strong> Nature Genet. 14: 25-32, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782816</a>] [<a href="https://doi.org/10.1038/ng0996-25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782816">Stickens et al. (1996)</a> identified the EXT2 gene in the multiple exostoses type II critical region on chromosome 11p12-p11. <a href="#4" class="mim-tip-reference" title="Clines, G. A., Ashley, J. A., Shah, S., Lovett, M. <strong>The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and Caenorhabditis elegans.</strong> Genome Res. 7: 359-367, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9110175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9110175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9110175[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gr.7.4.359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9110175">Clines et al. (1997)</a> mapped the mouse Ext2 gene to chromosome 2. Information on the mapping of the EXT2 locus to 11p12-p11 was provided by <a href="#21" class="mim-tip-reference" title="Wu, Y.-Q., Heutink, P., de Vries, B. B. A., Sandkuijl, L. A., van den Ouweland, A. M. W., Niermeijer, M. F., Galjaard, H., Reyniers, E., Willems, P. J., Halley, D. J. J. <strong>Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11.</strong> Hum. Molec. Genet. 3: 167-171, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162019</a>] [<a href="https://doi.org/10.1093/hmg/3.1.167" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162019">Wu et al. (1994)</a>, <a href="#10" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Strong, L. C., Hansen, M. F., Blanton, S. H., Wagner, M. <strong>Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8.</strong> Am. J. Hum. Genet. 56: 1125-1131, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726168</a>]" pmid="7726168">Hecht et al. (1995)</a>, <a href="#22" class="mim-tip-reference" title="Wuyts, W., Ramlakhan, S., Van Hul, W., Hecht, J. T., van den Ouweland, A. M. W., Raskind, W. H., Hofstede, F. C., Reyniers, E., Wells, D. E., de Vries, B., Conrad, E. U., Hill, A., Zalatayev, D., Weissenbach, J., Wagner, M. J., Bakker, E., Halley, D. J. J., Willems, P. J. <strong>Refinement of the multiple exostoses locus (EXT2) to a 3-cM interval on chromosome 11.</strong> Am. J. Hum. Genet. 57: 382-387, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7668264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7668264</a>]" pmid="7668264">Wuyts et al. (1995)</a>, and <a href="#2" class="mim-tip-reference" title="Blanton, S. H., Hogue, D., Wagner, M., Wells, D., Young, I. D., Hecht, J. T. <strong>Hereditary multiple exostoses: confirmation of linkage to chromosomes 8 and 11.</strong> Am. J. Med. Genet. 62: 150-159, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8882395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8882395</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19960315)62:2<150::AID-AJMG7>3.0.CO;2-#" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8882395">Blanton et al. (1996)</a>, using linkage methods. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8162019+8882395+9110175+7726168+7668264+8782816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Strong, L. C., Hansen, M. F., Blanton, S. H., Wagner, M. <strong>Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8.</strong> Am. J. Hum. Genet. 56: 1125-1131, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726168</a>]" pmid="7726168">Hecht et al. (1995)</a> and <a href="#17" class="mim-tip-reference" title="Raskind, W. H., Conrad, E. U., Chansky, H., Matsushita, M. <strong>Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11.</strong> Am. J. Hum. Genet. 56: 1132-1139, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726169</a>]" pmid="7726169">Raskind et al. (1995)</a> presented evidence suggesting that the EXT1 gene on chromosome 8 and the EXT2 gene on chromosome 11 have a tumor suppressor function. They found loss of heterozygosity (LOH) for markers linked to these 2 genes in chondrosarcomas originating in individuals with multiple exostoses as well as in sporadic chondrosarcomas. To explain the fact that normal bone growth occurs concurrently with abnormal exostosis tumor growth, <a href="#10" class="mim-tip-reference" title="Hecht, J. T., Hogue, D., Strong, L. C., Hansen, M. F., Blanton, S. H., Wagner, M. <strong>Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8.</strong> Am. J. Hum. Genet. 56: 1125-1131, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726168</a>]" pmid="7726168">Hecht et al. (1995)</a> and <a href="#17" class="mim-tip-reference" title="Raskind, W. H., Conrad, E. U., Chansky, H., Matsushita, M. <strong>Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11.</strong> Am. J. Hum. Genet. 56: 1132-1139, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726169</a>]" pmid="7726169">Raskind et al. (1995)</a> proposed a 2-hit tumor formation model according to the Knudson hypothesis (<a href="#12" class="mim-tip-reference" title="Knudson, A. G., Jr. <strong>Mutation and cancer: statistical study of retinoblastoma.</strong> Proc. Nat. Acad. Sci. 68: 820-823, 1971.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5279523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5279523</a>] [<a href="https://doi.org/10.1073/pnas.68.4.820" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5279523">Knudson, 1971</a>). In this model, a single germline mutation results in the predisposition for disease and a second somatic mutational hit, usually LOH, allows for aberrant growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5279523+7726169+7726168" 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 addition to their presumed role as tumor suppressor genes, EXT1 and EXT2 may have roles in modulation of the hedgehog signaling pathway (see <a href="/entry/600725">600725</a>) and glycosaminoglycan synthesis. <a href="#1" class="mim-tip-reference" title="Bellaiche, Y., The, I., Perrimon, N. <strong>Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion.</strong> Nature 394: 85-88, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9665133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9665133</a>] [<a href="https://doi.org/10.1038/27932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9665133">Bellaiche et al. (1998)</a> determined that the Drosophila homolog of EXT1, dubbed 'tout-velu,' is required for diffusion of the signaling protein hedgehog. <a href="#14" class="mim-tip-reference" title="Lind, T., Tufaro, F., McCormick, C., Lindahl, U., Lidholt, K. <strong>The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate.</strong> J. Biol. Chem. 273: 26265-26268, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9756849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9756849</a>] [<a href="https://doi.org/10.1074/jbc.273.41.26265" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9756849">Lind et al. (1998)</a> concluded that EXT1 and EXT2 are glycosyltransferases, based on copurification of EXT2 in a bovine serum extract exhibiting this enzymatic activity as well as increased glycosyltransferase activity in cells overexpressing EXT2 in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9665133+9756849" 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>Using yeast 2-hybrid analysis, <a href="#18" class="mim-tip-reference" title="Simmons, A. D., Musy, M. M., Lopes, C. S., Hwang, L.-Y., Yang, Y.-P., Lovett, M. <strong>A direct interaction between EXT proteins and glycosyltransferases is defective in hereditary multiple exostoses.</strong> Hum. Molec. Genet. 8: 2155-2164, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10545594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10545594</a>] [<a href="https://doi.org/10.1093/hmg/8.12.2155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10545594">Simmons et al. (1999)</a> found that a conserved C-terminal region of EXT2 interacted with TRAP1 (<a href="/entry/606219">606219</a>) and the glycosyltransferase GALNT5 (<a href="/entry/615129">615129</a>). Deletion of a conserved histidine in EXT2 (his601) weakened its interaction with GALNT5 and abrogated its interaction with TRAP1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10545594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="McCormick, C., Duncan, G., Goutsos, K. T., Tufaro, F. <strong>The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate.</strong> Proc. Nat. Acad. Sci. 97: 668-673, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10639137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10639137</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10639137[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.97.2.668" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10639137">McCormick et al. (2000)</a> noted that the proteins encoded by the EXT1 and EXT2 genes are endoplasmic reticulum-localized type II transmembrane glycoproteins that possess or are tightly associated with glycosyltransferase activities involved in the polymerization of heparan sulfate. By testing a cell line with a specific defect in EXT1 in in vivo and in vitro assays, <a href="#15" class="mim-tip-reference" title="McCormick, C., Duncan, G., Goutsos, K. T., Tufaro, F. <strong>The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate.</strong> Proc. Nat. Acad. Sci. 97: 668-673, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10639137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10639137</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10639137[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.97.2.668" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10639137">McCormick et al. (2000)</a> showed that EXT2 does not harbor significant glycosyltransferase activity in the absence of EXT1. Instead, it appears that EXT1 and EXT2 form a heterooligomeric complex in vivo that leads to the accumulation of both proteins in the Golgi apparatus. Remarkably, the Golgi-localized EXT1/EXT2 complex possesses substantially higher glycosyltransferase activity than EXT1 or EXT2 alone, suggesting that the complex represents the biologically relevant form of the enzyme(s). These findings provided a rationale for the causation of hereditary multiple exostoses by loss of activity in either of the EXT genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10639137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Multiple Exostoses, Type II</em></strong></p><p>
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In a family with multiple exostoses type II (EXT2; <a href="/entry/133701">133701</a>), <a href="#19" class="mim-tip-reference" title="Stickens, D., Clines, G., Burbee, D., Ramos, P., Thomas, S., Hogue, D., Hecht, J. T., Lovett, M., Evans, G. A. <strong>The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes.</strong> Nature Genet. 14: 25-32, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782816</a>] [<a href="https://doi.org/10.1038/ng0996-25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782816">Stickens et al. (1996)</a> identified a heterozygous 4-bp deletion in the EXT2 gene (<a href="#0001">608210.0001</a>), resulting in a premature stop codon and truncated gene product. <a href="#19" class="mim-tip-reference" title="Stickens, D., Clines, G., Burbee, D., Ramos, P., Thomas, S., Hogue, D., Hecht, J. T., Lovett, M., Evans, G. A. <strong>The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes.</strong> Nature Genet. 14: 25-32, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782816</a>] [<a href="https://doi.org/10.1038/ng0996-25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782816">Stickens et al. (1996)</a> speculated that a second mutation event was necessary for the development of exostoses, thus accounting for the asymmetry of exostoses observed in the long bones. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782816" 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 2 families with multiple exostoses, <a href="#24" class="mim-tip-reference" title="Wuyts, W., Van Hul, W., Wauters, J., Nemtsova, M., Reyniers, E., Van Hul, E., De Boulle, K., de Vries, B. B. A., Hendrickx, J., Herrygers, I., Bossuyt, P., Balemans, W., Fransen, E., Vits, L., Coucke, P., Nowak, N. J., Shows, T. B., Mallet, L., van den Ouweland, A. M. W., McGaughran, J., Halley, D. J. J., Willems, P. J. <strong>Positional cloning of a gene involved in hereditary multiple exostoses.</strong> Hum. Molec. Genet. 5: 1547-1557, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8894688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8894688</a>] [<a href="https://doi.org/10.1093/hmg/5.10.1547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8894688">Wuyts et al. (1996)</a> identified 2 different mutations in the EXT2 gene: a nonsense mutation (<a href="#0002">608210.0002</a>) and a splice site mutation (<a href="#0003">608210.0003</a>). In 5 of 17 (29%) families with hereditary multiple exostoses, <a href="#16" class="mim-tip-reference" title="Philippe, C., Porter, D. E., Emerton, M. E., Wells, D. E., Simpson, A. H. R. W., Monaco, A. P. <strong>Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses.</strong> Am. J. Hum. Genet. 61: 520-528, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326317</a>] [<a href="https://doi.org/10.1086/515505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326317">Philippe et al. (1997)</a> identified 4 mutations in the EXT2 gene, including a missense mutation (<a href="#0004">608210.0004</a>) and 3 alterations that resulted in premature stop codons. Seven (41%) of the families had mutations in the EXT1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9326317+8894688" 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="#23" class="mim-tip-reference" title="Wuyts, W., Van Hul, W., De Boulle, K., Hendrickx, J., Bakker, E., Vanhoenacker, F., Mollica, F., Ludecke, H.-J., Sayli, B. S., Pazzaglia, U. E., Mortier, G., Hamel, B., Conrad, E. U., Matsushita, M., Raskind, W. H., Willems, P. J. <strong>Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.</strong> Am. J. Hum. Genet. 62: 346-354, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9463333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9463333</a>] [<a href="https://doi.org/10.1086/301726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9463333">Wuyts et al. (1998)</a> analyzed the EXT1 and EXT2 genes in 26 EXT families originating from 9 countries. Of the 26 families, 10 had an EXT1 mutation and 10 had an EXT2 mutation. Twelve of these mutations had not previously been described. From a review of these and previously reported mutations, <a href="#23" class="mim-tip-reference" title="Wuyts, W., Van Hul, W., De Boulle, K., Hendrickx, J., Bakker, E., Vanhoenacker, F., Mollica, F., Ludecke, H.