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<title>
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Entry
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- *602952 - NUCLEAR RECEPTOR-BINDING SET DOMAIN PROTEIN 2; NSD2
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- OMIM
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*602952</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<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="#geneFunction">Gene Function</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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<li role="presentation" style="margin-left: 1em">
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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="#cytogenetics">Cytogenetics</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/602952">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>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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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=ENSG00000109685;t=ENST00000508803" 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=7468" 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=602952" 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=ENSG00000109685;t=ENST00000508803" 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_001042424,NM_007331,NM_133330,NM_133331,NM_133334,NM_133335,XM_005248001,XM_005248002,XM_005248005,XM_011513560,XM_047416137,XM_047416138,XM_047416139,XM_047416141,XM_047416142,XM_047416143,XM_047416144" 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_001042424" 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=602952" 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=04259&isoform_id=04259_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/NSD2" 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/3249713,3249715,4378019,4378020,4378021,4378022,4521954,4521955,5123789,6594683,6683808,6683809,12642795,19913348,19913350,19913356,19913358,30354464,40789042,47682677,51703247,74706096,109633019,116283645,119602954,119602955,119602956,119602957,119602958,119602959,119602960,119602961,119602962,119602963,119602964,133777178,146327785,158260417,530376139,530376141,530376147,767929369,2217351937,2217351939,2217351942,2217351945,2217351947,2217351949,2217351952,2462598806,2462598808,2462598810,2462598812,2462598814,2462598816,2462598818,2462598820,2462598822,2462598824,2462598826,2462598828" 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/O96028" 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=7468" 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=ENSG00000109685;t=ENST00000508803" 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=NSD2" 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=NSD2" 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+7468" 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/NSD2" 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:7468" 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/7468" 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=chr4&hgg_gene=ENST00000508803.6&hgg_start=1871393&hgg_end=1982192&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:12766" 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:12766" 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/nsd2" 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=602952[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=602952[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/NSD2/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/ENSG00000109685" 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=NSD2" 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=NSD2" 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=NSD2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=NSD2&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/PA37369" 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:12766" 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/FBgn0039559.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:1276574" 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/NSD2#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:1276574" 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/7468/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=7468" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00003222;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-2581" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7468" 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=NSD2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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602952
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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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NUCLEAR RECEPTOR-BINDING SET DOMAIN PROTEIN 2; NSD2
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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WOLF-HIRSCHHORN SYNDROME CANDIDATE 1; WHSC1<br />
|
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MULTIPLE MYELOMA SET DOMAIN; MMSET
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</span>
|
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=NSD2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">NSD2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: <a href="/geneMap/4/36?start=-3&limit=10&highlight=36">4p16.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr4:1871393-1982192&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'})">4:1,871,393-1,982,192</a> </span>
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/602952" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/602952" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>The NSD2 gene encodes a SET domain-containing transcriptional regulatory protein with histone methyltransferase activity associated with actively transcribed regions of the genome during embryonic development. NSD2 is the principal enzyme that dimethylates histone H3 at lysine 36 (H3K36me2) in most cells and tissues (summary by <a href="#2" class="mim-tip-reference" title="Boczek, N. J., Lahner, C. A., Nguyen, T., Ferber, M. J., Hasadsri, L., Thorland, E. C., Niu, Z., Gavrilova, R. H. <strong>Developmental delay and failure to thrive associated with a loss-of-function variant in WHSC1 (NSD2).</strong> Am. J. Med. Genet. 176A: 2798-2802, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30345613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30345613</a>] [<a href="https://doi.org/10.1002/ajmg.a.40498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30345613">Boczek et al., 2018</a> and <a href="#13" class="mim-tip-reference" title="Zanoni, P., Steindl, K., Sengupta, D., Joset, P., Bahr, A., Sticht, H., Lang-Muritano, M., van Ravenswaaij-Arts, C. M. A., Shinawi, M., Andrews, M., Attie-Bitach, T., Maystadt, I., and 22 others. <strong>Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype.</strong> Genet. Med. 23: 1474-1483, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33941880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33941880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33941880[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41436-021-01158-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33941880">Zanoni et al., 2021</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=30345613+33941880" 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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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<p>Wolf-Hirschhorn syndrome (WHS; <a href="/entry/194190">194190</a>) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4 (4p16.3). The shortest region of overlap of the deletions observed in WHS patients, the WHS critical region, has been confined to a region of 165 kb (<a href="#12" class="mim-tip-reference" title="Wright, T. J., Ricke, D. O., Denison, K., Abmayr, S., Cotter, P. D., Hirschhorn, K., Keinanen, M., McDonald-McGinn, D., Somer, M., Spinner, N., Yang-Feng, T., Zackai, E., Altherr, M. R. <strong>A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region.</strong> Hum. Molec. Genet. 6: 317-324, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063753</a>] [<a href="https://doi.org/10.1093/hmg/6.2.317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063753">Wright et al., 1997</a>). This region was sequenced completely during the search for the Huntington disease gene (<a href="#1" class="mim-tip-reference" title="Baxendale, S., MacDonald, M. E., Mott, R., Francis, F., Lin, C., Kirby, S. F., James, M., Zehetner, G., Hummerich, H., Valdes, J., Collins, F. S., Deaven, L. J., Gusella, J. F., Lehrach, H., Bates, G. P. <strong>A cosmid contig and high resolution restriction map of the 2 megabase region containing the Huntington's disease gene.</strong> Nature Genet. 4: 181-186, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8348156/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8348156</a>] [<a href="https://doi.org/10.1038/ng0693-181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8348156">Baxendale et al., 1993</a>). <a href="#11" class="mim-tip-reference" title="Stec, I., Wright, T. J., van Ommen, G.-J. B., de Boer, P. A. J., van Haeringen, A., Moorman, A. F. M., Altherr, M. R., den Dunnen, J. T. <strong>WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma.</strong> Hum. Molec. Genet. 7: 1071-1082, 1998. Note: Erratum: Hum. Molec. Genet. 7: 1527-1528 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618163</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618163">Stec et al. (1998)</a> described a novel developmental gene, two-thirds of which maps in the distal part of the WHS critical region. They designated the gene WHSC1 (Wolf-Hirschhorn syndrome candidate-1). The WHSC1 gene was identified initially through its high similarity to the translation product of an expressed sequence tag