-J., Sayli, B. S., Pazzaglia, U. E., Mortier, G., Hamel, B., Conrad, E. U., Matsushita, M., Raskind, W. H., Willems, P. J. <strong>Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.</strong> Am. J. Hum. Genet. 62: 346-354, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9463333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9463333</a>] [<a href="https://doi.org/10.1086/301726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9463333">Wuyts et al. (1998)</a> concluded that mutations in either the EXT1 or the EXT2 gene are responsible for most cases of multiple exostoses. Most of the mutations in these 2 genes cause premature termination of the EXT proteins, whereas missense mutations are rare. The authors concluded that the development of exostoses is mainly due to loss of function of EXT genes, consistent with the hypothesis that the EXT genes have a tumor suppressor function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9463333" 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>Analyzing for EXT1 and EXT2 mutations in 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas, <a href="#3" class="mim-tip-reference" title="Bovee, J. V. M. G., Cleton-Jansen, A.-M., Wuyts, W., Caethoven, G., Taminiau, A. H. M., Bakker, E., Van Hul, W., Cornelisse, C. J., Hogendoorn, P. C. W. <strong>EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas.</strong> Am. J. Hum. Genet. 65: 689-698, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441575</a>] [<a href="https://doi.org/10.1086/302532" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441575">Bovee et al. (1999)</a> found mutations in the EXT1 gene, but none in the EXT2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441575" 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="#25" class="mim-tip-reference" title="Wuyts, W., Van Hul, W. <strong>Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes.</strong> Hum. Mutat. 15: 220-227, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10679937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10679937</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(200003)15:3<220::AID-HUMU2>3.0.CO;2-K" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10679937">Wuyts and Van Hul (2000)</a> stated that 49 different EXT1 and 25 different EXT2 mutations had been identified in patients with multiple exostoses and that mutations in these 2 genes were responsible for over 70% of the EXT cases. Most of the mutations caused loss of function, which is consistent with the presumed tumor suppressor function of the EXT genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10679937" 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 fluorescence in situ hybridization, <a href="#13" class="mim-tip-reference" title="Ligon, A. H., Potocki, L., Shaffer, L. G., Stickens, D., Evans, G. A. <strong>Gene for multiple exostoses (EXT2) maps to 11(p11.2p12) and is deleted in patients with a contiguous gene syndrome. (Letter)</strong> Am. J. Med. Genet. 75: 538-540, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9489802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9489802</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980217)75:5<538::aid-ajmg17>3.0.co;2-l" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9489802">Ligon et al. (1998)</a> showed that the EXT2 gene is deleted in patients with the del(11)(p11.2p12) syndrome. Since patients with mutations in EXT2 have only multiple exostoses, deletions affecting only the EXT2 locus cannot explain the craniofacial anomalies, biparietal foramina, mental retardation, or genitourinary anomalies observed in patients with proximal 11p deletions. Therefore, deletion of other neighboring genes must be responsible for the additional anomalies, and this chromosomal aberration represents a true contiguous gene deletion syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9489802" 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="#11" class="mim-tip-reference" title="Heinritz, W., Huffmeier, U., Strenge, S., Miterski, B., Zweier, C., Leinung, S., Bohring, A., Mitulla, B., Peters, U., Froster, U. G. <strong>New mutations of EXT1 and EXT2 genes in German patients with multiple osteochondromas.</strong> Ann. Hum. Genet. 73: 283-291, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19344451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19344451</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2009.00508.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19344451">Heinritz et al. (2009)</a> identified 9 different mutations in the EXT2 gene in 11 of 23 German patients with multiple exostoses. Eleven other patients had mutations in the EXT1 gene; 1 patient had no detectable mutations. Among the EXT2 mutations, there were 3 recurrent mutations, Q172X (<a href="#0002">608210.0002</a>), D227N (<a href="#0004">608210.0004</a>), and Q258X (<a href="#0006">608210.0006</a>), and 6 novel mutations (see, e.g., <a href="#0007">608210.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19344451" 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 35 unrelated Italian patients with multiple exostoses type II, <a href="#7" class="mim-tip-reference" title="Fusco, C., Nardella, G., Fischetto, R., Copetti, M., Petracca, A., Annunziata, F., Augello, B., D'Asdia, M. C., Petrucci, S., Mattina, T., Rella, A., Cassina, M., and 10 others. <strong>Mutational spectrum and clinical signatures in 114 families with hereditary multiple properties of selected exostosin variants.</strong> Hum. Molec. Genet. 28: 2133-2142, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30806661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30806661</a>] [<a href="https://doi.org/10.1093/hmg/ddz046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30806661">Fusco et al. (2019)</a> identified 25 different heterozygous mutations in the EXT2 gene, of which 19 were novel. The mutations were identified by direct sequencing or by MLPA analysis followed by confirmation with quantitative real-time PCR. The mutations included 13 frameshifts, 6 nonsense, 4 missense, and 2 intragenic rearrangements. The most common mutation was N288S (<a href="#0013">608210.0013</a>), which occurred in 10 families. To evaluate the functional importance of EXT2 domains, <a href="#7" class="mim-tip-reference" title="Fusco, C., Nardella, G., Fischetto, R., Copetti, M., Petracca, A., Annunziata, F., Augello, B., D'Asdia, M. C., Petrucci, S., Mattina, T., Rella, A., Cassina, M., and 10 others. <strong>Mutational spectrum and clinical signatures in 114 families with hereditary multiple properties of selected exostosin variants.</strong> Hum. Molec. Genet. 28: 2133-2142, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30806661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30806661</a>] [<a href="https://doi.org/10.1093/hmg/ddz046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30806661">Fusco et al. (2019)</a> tested the effects of 2 mutations with a premature termination (Pro243Glnfs27 and Leu335Tyrfs101), comprising the N-terminal exostosin domain or the C-terminal glycosyltransferase family 64 domain, as well as the effects of a missense mutation (P351L; <a href="#0014">608210.0014</a>) in U2OS cells. The mutated proteins had abnormal localization patterns in the cell. When these mutant EXT2 proteins were expressed in HEK293 cells, the cells had slower growth compared to cells expressing wildtype EXT2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30806661" 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>Seizures, Scoliosis, and Macrocephaly/Microcephaly Syndrome</em></strong></p><p>
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In 4 sibs, born of consanguineous parents in the Old Order Mennonite community, with seizures, scoliosis, and macrocephaly/microcephaly syndrome (SSMS; <a href="/entry/616682">616682</a>), <a href="#6" class="mim-tip-reference" title="Farhan, S. M. K., Wang, J., Robinson, J. F., Prasad, A. N., Rupar, C. A., Siu, V. M., FORGE Canada Consortium, Hegele, R. A. <strong>Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses.</strong> J. Med. Genet. 52: 666-675, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26246518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26246518</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26246518">Farhan et al. (2015)</a> identified homozygosity for 2 missense mutations in cis in the EXT2 gene (M87R and R95C, <a href="#0008">608210.0008</a>). The mutations, which were found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. In vitro cellular expression studies indicated that both mutations individually resulted in decreased protein levels, with a synergistic effect of both mutations expressed at the same time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26246518" 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 2 brothers, born of consanguineous Syrian parents, with SSMS, <a href="#5" class="mim-tip-reference" title="El-Bazzal, L., Atkinson, A., Gillart, A.-C., Obeid, M., Delague, V., Megarbane, A. <strong>A novel EXT2 mutation in a consanguineous family with severe developmental delay, microcephaly, seizures, feeding difficulties, and osteopenia extends the phenotypic spectrum of autosomal recessive EXT2-related syndrome (AREXT2).</strong> Europ. J. Med. Genet. 62: 259-264, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30075207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30075207</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.07.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30075207">El-Bazzal et al. (2019)</a> identified a homozygous missense mutation in the EXT2 gene (S4L; <a href="#0009">608210.0009</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. 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=30075207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 14-year-old girl with SSMS, <a href="#9" class="mim-tip-reference" title="Gupta, A., Ewing, S. A., Renaud, D. L., Hasadsri, L., Raymond, K. M., Klee, E. W., Gavrilova, R. H. <strong>Developmental delay, coarse facies, and epilepsy in a patient with EXT2 gene variants.</strong> Clin. Case Rep. 7: 632-637, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30997052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30997052</a>] [<a href="https://doi.org/10.1002/ccr3.2010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30997052">Gupta et al. (2019)</a> identified compound heterozygous missense mutations in the EXT2 gene (V373D, <a href="#0010">608210.0010</a> and T672M, <a href="#0011">608210.0011</a>). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. The patient also carried a rare heterozygous missense variant (R454C) in the NDST1 gene (<a href="/entry/600853">600853</a>) gene inherited from the unaffected mother, but the contribution of this variant to the phenotype was unknown. The proband's fraternal twin sister, who was less severely affected, carried all 3 variants. Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30997052" 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 2 sibs with SSMS, <a href="#8" class="mim-tip-reference" title="Gentile, M., Agolini, E., Cocciadiferro, D., Ficarella, R., Ponzi, E., Bellachio, E., Antonucci, M. F., Novelli, A. <strong>Novel exostosin-2 missense variants in a family with autosomal recessive exostosin-2-related syndrome: further evidences on the phenotype.</strong> Clin. Genet. 95: 165-171, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30288735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30288735</a>] [<a href="https://doi.org/10.1111/cge.13458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30288735">Gentile et al. (2019)</a> identified compound heterozygous missense mutations in the EXT2 gene (Y608C, <a href="#0012">608210.0012</a> and D227N, <a href="#0004">608210.0004</a>). The mutations, which were found by targeted exome sequencing, segregated with the disorder in the family. The D227N variant, which had been found in patients with multiple exostoses type II (EXT2; <a href="/entry/133701">133701</a>), was inherited from the mother, who also had EXT2 as well as a family history of exostosis, and both sibs had EXT2. The father, who carried the Y608C variant, did not have exostosis. These findings indicated that D227N is a specific variant that contributes to exostosis. Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30288735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=608210[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864309636 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864309636;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=rs864309636" 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=rs864309636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<div class="mim-changed mim-change"><p>In a family with multiple exostoses type II (EXT2; <a href="/entry/133701">133701</a>), <a href="#19" class="mim-tip-reference" title="Stickens, D., Clines, G., Burbee, D., Ramos, P., Thomas, S., Hogue, D., Hecht, J. T., Lovett, M., Evans, G. A. <strong>The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes.</strong> Nature Genet. 14: 25-32, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8782816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8782816</a>] [<a href="https://doi.org/10.1038/ng0996-25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8782816">Stickens et al. (1996)</a> identified a heterozygous 4-bp deletion (c.784-c.787) in the EXT2 gene, resulting in a frameshift and premature termination of translation, generating a truncated EXT2 gene product. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8782816" 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></div>
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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> rs121918279 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918279;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/rs121918279?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=rs121918279" 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=rs121918279" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<div class="mim-changed mim-change"><p>In affected members of a large family with multiple exostoses II (EXT2; <a href="/entry/133701">133701</a>) family, <a href="#24" class="mim-tip-reference" title="Wuyts, W., Van Hul, W., Wauters, J., Nemtsova, M., Reyniers, E., Van Hul, E., De Boulle, K., de Vries, B. B. A., Hendrickx, J., Herrygers, I., Bossuyt, P., Balemans, W., Fransen, E., Vits, L., Coucke, P., Nowak, N. J., Shows, T. B., Mallet, L., van den Ouweland, A. M. W., McGaughran, J., Halley, D. J. J., Willems, P. J. <strong>Positional cloning of a gene involved in hereditary multiple exostoses.</strong> Hum. Molec. Genet. 5: 1547-1557, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8894688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8894688</a>] [<a href="https://doi.org/10.1093/hmg/5.10.1547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8894688">Wuyts et al. (1996)</a> identified a c.514C-T transition in the EXT2 gene, resulting in a gln172-to-ter (Q172X) substitution. The mutation was detected by SSCP analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8894688" 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></div>
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<p><a href="#11" class="mim-tip-reference" title="Heinritz, W., Huffmeier, U., Strenge, S., Miterski, B., Zweier, C., Leinung, S., Bohring, A., Mitulla, B., Peters, U., Froster, U. G. <strong>New mutations of EXT1 and EXT2 genes in German patients with multiple osteochondromas.</strong> Ann. Hum. Genet. 73: 283-291, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19344451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19344451</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2009.00508.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19344451">Heinritz et al. (2009)</a> identified the Q172X mutation in a German patient with EXT2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19344451" 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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EXT2, IVSDS, G-A, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864309637 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864309637;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=rs864309637" 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=rs864309637" 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=RCV000002577" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002577" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002577</a>
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<p>In affected members of a large Belgian family with multiple exostoses II (EXT2; <a href="/entry/133701">133701</a>), <a href="#24" class="mim-tip-reference" title="Wuyts, W., Van Hul, W., Wauters, J., Nemtsova, M., Reyniers, E., Van Hul, E., De Boulle, K., de Vries, B. B. A., Hendrickx, J., Herrygers, I., Bossuyt, P., Balemans, W., Fransen, E., Vits, L., Coucke, P., Nowak, N. J., Shows, T. B., Mallet, L., van den Ouweland, A. M. W., McGaughran, J., Halley, D. J. J., Willems, P. J. <strong>Positional cloning of a gene involved in hereditary multiple exostoses.</strong> Hum. Molec. Genet. 5: 1547-1557, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8894688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8894688</a>] [<a href="https://doi.org/10.1093/hmg/5.10.1547" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8894688">Wuyts et al. (1996)</a> identified a G-A transition within a 5-prime donor splice site of the EXT2 gene, resulting in aberrant splicing, exon skipping, and loss of 94 nucleotides of the transcript (nucleotides 1080-1173) corresponding to amino acid residues alanine-361 through glutamine-391. The deletion also produced a frameshift and generated a stop signal at codon 404. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8894688" 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="0004" class="mim-anchor"></a>
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<strong>.0004 EXOSTOSES, MULTIPLE, TYPE II</strong>
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SEIZURES, SCOLIOSIS, AND MACROCEPHALY SYNDROME, INCLUDED
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EXT2, ASP227ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918280 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918280;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=rs121918280" 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=rs121918280" 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=RCV000002578 OR RCV000791300 OR RCV001091958 OR RCV002490297" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002578, RCV000791300, RCV001091958, RCV002490297" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002578...</a>
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<p><strong><em>Multiple Exostoses Type II</em></strong></p><p>
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In affected members of 2 families with multiple exostoses type II (EXT2; <a href="/entry/133701">133701</a>), <a href="#16" class="mim-tip-reference" title="Philippe, C., Porter, D. E., Emerton, M. E., Wells, D. E., Simpson, A. H. R. W., Monaco, A. P. <strong>Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses.</strong> Am. J. Hum. Genet. 61: 520-528, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326317</a>] [<a href="https://doi.org/10.1086/515505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326317">Philippe et al. (1997)</a> found that the probands had a G-A transition in exon 4 of the EXT2 gene, resulting in an asp227-to-asn (D227N) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9326317" 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="#11" class="mim-tip-reference" title="Heinritz, W., Huffmeier, U., Strenge, S., Miterski, B., Zweier, C., Leinung, S., Bohring, A., Mitulla, B., Peters, U., Froster, U. G. <strong>New mutations of EXT1 and EXT2 genes in German patients with multiple osteochondromas.</strong> Ann. Hum. Genet. 73: 283-291, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19344451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19344451</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2009.00508.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19344451">Heinritz et al. (2009)</a> identified the D227N mutation in 3 unrelated German patients with multiple exostoses. One patient developed a pelvic chondrosarcoma at age 40 years: tumor DNA showed loss of heterozygosity at the EXT1 and EXT2 loci. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19344451" 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>Seizures, Scoliosis, and Macrocephaly Syndrome</em></strong></p><p>
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For discussion of the c.679G-A transition (c.679G-A, NM_207122) in the EXT2 gene, resulting in a D227N substitution, that was found in compound heterozygous state in 2 sibs with seizures, scoliosis, and macrocephaly syndrome (SSMS; <a href="/entry/616682">616682</a>), who also had multiple exostoses, by <a href="#8" class="mim-tip-reference" title="Gentile, M., Agolini, E., Cocciadiferro, D., Ficarella, R., Ponzi, E., Bellachio, E., Antonucci, M. F., Novelli, A. <strong>Novel exostosin-2 missense variants in a family with autosomal recessive exostosin-2-related syndrome: further evidences on the phenotype.</strong> Clin. Genet. 95: 165-171, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30288735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30288735</a>] [<a href="https://doi.org/10.1111/cge.13458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30288735">Gentile et al. (2019)</a>, see <a href="#0012">608210.0012</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30288735" 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="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 EXOSTOSES, MULTIPLE, TYPE II</strong>
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</span>
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</h4>
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EXT2, TYR222TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918281 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918281;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=rs121918281" 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=rs121918281" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002579 OR RCV003894785 OR RCV005041972" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002579, RCV003894785, RCV005041972" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002579...</a>
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</span>
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<span class="mim-text-font">
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<p>In affected members of a family with multiple exostoses type II (EXT2; <a href="/entry/133701">133701</a>), <a href="#16" class="mim-tip-reference" title="Philippe, C., Porter, D. E., Emerton, M. E., Wells, D. E., Simpson, A. H. R. W., Monaco, A. P. <strong>Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses.</strong> Am. J. Hum. Genet. 61: 520-528, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326317/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326317</a>] [<a href="https://doi.org/10.1086/515505" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326317">Philippe et al. (1997)</a> found a C-G transversion in exon 4 of the EXT2 gene, resulting in a stop codon (Y222X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9326317" 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="0006" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0006 EXOSTOSES, MULTIPLE, TYPE II</strong>
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</h4>
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EXT2, GLN258TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606786 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606786;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=rs267606786" 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=rs267606786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002580" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002580" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002580</a>
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<span class="mim-text-font">
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<div class="mim-changed mim-change"><p>In a German patient with multiple exostoses type II (EXT2; <a href="/entry/133701">133701</a>), <a href="#11" class="mim-tip-reference" title="Heinritz, W., Huffmeier, U., Strenge, S., Miterski, B., Zweier, C., Leinung, S., Bohring, A., Mitulla, B., Peters, U., Froster, U. G. <strong>New mutations of EXT1 and EXT2 genes in German patients with multiple osteochondromas.</strong> Ann. Hum. Genet. 73: 283-291, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19344451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19344451</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2009.00508.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19344451">Heinritz et al. (2009)</a> identified a heterozygous c.772C-T transition in the EXT2 gene, resulting in a gln258-to-ter (Q258X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19344451" 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></div>
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<strong>.0007 EXOSTOSES, MULTIPLE, TYPE II</strong>
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EXT2, IVS4AS, A-C, -2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs864309638 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864309638;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=rs864309638" 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=rs864309638" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002581 OR RCV003398422" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002581, RCV003398422" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002581...</a>
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<div class="mim-changed mim-change"><p>In a German patient with multiple exostoses type II (EXT2; <a href="/entry/133701">133701</a>), <a href="#11" class="mim-tip-reference" title="Heinritz, W., Huffmeier, U., Strenge, S., Miterski, B., Zweier, C., Leinung, S., Bohring, A., Mitulla, B., Peters, U., Froster, U. G. <strong>New mutations of EXT1 and EXT2 genes in German patients with multiple osteochondromas.</strong> Ann. Hum. Genet. 73: 283-291, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19344451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19344451</a>] [<a href="https://doi.org/10.1111/j.1469-1809.2009.00508.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19344451">Heinritz et al. (2009)</a> identified a heterozygous A-to-C transversion (c.744-2A-C) in a highly conserved nucleotide in intron 4 of the EXT2 gene. RT-PCR analysis identified 2 different splice variants skipping either only exon 5 or both exons 5 and 6. Loss of exon 5 results in a frameshift and premature termination, whereas loss of exons 5 and 6 leads to an in-frame deletion of 112 residues important for catalytic activity of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19344451" 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></div>
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<strong>.0008 SEIZURES, SCOLIOSIS, AND MACROCEPHALY SYNDROME</strong>
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EXT2, MET87ARG AND ARG95CYS
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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> rs140075817 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs140075817;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/rs140075817?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=rs140075817" 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=rs140075817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs376292686 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs376292686;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/rs376292686?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=rs376292686" 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=rs376292686" 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=RCV000120884 OR RCV000203245 OR RCV000988530 OR RCV001056120 OR RCV001705882" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000120884, RCV000203245, RCV000988530, RCV001056120, RCV001705882" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000120884...</a>
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<p>In 4 sibs, born of consanguineous parents in the Old Order Mennonite community, with seizures, scoliosis, and macrocephaly syndrome (SSMS; <a href="/entry/616682">616682</a>), <a href="#6" class="mim-tip-reference" title="Farhan, S. M. K., Wang, J., Robinson, J. F., Prasad, A. N., Rupar, C. A., Siu, V. M., FORGE Canada Consortium, Hegele, R. A. <strong>Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses.</strong> J. Med. Genet. 52: 666-675, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26246518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26246518</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26246518">Farhan et al. (2015)</a> identified homozygosity for 2 missense mutations in cis in the EXT2 gene: a c.260T-G transversion, resulting in a met87-to-arg (M87R) substitution, and a c.283C-T transition, resulting in an arg95-to-cys (R95C) substitution. Both mutations occurred at well-conserved residues. The mutations, which were found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family: each unaffected parent was heterozygous for both mutations in cis. The M87R and R95C mutations were present in the Exome Sequencing Project at frequencies of 0.0545 and 0.015%, respectively. Neither mutation was found in 311 Caucasian controls; the heterozygous M87R variant was found at a frequency of 3.85% among the Old Order Mennonite community, whereas R95C was not found in this population. Patient-derived fibroblasts showed significantly decreased EXT2 protein and mRNA levels compared to controls. Levels of the EXT2-interacting protein NDST1 (<a href="/entry/600853">600853</a>) were abolished in patient cells, although transcript levels were normal. In vitro cellular expression studies indicated that both mutations individually resulted in decreased protein levels, with a synergistic effect of both mutations expressed at the same time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26246518" 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="0009" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0009 SEIZURES, SCOLIOSIS, AND MICROCEPHALY SYNDROME</strong>
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EXT2, SER4LEU
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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> rs527624522 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs527624522;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/rs527624522?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=rs527624522" 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=rs527624522" 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=RCV000371317 OR RCV000663343 OR RCV005044571" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000371317, RCV000663343, RCV005044571" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000371317...</a>
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<p>In 2 brothers, born of consanguineous Syrian parents, with seizures, scoliosis, and microcephaly syndrome (SSMS; <a href="/entry/616682">616682</a>), <a href="#5" class="mim-tip-reference" title="El-Bazzal, L., Atkinson, A., Gillart, A.-C., Obeid, M., Delague, V., Megarbane, A. <strong>A novel EXT2 mutation in a consanguineous family with severe developmental delay, microcephaly, seizures, feeding difficulties, and osteopenia extends the phenotypic spectrum of autosomal recessive EXT2-related syndrome (AREXT2).</strong> Europ. J. Med. Genet. 62: 259-264, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30075207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30075207</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.07.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30075207">El-Bazzal et al. (2019)</a> identified a homozygous c.11C-T transition (c.11C-T, NM_207122) in exon 2 of the EXT2 gene, resulting in a ser4-to-leu (S4L) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found at a low frequency in the gnomAD database (6.908 x 10(-5)). 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=30075207" 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="0010" class="mim-anchor"></a>
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<strong>.0010 SEIZURES, SCOLIOSIS, AND MACROCEPHALY SYNDROME</strong>
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EXT2, VAL373ASP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs371996957;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs371996957</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs371996957 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs371996957;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/rs371996957?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=rs371996957" 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=rs371996957" 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=RCV000660595 OR RCV001104529" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000660595, RCV001104529" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000660595...</a>
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<p>In a 14-year-old girl with seizures, scoliosis, and macrocephaly syndrome (SSMS; <a href="/entry/616682">616682</a>), <a href="#9" class="mim-tip-reference" title="Gupta, A., Ewing, S. A., Renaud, D. L., Hasadsri, L., Raymond, K. M., Klee, E. W., Gavrilova, R. H. <strong>Developmental delay, coarse facies, and epilepsy in a patient with EXT2 gene variants.</strong> Clin. Case Rep. 7: 632-637, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30997052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30997052</a>] [<a href="https://doi.org/10.1002/ccr3.2010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30997052">Gupta et al. (2019)</a> identified compound heterozygous missense mutations in the EXT2 gene: a c.1118T-A transversion (c.1118T-A, NM_000401.3) in exon 6, resulting in a val373-to-asp (V373D) substitution, and a c.2015C-T transition in exon 12, resulting in a thr672-to-met (T672M; <a href="#0011">608210.0011</a>) substitution. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Both variants occurred at conserved residues in functional domains and were found only in the heterozygous state at very low frequencies in the gnomAD database (less than 0.007%). The patient also carried a rare heterozygous missense variant (R454C) in the NDST1 gene (<a href="/entry/600853">600853</a>) gene inherited from the unaffected mother, but the contribution of this variant to the phenotype was unknown. The proband's fraternal twin sister, who was less severely affected, carried all 3 variants. Functional studies of the variants and studies of patient cells were not performed, but heparan sulfate levels in blood and urine were decreased compared to control values. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30997052" 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 SEIZURES, SCOLIOSIS, AND MACROCEPHALY SYNDROME</strong>
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EXT2, THR672MET (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs138722406;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs138722406</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs138722406 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs138722406;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/rs138722406?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=rs138722406" 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=rs138722406" 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=RCV000120878 OR RCV000660594 OR RCV000806392 OR RCV005049423" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000120878, RCV000660594, RCV000806392, RCV005049423" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000120878...</a>
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<div class="mim-changed mim-change"><p>For discussion of the c.2015C-T transition (c.2015C-T, NM_000401.3) in exon 12 of the EXT2 gene, resulting in a thr672-to-met (T672M) substitution, that was found in compound heterozygous state in a patient with seizures, scoliosis, and macrocephaly syndrome (SSMS; <a href="/entry/616682">616682</a>) by <a href="#9" class="mim-tip-reference" title="Gupta, A., Ewing, S. A., Renaud, D. L., Hasadsri, L., Raymond, K. M., Klee, E. W., Gavrilova, R. H. <strong>Developmental delay, coarse facies, and epilepsy in a patient with EXT2 gene variants.</strong> Clin. Case Rep. 7: 632-637, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30997052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30997052</a>] [<a href="https://doi.org/10.1002/ccr3.2010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30997052">Gupta et al. (2019)</a>, see <a href="#0010">608210.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30997052" 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></div>
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<strong>.0012 SEIZURES, SCOLIOSIS, AND MACROCEPHALY SYNDROME</strong>
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EXT2, TYR608CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1590667793 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1590667793;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=rs1590667793" 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=rs1590667793" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 sibs with seizures, scoliosis, and macrocephaly syndrome (SSMS; <a href="/entry/616682">616682</a>), <a href="#8" class="mim-tip-reference" title="Gentile, M., Agolini, E., Cocciadiferro, D., Ficarella, R., Ponzi, E., Bellachio, E., Antonucci, M. F., Novelli, A. <strong>Novel exostosin-2 missense variants in a family with autosomal recessive exostosin-2-related syndrome: further evidences on the phenotype.</strong> Clin. Genet. 95: 165-171, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30288735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30288735</a>] [<a href="https://doi.org/10.1111/cge.13458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30288735">Gentile et al. (2019)</a> identified compound heterozygous missense mutations in the EXT2 gene: a c.1823A-G transition (c.1823A-G, NM_207122), resulting in a tyr608-to-cys (Y608C) substitution at a conserved residue in the C-terminal glycosyltransferase domain, and D227N (<a href="#0004">608210.0004</a>), in the exostosin domain. The mutations, which were found by targeted exome sequencing, segregated with the disorder in the family. The Y608C variant is not present in the dbSNP, 1000 Genomes Project, Exome Variant Server, ExAC, or gnomAD databases. The D227N variant, which had been found in patients with multiple exostoses type II (EXT2; <a href="/entry/133701">133701</a>), was inherited from the mother, who also had EXT2, and both sibs had EXT2, indicating that that specific variant contributes to that phenotype. The father, who carried the Y608C variant, did not have exostosis. Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30288735" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs745738318 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs745738318;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/rs745738318?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=rs745738318" 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=rs745738318" 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=RCV001263554" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001263554" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001263554</a>
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<p>In 10 unrelated Italian patients with multiple exostoses type II (EXT2; <a href="/entry/133701">133701</a>), <a href="#7" class="mim-tip-reference" title="Fusco, C., Nardella, G., Fischetto, R., Copetti, M., Petracca, A., Annunziata, F., Augello, B., D'Asdia, M. C., Petrucci, S., Mattina, T., Rella, A., Cassina, M., and 10 others. <strong>Mutational spectrum and clinical signatures in 114 families with hereditary multiple properties of selected exostosin variants.</strong> Hum. Molec. Genet. 28: 2133-2142, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30806661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30806661</a>] [<a href="https://doi.org/10.1093/hmg/ddz046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30806661">Fusco et al. (2019)</a> identified a heterozygous c.863A-G transition (c.863A-G, NM_207122.1) in exon 5 of the EXT2 gene, resulting in an asn288-to-ser (N288S) substitution. The mutation was identified by direct sequencing of the EXT2 gene. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30806661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 EXOSTOSES, MULTIPLE, TYPE II</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">rs1954415964 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1954415964;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=rs1954415964" 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=rs1954415964" 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=RCV001263555" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001263555" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001263555</a>
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<p>In 2 unrelated Italian patients with multiple exostoses type II (EXT2; <a href="/entry/133701">133701</a>), <a href="#7" class="mim-tip-reference" title="Fusco, C., Nardella, G., Fischetto, R., Copetti, M., Petracca, A., Annunziata, F., Augello, B., D'Asdia, M. C., Petrucci, S., Mattina, T., Rella, A., Cassina, M., and 10 others. <strong>Mutational spectrum and clinical signatures in 114 families with hereditary multiple properties of selected exostosin variants.</strong> Hum. Molec. Genet. 28: 2133-2142, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30806661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30806661</a>] [<a href="https://doi.org/10.1093/hmg/ddz046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30806661">Fusco et al. (2019)</a> identified a heterozygous c.1052C-T transition (c.1052C-T, NM_207122.1) in exon 6 of the EXT2 gene, resulting in a pro351-to-leu (P351L) substitution. The mutation was identified by direct sequencing of the EXT2 gene. Expression of EXT2 containing the P351L mutation in U2OS cells showed a physiologic Golgi localization but also partial localization to the perinuclear region. Expression of the mutant EXT2 protein in HEK293 cells showed that the cells had slower growth compared to cells expressing wildtype EXT2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30806661" 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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Bellaiche, Y., The, I., Perrimon, N.
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<strong>Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion.</strong>
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Nature 394: 85-88, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9665133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9665133</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9665133" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/27932" target="_blank">Full Text</a>]
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Blanton, S. H., Hogue, D., Wagner, M., Wells, D., Young, I. D., Hecht, J. T.
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<strong>Hereditary multiple exostoses: confirmation of linkage to chromosomes 8 and 11.</strong>
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Am. J. Med. Genet. 62: 150-159, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8882395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8882395</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8882395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(SICI)1096-8628(19960315)62:2<150::AID-AJMG7>3.0.CO;2-#" target="_blank">Full Text</a>]
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Bovee, J. V. M. G., Cleton-Jansen, A.-M., Wuyts, W., Caethoven, G., Taminiau, A. H. M., Bakker, E., Van Hul, W., Cornelisse, C. J., Hogendoorn, P. C. W.
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<strong>EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas.</strong>
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Am. J. Hum. Genet. 65: 689-698, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441575</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/302532" target="_blank">Full Text</a>]
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Clines, G. A., Ashley, J. A., Shah, S., Lovett, M.
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<strong>The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and Caenorhabditis elegans.</strong>
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Genome Res. 7: 359-367, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9110175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9110175</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9110175[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=9110175" 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/10.1101/gr.7.4.359" target="_blank">Full Text</a>]
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El-Bazzal, L., Atkinson, A., Gillart, A.-C., Obeid, M., Delague, V., Megarbane, A.
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<strong>A novel EXT2 mutation in a consanguineous family with severe developmental delay, microcephaly, seizures, feeding difficulties, and osteopenia extends the phenotypic spectrum of autosomal recessive EXT2-related syndrome (AREXT2).</strong>
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Europ. J. Med. Genet. 62: 259-264, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30075207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30075207</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30075207" 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.ejmg.2018.07.025" target="_blank">Full Text</a>]
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Farhan, S. M. K., Wang, J., Robinson, J. F., Prasad, A. N., Rupar, C. A., Siu, V. M., FORGE Canada Consortium, Hegele, R. A.
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<strong>Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses.</strong>
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J. Med. Genet. 52: 666-675, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26246518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26246518</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26246518" 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-2015-103279" target="_blank">Full Text</a>]
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Fusco, C., Nardella, G., Fischetto, R., Copetti, M., Petracca, A., Annunziata, F., Augello, B., D'Asdia, M. C., Petrucci, S., Mattina, T., Rella, A., Cassina, M., and 10 others.
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<strong>Mutational spectrum and clinical signatures in 114 families with hereditary multiple properties of selected exostosin variants.</strong>
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Hum. Molec. Genet. 28: 2133-2142, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30806661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30806661</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30806661" 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/ddz046" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/cge.13458" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ccr3.2010" target="_blank">Full Text</a>]
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<strong>Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8.</strong>
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[<a href="https://doi.org/10.1111/j.1469-1809.2009.00508.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.68.4.820" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19980217)75:5<538::aid-ajmg17>3.0.co;2-l" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.273.41.26265" target="_blank">Full Text</a>]
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<strong>The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate.</strong>
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[<a href="https://doi.org/10.1073/pnas.97.2.668" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/515505" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/8.12.2155" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0996-25" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/bmme.1997.2588" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/3.1.167" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/301726" target="_blank">Full Text</a>]
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Wuyts, W., Van Hul, W., Wauters, J., Nemtsova, M., Reyniers, E., Van Hul, E., De Boulle, K., de Vries, B. B. A., Hendrickx, J., Herrygers, I., Bossuyt, P., Balemans, W., Fransen, E., Vits, L., Coucke, P., Nowak, N. J., Shows, T. B., Mallet, L., van den Ouweland, A. M. W., McGaughran, J., Halley, D. J. J., Willems, P. J.
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<strong>Positional cloning of a gene involved in hereditary multiple exostoses.</strong>
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Hum. Molec. Genet. 5: 1547-1557, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8894688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8894688</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8894688" 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/5.10.1547" target="_blank">Full Text</a>]
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<a id="25" class="mim-anchor"></a>
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<a id="Wuyts2000" class="mim-anchor"></a>
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<p class="mim-text-font">
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Wuyts, W., Van Hul, W.
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<strong>Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes.</strong>
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Hum. Mutat. 15: 220-227, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10679937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10679937</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10679937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(200003)15:3<220::AID-HUMU2>3.0.CO;2-K" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 11/06/2020
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Cassandra L. Kniffin - updated : 07/30/2019<br>Cassandra L. Kniffin - updated : 12/21/2015<br>Patricia A. Hartz - updated : 2/28/2013<br>Cassandra L. Kniffin - updated : 11/10/2009<br>Victor A. McKusick - updated : 1/14/2004
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Creation Date:
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Cassandra L. Kniffin : 10/28/2003
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carol : 02/04/2025
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alopez : 02/03/2025<br>carol : 11/21/2024<br>carol : 11/06/2020<br>alopez : 08/02/2019<br>ckniffin : 07/30/2019<br>carol : 04/29/2019<br>carol : 08/17/2016<br>carol : 12/29/2015<br>carol : 12/29/2015<br>ckniffin : 12/21/2015<br>carol : 2/18/2015<br>carol : 10/11/2013<br>carol : 9/19/2013<br>mgross : 3/22/2013<br>terry : 2/28/2013<br>wwang : 3/3/2010<br>wwang : 12/8/2009<br>ckniffin : 11/10/2009<br>terry : 1/14/2004<br>carol : 10/30/2003<br>ckniffin : 10/29/2003
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<strong>*</strong> 608210
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EXOSTOSIN GLYCOSYLTRANSFERASE 2; EXT2
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<em>Alternative titles; symbols</em>
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EXOSTOSIN 2
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<strong><em>HGNC Approved Gene Symbol: EXT2</em></strong>
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<strong>SNOMEDCT:</strong> 1187250005;
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Cytogenetic location: 11p11.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:44,095,678-44,251,962 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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11p11.2
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Exostoses, multiple, type 2
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<span class="mim-font">
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133701
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Autosomal dominant
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3
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Seizures, scoliosis, and macrocephaly syndrome
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<span class="mim-font">
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616682
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Autosomal recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>The EXT2 gene encodes a glycosyltransferase involved in the synthesis of heparan sulfate proteoglycans, which are involved in multiple cellular functions (summary by Farhan et al., 2015). </p>
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<div>
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<strong>Cloning and Expression</strong>
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<p>Hecht et al. (1995) identified the candidate region for the gene responsible for hereditary multiple exostoses linked to chromosome 11 (133701) in an affected patient who also had a chondrosarcoma. By positional cloning and use of a chromosome 11-specific fetal brain cDNA library, Stickens et al. (1996) identified the putative EXT2 gene, which was predicted to encode a 718-amino acid protein with a molecular mass of 82 kD. Both protein and DNA sequence-based algorithms detected significant similarity with the product of the EXT1 gene (608177), suggesting that the 2 genes are evolutionarily and functionally related. Northern blot analysis detected a major 3.5-kb mRNA transcript and a minor band of 3.7 to 4.0 kb in most tissues. Stickens et al. (1996) suggested that the EXT2 gene may be expressed as a complex set of alternatively spliced forms. </p><p>Wuyts et al. (1996) constructed a contig of YAC and P1 clones covering the EXT2 candidate region on chromosome 11p12-p11. The EXT2 region had been defined in large families with multiple exostoses by linkage analysis. They also defined the candidate region through deletion analysis in families with the Potocki-Shaffer syndrome (601224). From the EXT2 candidate region, Wuyts et al. (1996) isolated a transcribed sequence with homology to EXT1. Alignment of the EXT1 and EXT2 genes at the amino acid level revealed an overall sequence identity of 30.9%. The amino acid homology is 18% in the 5-prime region and 48% in the 3-prime region. </p><p>Stickens and Evans (1997) isolated and characterized the mouse EXT2 gene. They found that the mouse EXT2 cDNA contains an open reading frame encoding a predicted protein of 718 amino acids. The mouse amino acid sequence is 95% identical to the human EXT2 protein. Northern blot analysis showed that the gene is expressed in early stages of embryonic development, and in situ hybridization suggested that EXT2 plays a role in limb development. </p><p>Clines et al. (1997) noted that at least 2 homologs of the human and mouse EXT2 genes were found in Caenorhabditis elegans, suggesting to the authors that the genes do not function exclusively as regulators of bone growth. </p>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>Clines et al. (1997) found that the EXT2 gene contains 14 exons, plus 2 alternative exons. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>By positional cloning, Stickens et al. (1996) identified the EXT2 gene in the multiple exostoses type II critical region on chromosome 11p12-p11. Clines et al. (1997) mapped the mouse Ext2 gene to chromosome 2. Information on the mapping of the EXT2 locus to 11p12-p11 was provided by Wu et al. (1994), Hecht et al. (1995), Wuyts et al. (1995), and Blanton et al. (1996), using linkage methods. </p>
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</span>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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<span class="mim-text-font">
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<p>Hecht et al. (1995) and Raskind et al. (1995) presented evidence suggesting that the EXT1 gene on chromosome 8 and the EXT2 gene on chromosome 11 have a tumor suppressor function. They found loss of heterozygosity (LOH) for markers linked to these 2 genes in chondrosarcomas originating in individuals with multiple exostoses as well as in sporadic chondrosarcomas. To explain the fact that normal bone growth occurs concurrently with abnormal exostosis tumor growth, Hecht et al. (1995) and Raskind et al. (1995) proposed a 2-hit tumor formation model according to the Knudson hypothesis (Knudson, 1971). In this model, a single germline mutation results in the predisposition for disease and a second somatic mutational hit, usually LOH, allows for aberrant growth. </p><p>In addition to their presumed role as tumor suppressor genes, EXT1 and EXT2 may have roles in modulation of the hedgehog signaling pathway (see 600725) and glycosaminoglycan synthesis. Bellaiche et al. (1998) determined that the Drosophila homolog of EXT1, dubbed 'tout-velu,' is required for diffusion of the signaling protein hedgehog. Lind et al. (1998) concluded that EXT1 and EXT2 are glycosyltransferases, based on copurification of EXT2 in a bovine serum extract exhibiting this enzymatic activity as well as increased glycosyltransferase activity in cells overexpressing EXT2 in vitro. </p><p>Using yeast 2-hybrid analysis, Simmons et al. (1999) found that a conserved C-terminal region of EXT2 interacted with TRAP1 (606219) and the glycosyltransferase GALNT5 (615129). Deletion of a conserved histidine in EXT2 (his601) weakened its interaction with GALNT5 and abrogated its interaction with TRAP1. </p><p>McCormick et al. (2000) noted that the proteins encoded by the EXT1 and EXT2 genes are endoplasmic reticulum-localized type II transmembrane glycoproteins that possess or are tightly associated with glycosyltransferase activities involved in the polymerization of heparan sulfate. By testing a cell line with a specific defect in EXT1 in in vivo and in vitro assays, McCormick et al. (2000) showed that EXT2 does not harbor significant glycosyltransferase activity in the absence of EXT1. Instead, it appears that EXT1 and EXT2 form a heterooligomeric complex in vivo that leads to the accumulation of both proteins in the Golgi apparatus. Remarkably, the Golgi-localized EXT1/EXT2 complex possesses substantially higher glycosyltransferase activity than EXT1 or EXT2 alone, suggesting that the complex represents the biologically relevant form of the enzyme(s). These findings provided a rationale for the causation of hereditary multiple exostoses by loss of activity in either of the EXT genes. </p>
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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>Multiple Exostoses, Type II</em></strong></p><p>
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In a family with multiple exostoses type II (EXT2; 133701), Stickens et al. (1996) identified a heterozygous 4-bp deletion in the EXT2 gene (608210.0001), resulting in a premature stop codon and truncated gene product. Stickens et al. (1996) speculated that a second mutation event was necessary for the development of exostoses, thus accounting for the asymmetry of exostoses observed in the long bones. </p><p>In 2 families with multiple exostoses, Wuyts et al. (1996) identified 2 different mutations in the EXT2 gene: a nonsense mutation (608210.0002) and a splice site mutation (608210.0003). In 5 of 17 (29%) families with hereditary multiple exostoses, Philippe et al. (1997) identified 4 mutations in the EXT2 gene, including a missense mutation (608210.0004) and 3 alterations that resulted in premature stop codons. Seven (41%) of the families had mutations in the EXT1 gene. </p><p>Wuyts et al. (1998) analyzed the EXT1 and EXT2 genes in 26 EXT families originating from 9 countries. Of the 26 families, 10 had an EXT1 mutation and 10 had an EXT2 mutation. Twelve of these mutations had not previously been described. From a review of these and previously reported mutations, Wuyts et al. (1998) concluded that mutations in either the EXT1 or the EXT2 gene are responsible for most cases of multiple exostoses. Most of the mutations in these 2 genes cause premature termination of the EXT proteins, whereas missense mutations are rare. The authors concluded that the development of exostoses is mainly due to loss of function of EXT genes, consistent with the hypothesis that the EXT genes have a tumor suppressor function. </p><p>Analyzing for EXT1 and EXT2 mutations in 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas, Bovee et al. (1999) found mutations in the EXT1 gene, but none in the EXT2 gene. </p><p>Wuyts and Van Hul (2000) stated that 49 different EXT1 and 25 different EXT2 mutations had been identified in patients with multiple exostoses and that mutations in these 2 genes were responsible for over 70% of the EXT cases. Most of the mutations caused loss of function, which is consistent with the presumed tumor suppressor function of the EXT genes. </p><p>By fluorescence in situ hybridization, Ligon et al. (1998) showed that the EXT2 gene is deleted in patients with the del(11)(p11.2p12) syndrome. Since patients with mutations in EXT2 have only multiple exostoses, deletions affecting only the EXT2 locus cannot explain the craniofacial anomalies, biparietal foramina, mental retardation, or genitourinary anomalies observed in patients with proximal 11p deletions. Therefore, deletion of other neighboring genes must be responsible for the additional anomalies, and this chromosomal aberration represents a true contiguous gene deletion syndrome. </p><p>Heinritz et al. (2009) identified 9 different mutations in the EXT2 gene in 11 of 23 German patients with multiple exostoses. Eleven other patients had mutations in the EXT1 gene; 1 patient had no detectable mutations. Among the EXT2 mutations, there were 3 recurrent mutations, Q172X (608210.0002), D227N (608210.0004), and Q258X (608210.0006), and 6 novel mutations (see, e.g., 608210.0007). </p><p>In 35 unrelated Italian patients with multiple exostoses type II, Fusco et al. (2019) identified 25 different heterozygous mutations in the EXT2 gene, of which 19 were novel. The mutations were identified by direct sequencing or by MLPA analysis followed by confirmation with quantitative real-time PCR. The mutations included 13 frameshifts, 6 nonsense, 4 missense, and 2 intragenic rearrangements. The most common mutation was N288S (608210.0013), which occurred in 10 families. To evaluate the functional importance of EXT2 domains, Fusco et al. (2019) tested the effects of 2 mutations with a premature termination (Pro243Glnfs27 and Leu335Tyrfs101), comprising the N-terminal exostosin domain or the C-terminal glycosyltransferase family 64 domain, as well as the effects of a missense mutation (P351L; 608210.0014) in U2OS cells. The mutated proteins had abnormal localization patterns in the cell. When these mutant EXT2 proteins were expressed in HEK293 cells, the cells had slower growth compared to cells expressing wildtype EXT2. </p><p><strong><em>Seizures, Scoliosis, and Macrocephaly/Microcephaly Syndrome</em></strong></p><p>
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In 4 sibs, born of consanguineous parents in the Old Order Mennonite community, with seizures, scoliosis, and macrocephaly/microcephaly syndrome (SSMS; 616682), Farhan et al. (2015) identified homozygosity for 2 missense mutations in cis in the EXT2 gene (M87R and R95C, 608210.0008). The mutations, which were found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. In vitro cellular expression studies indicated that both mutations individually resulted in decreased protein levels, with a synergistic effect of both mutations expressed at the same time. </p><p>In 2 brothers, born of consanguineous Syrian parents, with SSMS, El-Bazzal et al. (2019) identified a homozygous missense mutation in the EXT2 gene (S4L; 608210.0009). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. </p><p>In a 14-year-old girl with SSMS, Gupta et al. (2019) identified compound heterozygous missense mutations in the EXT2 gene (V373D, 608210.0010 and T672M, 608210.0011). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. The patient also carried a rare heterozygous missense variant (R454C) in the NDST1 gene (600853) gene inherited from the unaffected mother, but the contribution of this variant to the phenotype was unknown. The proband's fraternal twin sister, who was less severely affected, carried all 3 variants. Functional studies of the variants and studies of patient cells were not performed. </p><p>In 2 sibs with SSMS, Gentile et al. (2019) identified compound heterozygous missense mutations in the EXT2 gene (Y608C, 608210.0012 and D227N, 608210.0004). The mutations, which were found by targeted exome sequencing, segregated with the disorder in the family. The D227N variant, which had been found in patients with multiple exostoses type II (EXT2; 133701), was inherited from the mother, who also had EXT2 as well as a family history of exostosis, and both sibs had EXT2. The father, who carried the Y608C variant, did not have exostosis. These findings indicated that D227N is a specific variant that contributes to exostosis. Functional studies of the variants and studies of patient cells were not performed. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>14 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 EXOSTOSES, MULTIPLE, TYPE II</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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EXT2, 4-BP DEL
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<br />
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SNP: rs864309636,
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ClinVar: RCV000002575, RCV003415629
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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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<div class="mim-changed mim-change"><p>In a family with multiple exostoses type II (EXT2; 133701), Stickens et al. (1996) identified a heterozygous 4-bp deletion (c.784-c.787) in the EXT2 gene, resulting in a frameshift and premature termination of translation, generating a truncated EXT2 gene product. </p></div>
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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 EXOSTOSES, MULTIPLE, TYPE II</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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EXT2, GLN172TER
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<br />
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SNP: rs121918279,
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gnomAD: rs121918279,
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ClinVar: RCV000002576, RCV000255256, RCV000762843, RCV000850054
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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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<div class="mim-changed mim-change"><p>In affected members of a large family with multiple exostoses II (EXT2; 133701) family, Wuyts et al. (1996) identified a c.514C-T transition in the EXT2 gene, resulting in a gln172-to-ter (Q172X) substitution. The mutation was detected by SSCP analysis. </p></div>
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<p>Heinritz et al. (2009) identified the Q172X mutation in a German patient with EXT2. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 EXOSTOSES, MULTIPLE, TYPE II</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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EXT2, IVSDS, G-A, +1
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<br />
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SNP: rs864309637,
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ClinVar: RCV000002577
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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 affected members of a large Belgian family with multiple exostoses II (EXT2; 133701), Wuyts et al. (1996) identified a G-A transition within a 5-prime donor splice site of the EXT2 gene, resulting in aberrant splicing, exon skipping, and loss of 94 nucleotides of the transcript (nucleotides 1080-1173) corresponding to amino acid residues alanine-361 through glutamine-391. The deletion also produced a frameshift and generated a stop signal at codon 404. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 EXOSTOSES, MULTIPLE, TYPE II</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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SEIZURES, SCOLIOSIS, AND MACROCEPHALY SYNDROME, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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EXT2, ASP227ASN
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<br />
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SNP: rs121918280,
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ClinVar: RCV000002578, RCV000791300, RCV001091958, RCV002490297
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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 />
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<p><strong><em>Multiple Exostoses Type II</em></strong></p><p>
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In affected members of 2 families with multiple exostoses type II (EXT2; 133701), Philippe et al. (1997) found that the probands had a G-A transition in exon 4 of the EXT2 gene, resulting in an asp227-to-asn (D227N) substitution. </p><p>Heinritz et al. (2009) identified the D227N mutation in 3 unrelated German patients with multiple exostoses. One patient developed a pelvic chondrosarcoma at age 40 years: tumor DNA showed loss of heterozygosity at the EXT1 and EXT2 loci. </p><p><strong><em>Seizures, Scoliosis, and Macrocephaly Syndrome</em></strong></p><p>
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For discussion of the c.679G-A transition (c.679G-A, NM_207122) in the EXT2 gene, resulting in a D227N substitution, that was found in compound heterozygous state in 2 sibs with seizures, scoliosis, and macrocephaly syndrome (SSMS; 616682), who also had multiple exostoses, by Gentile et al. (2019), see 608210.0012. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 EXOSTOSES, MULTIPLE, TYPE II</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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EXT2, TYR222TER
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<br />
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SNP: rs121918281,
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ClinVar: RCV000002579, RCV003894785, RCV005041972
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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 affected members of a family with multiple exostoses type II (EXT2; 133701), Philippe et al. (1997) found a C-G transversion in exon 4 of the EXT2 gene, resulting in a stop codon (Y222X). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 EXOSTOSES, MULTIPLE, TYPE II</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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EXT2, GLN258TER
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<br />
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SNP: rs267606786,
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ClinVar: RCV000002580
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a German patient with multiple exostoses type II (EXT2; 133701), Heinritz et al. (2009) identified a heterozygous c.772C-T transition in the EXT2 gene, resulting in a gln258-to-ter (Q258X) substitution. </p></div>
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|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 EXOSTOSES, MULTIPLE, TYPE II</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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EXT2, IVS4AS, A-C, -2
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<br />
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|
|
SNP: rs864309638,
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|
|
ClinVar: RCV000002581, RCV003398422
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</span>
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</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<div class="mim-changed mim-change"><p>In a German patient with multiple exostoses type II (EXT2; 133701), Heinritz et al. (2009) identified a heterozygous A-to-C transversion (c.744-2A-C) in a highly conserved nucleotide in intron 4 of the EXT2 gene. RT-PCR analysis identified 2 different splice variants skipping either only exon 5 or both exons 5 and 6. Loss of exon 5 results in a frameshift and premature termination, whereas loss of exons 5 and 6 leads to an in-frame deletion of 112 residues important for catalytic activity of the protein. </p></div>
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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>.0008 SEIZURES, SCOLIOSIS, AND MACROCEPHALY SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
|
EXT2, MET87ARG AND ARG95CYS
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<br />
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|
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SNP: rs140075817, rs376292686,
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|
|
gnomAD: rs140075817, rs376292686,
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|
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ClinVar: RCV000120884, RCV000203245, RCV000988530, RCV001056120, RCV001705882
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 sibs, born of consanguineous parents in the Old Order Mennonite community, with seizures, scoliosis, and macrocephaly syndrome (SSMS; 616682), Farhan et al. (2015) identified homozygosity for 2 missense mutations in cis in the EXT2 gene: a c.260T-G transversion, resulting in a met87-to-arg (M87R) substitution, and a c.283C-T transition, resulting in an arg95-to-cys (R95C) substitution. Both mutations occurred at well-conserved residues. The mutations, which were found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family: each unaffected parent was heterozygous for both mutations in cis. The M87R and R95C mutations were present in the Exome Sequencing Project at frequencies of 0.0545 and 0.015%, respectively. Neither mutation was found in 311 Caucasian controls; the heterozygous M87R variant was found at a frequency of 3.85% among the Old Order Mennonite community, whereas R95C was not found in this population. Patient-derived fibroblasts showed significantly decreased EXT2 protein and mRNA levels compared to controls. Levels of the EXT2-interacting protein NDST1 (600853) were abolished in patient cells, although transcript levels were normal. In vitro cellular expression studies indicated that both mutations individually resulted in decreased protein levels, with a synergistic effect of both mutations expressed at the same time. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0009 SEIZURES, SCOLIOSIS, AND MICROCEPHALY SYNDROME</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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EXT2, SER4LEU
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<br />
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SNP: rs527624522,
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gnomAD: rs527624522,
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ClinVar: RCV000371317, RCV000663343, RCV005044571
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 brothers, born of consanguineous Syrian parents, with seizures, scoliosis, and microcephaly syndrome (SSMS; 616682), El-Bazzal et al. (2019) identified a homozygous c.11C-T transition (c.11C-T, NM_207122) in exon 2 of the EXT2 gene, resulting in a ser4-to-leu (S4L) substitution at a conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found at a low frequency in the gnomAD database (6.908 x 10(-5)). Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SEIZURES, SCOLIOSIS, AND MACROCEPHALY SYNDROME</strong>
|
|
</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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EXT2, VAL373ASP ({dbSNP rs371996957})
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<br />
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SNP: rs371996957,
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gnomAD: rs371996957,
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ClinVar: RCV000660595, RCV001104529
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 14-year-old girl with seizures, scoliosis, and macrocephaly syndrome (SSMS; 616682), Gupta et al. (2019) identified compound heterozygous missense mutations in the EXT2 gene: a c.1118T-A transversion (c.1118T-A, NM_000401.3) in exon 6, resulting in a val373-to-asp (V373D) substitution, and a c.2015C-T transition in exon 12, resulting in a thr672-to-met (T672M; 608210.0011) substitution. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Both variants occurred at conserved residues in functional domains and were found only in the heterozygous state at very low frequencies in the gnomAD database (less than 0.007%). The patient also carried a rare heterozygous missense variant (R454C) in the NDST1 gene (600853) gene inherited from the unaffected mother, but the contribution of this variant to the phenotype was unknown. The proband's fraternal twin sister, who was less severely affected, carried all 3 variants. Functional studies of the variants and studies of patient cells were not performed, but heparan sulfate levels in blood and urine were decreased compared to control values. </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>.0011 SEIZURES, SCOLIOSIS, AND MACROCEPHALY SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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EXT2, THR672MET ({dbSNP rs138722406})
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<br />
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SNP: rs138722406,
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gnomAD: rs138722406,
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ClinVar: RCV000120878, RCV000660594, RCV000806392, RCV005049423
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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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<div class="mim-changed mim-change"><p>For discussion of the c.2015C-T transition (c.2015C-T, NM_000401.3) in exon 12 of the EXT2 gene, resulting in a thr672-to-met (T672M) substitution, that was found in compound heterozygous state in a patient with seizures, scoliosis, and macrocephaly syndrome (SSMS; 616682) by Gupta et al. (2019), see 608210.0010. </p></div>
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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>.0012 SEIZURES, SCOLIOSIS, AND MACROCEPHALY SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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EXT2, TYR608CYS
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<br />
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SNP: rs1590667793,
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ClinVar: RCV000791304, RCV002535841
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sibs with seizures, scoliosis, and macrocephaly syndrome (SSMS; 616682), Gentile et al. (2019) identified compound heterozygous missense mutations in the EXT2 gene: a c.1823A-G transition (c.1823A-G, NM_207122), resulting in a tyr608-to-cys (Y608C) substitution at a conserved residue in the C-terminal glycosyltransferase domain, and D227N (608210.0004), in the exostosin domain. The mutations, which were found by targeted exome sequencing, segregated with the disorder in the family. The Y608C variant is not present in the dbSNP, 1000 Genomes Project, Exome Variant Server, ExAC, or gnomAD databases. The D227N variant, which had been found in patients with multiple exostoses type II (EXT2; 133701), was inherited from the mother, who also had EXT2, and both sibs had EXT2, indicating that that specific variant contributes to that phenotype. The father, who carried the Y608C variant, did not have exostosis. Functional studies of the variants and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0013 EXOSTOSES, MULTIPLE, TYPE II</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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EXT2, ASN288SER
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<br />
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SNP: rs745738318,
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gnomAD: rs745738318,
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ClinVar: RCV001263554
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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 10 unrelated Italian patients with multiple exostoses type II (EXT2; 133701), Fusco et al. (2019) identified a heterozygous c.863A-G transition (c.863A-G, NM_207122.1) in exon 5 of the EXT2 gene, resulting in an asn288-to-ser (N288S) substitution. The mutation was identified by direct sequencing of the EXT2 gene. Functional studies were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0014 EXOSTOSES, MULTIPLE, TYPE II</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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EXT2, PRO351LEU
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<br />
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SNP: rs1954415964,
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ClinVar: RCV001263555
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated Italian patients with multiple exostoses type II (EXT2; 133701), Fusco et al. (2019) identified a heterozygous c.1052C-T transition (c.1052C-T, NM_207122.1) in exon 6 of the EXT2 gene, resulting in a pro351-to-leu (P351L) substitution. The mutation was identified by direct sequencing of the EXT2 gene. Expression of EXT2 containing the P351L mutation in U2OS cells showed a physiologic Golgi localization but also partial localization to the perinuclear region. Expression of the mutant EXT2 protein in HEK293 cells showed that the cells had slower growth compared to cells expressing wildtype EXT2. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Bellaiche, Y., The, I., Perrimon, N.
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<strong>Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion.</strong>
|
|
Nature 394: 85-88, 1998.
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[PubMed: 9665133]
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[Full Text: https://doi.org/10.1038/27932]
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</p>
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<p class="mim-text-font">
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Blanton, S. H., Hogue, D., Wagner, M., Wells, D., Young, I. D., Hecht, J. T.
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<strong>Hereditary multiple exostoses: confirmation of linkage to chromosomes 8 and 11.</strong>
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Am. J. Med. Genet. 62: 150-159, 1996.
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[PubMed: 8882395]
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[Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960315)62:2<150::AID-AJMG7>3.0.CO;2-#]
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<p class="mim-text-font">
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Bovee, J. V. M. G., Cleton-Jansen, A.-M., Wuyts, W., Caethoven, G., Taminiau, A. H. M., Bakker, E., Van Hul, W., Cornelisse, C. J., Hogendoorn, P. C. W.
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<strong>EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas.</strong>
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Am. J. Hum. Genet. 65: 689-698, 1999.
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[PubMed: 10441575]
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[Full Text: https://doi.org/10.1086/302532]
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<p class="mim-text-font">
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Clines, G. A., Ashley, J. A., Shah, S., Lovett, M.
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<strong>The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and Caenorhabditis elegans.</strong>
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Genome Res. 7: 359-367, 1997.
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[PubMed: 9110175]
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[Full Text: https://doi.org/10.1101/gr.7.4.359]
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</p>
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<li>
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<p class="mim-text-font">
|
|
El-Bazzal, L., Atkinson, A., Gillart, A.-C., Obeid, M., Delague, V., Megarbane, A.
|
|
<strong>A novel EXT2 mutation in a consanguineous family with severe developmental delay, microcephaly, seizures, feeding difficulties, and osteopenia extends the phenotypic spectrum of autosomal recessive EXT2-related syndrome (AREXT2).</strong>
|
|
Europ. J. Med. Genet. 62: 259-264, 2019.
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[PubMed: 30075207]
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[Full Text: https://doi.org/10.1016/j.ejmg.2018.07.025]
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</p>
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<li>
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<p class="mim-text-font">
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Farhan, S. M. K., Wang, J., Robinson, J. F., Prasad, A. N., Rupar, C. A., Siu, V. M., FORGE Canada Consortium, Hegele, R. A.
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<strong>Old gene, new phenotype: mutations in heparan sulfate synthesis enzyme, EXT2 leads to seizure and developmental disorder, no exostoses.</strong>
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J. Med. Genet. 52: 666-675, 2015.
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[PubMed: 26246518]
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[Full Text: https://doi.org/10.1136/jmedgenet-2015-103279]
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</p>
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<li>
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<p class="mim-text-font">
|
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Fusco, C., Nardella, G., Fischetto, R., Copetti, M., Petracca, A., Annunziata, F., Augello, B., D'Asdia, M. C., Petrucci, S., Mattina, T., Rella, A., Cassina, M., and 10 others.
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<strong>Mutational spectrum and clinical signatures in 114 families with hereditary multiple properties of selected exostosin variants.</strong>
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Hum. Molec. Genet. 28: 2133-2142, 2019.
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[PubMed: 30806661]
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[Full Text: https://doi.org/10.1093/hmg/ddz046]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Gentile, M., Agolini, E., Cocciadiferro, D., Ficarella, R., Ponzi, E., Bellachio, E., Antonucci, M. F., Novelli, A.
|
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<strong>Novel exostosin-2 missense variants in a family with autosomal recessive exostosin-2-related syndrome: further evidences on the phenotype.</strong>
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Clin. Genet. 95: 165-171, 2019.
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[PubMed: 30288735]
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[Full Text: https://doi.org/10.1111/cge.13458]
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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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Gupta, A., Ewing, S. A., Renaud, D. L., Hasadsri, L., Raymond, K. M., Klee, E. W., Gavrilova, R. H.
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<strong>Developmental delay, coarse facies, and epilepsy in a patient with EXT2 gene variants.</strong>
|
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Clin. Case Rep. 7: 632-637, 2019.
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[PubMed: 30997052]
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[Full Text: https://doi.org/10.1002/ccr3.2010]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Hecht, J. T., Hogue, D., Strong, L. C., Hansen, M. F., Blanton, S. H., Wagner, M.
|
|
<strong>Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8.</strong>
|
|
Am. J. Hum. Genet. 56: 1125-1131, 1995.
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|
|
|
|
|
[PubMed: 7726168]
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|
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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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|
Heinritz, W., Huffmeier, U., Strenge, S., Miterski, B., Zweier, C., Leinung, S., Bohring, A., Mitulla, B., Peters, U., Froster, U. G.
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<strong>New mutations of EXT1 and EXT2 genes in German patients with multiple osteochondromas.</strong>
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Ann. Hum. Genet. 73: 283-291, 2009.
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[PubMed: 19344451]
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[Full Text: https://doi.org/10.1111/j.1469-1809.2009.00508.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Knudson, A. G., Jr.
|
|
<strong>Mutation and cancer: statistical study of retinoblastoma.</strong>
|
|
Proc. Nat. Acad. Sci. 68: 820-823, 1971.
|
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|
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|
|
[PubMed: 5279523]
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|
|
[Full Text: https://doi.org/10.1073/pnas.68.4.820]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ligon, A. H., Potocki, L., Shaffer, L. G., Stickens, D., Evans, G. A.
|
|
<strong>Gene for multiple exostoses (EXT2) maps to 11(p11.2p12) and is deleted in patients with a contiguous gene syndrome. (Letter)</strong>
|
|
Am. J. Med. Genet. 75: 538-540, 1998.
|
|
|
|
|
|
[PubMed: 9489802]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/(sici)1096-8628(19980217)75:5<538::aid-ajmg17>3.0.co;2-l]
|
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|
</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Lind, T., Tufaro, F., McCormick, C., Lindahl, U., Lidholt, K.
|
|
<strong>The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate.</strong>
|
|
J. Biol. Chem. 273: 26265-26268, 1998.
|
|
|
|
|
|
[PubMed: 9756849]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.273.41.26265]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
McCormick, C., Duncan, G., Goutsos, K. T., Tufaro, F.
|
|
<strong>The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate.</strong>
|
|
Proc. Nat. Acad. Sci. 97: 668-673, 2000.
|
|
|
|
|
|
[PubMed: 10639137]
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|
|
[Full Text: https://doi.org/10.1073/pnas.97.2.668]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Philippe, C., Porter, D. E., Emerton, M. E., Wells, D. E., Simpson, A. H. R. W., Monaco, A. P.
|
|
<strong>Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses.</strong>
|
|
Am. J. Hum. Genet. 61: 520-528, 1997.
|
|
|
|
|
|
[PubMed: 9326317]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1086/515505]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Raskind, W. H., Conrad, E. U., Chansky, H., Matsushita, M.
|
|
<strong>Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11.</strong>
|
|
Am. J. Hum. Genet. 56: 1132-1139, 1995.
|
|
|
|
|
|
[PubMed: 7726169]
|
|
|
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Simmons, A. D., Musy, M. M., Lopes, C. S., Hwang, L.-Y., Yang, Y.-P., Lovett, M.
|
|
<strong>A direct interaction between EXT proteins and glycosyltransferases is defective in hereditary multiple exostoses.</strong>
|
|
Hum. Molec. Genet. 8: 2155-2164, 1999.
|
|
|
|
|
|
[PubMed: 10545594]
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[Full Text: https://doi.org/10.1093/hmg/8.12.2155]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Stickens, D., Clines, G., Burbee, D., Ramos, P., Thomas, S., Hogue, D., Hecht, J. T., Lovett, M., Evans, G. A.
|
|
<strong>The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes.</strong>
|
|
Nature Genet. 14: 25-32, 1996.
|
|
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|
|
[PubMed: 8782816]
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[Full Text: https://doi.org/10.1038/ng0996-25]
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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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Stickens, D., Evans, G. A.
|
|
<strong>Isolation and characterization of the murine homolog of the human EXT2 multiple exostoses gene.</strong>
|
|
Biochem. Molec. Med. 61: 16-21, 1997.
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|
|
[PubMed: 9232192]
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[Full Text: https://doi.org/10.1006/bmme.1997.2588]
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</p>
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</li>
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<li>
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Wu, Y.-Q., Heutink, P., de Vries, B. B. A., Sandkuijl, L. A., van den Ouweland, A. M. W., Niermeijer, M. F., Galjaard, H., Reyniers, E., Willems, P. J., Halley, D. J. J.
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<strong>Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11.</strong>
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Hum. Molec. Genet. 3: 167-171, 1994.
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[PubMed: 8162019]
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[Full Text: https://doi.org/10.1093/hmg/3.1.167]
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Wuyts, W., Ramlakhan, S., Van Hul, W., Hecht, J. T., van den Ouweland, A. M. W., Raskind, W. H., Hofstede, F. C., Reyniers, E., Wells, D. E., de Vries, B., Conrad, E. U., Hill, A., Zalatayev, D., Weissenbach, J., Wagner, M. J., Bakker, E., Halley, D. J. J., Willems, P. J.
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<strong>Refinement of the multiple exostoses locus (EXT2) to a 3-cM interval on chromosome 11.</strong>
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Am. J. Hum. Genet. 57: 382-387, 1995.
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[PubMed: 7668264]
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Wuyts, W., Van Hul, W., De Boulle, K., Hendrickx, J., Bakker, E., Vanhoenacker, F., Mollica, F., Ludecke, H.-J., Sayli, B. S., Pazzaglia, U. E., Mortier, G., Hamel, B., Conrad, E. U., Matsushita, M., Raskind, W. H., Willems, P. J.
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<strong>Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.</strong>
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Am. J. Hum. Genet. 62: 346-354, 1998.
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[PubMed: 9463333]
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[Full Text: https://doi.org/10.1086/301726]
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Wuyts, W., Van Hul, W., Wauters, J., Nemtsova, M., Reyniers, E., Van Hul, E., De Boulle, K., de Vries, B. B. A., Hendrickx, J., Herrygers, I., Bossuyt, P., Balemans, W., Fransen, E., Vits, L., Coucke, P., Nowak, N. J., Shows, T. B., Mallet, L., van den Ouweland, A. M. W., McGaughran, J., Halley, D. J. J., Willems, P. J.
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<strong>Positional cloning of a gene involved in hereditary multiple exostoses.</strong>
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Hum. Molec. Genet. 5: 1547-1557, 1996.
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[PubMed: 8894688]
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[Full Text: https://doi.org/10.1093/hmg/5.10.1547]
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Wuyts, W., Van Hul, W.
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<strong>Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes.</strong>
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Hum. Mutat. 15: 220-227, 2000.
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[PubMed: 10679937]
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[Full Text: https://doi.org/10.1002/(SICI)1098-1004(200003)15:3<220::AID-HUMU2>3.0.CO;2-K]
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Hilary J. Vernon - updated : 11/06/2020<br>Cassandra L. Kniffin - updated : 07/30/2019<br>Cassandra L. Kniffin - updated : 12/21/2015<br>Patricia A. Hartz - updated : 2/28/2013<br>Cassandra L. Kniffin - updated : 11/10/2009<br>Victor A. McKusick - updated : 1/14/2004
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Cassandra L. Kniffin : 10/28/2003
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carol : 02/04/2025<br>alopez : 02/03/2025<br>carol : 11/21/2024<br>carol : 11/06/2020<br>alopez : 08/02/2019<br>ckniffin : 07/30/2019<br>carol : 04/29/2019<br>carol : 08/17/2016<br>carol : 12/29/2015<br>carol : 12/29/2015<br>ckniffin : 12/21/2015<br>carol : 2/18/2015<br>carol : 10/11/2013<br>carol : 9/19/2013<br>mgross : 3/22/2013<br>terry : 2/28/2013<br>wwang : 3/3/2010<br>wwang : 12/8/2009<br>ckniffin : 11/10/2009<br>terry : 1/14/2004<br>carol : 10/30/2003<br>ckniffin : 10/29/2003
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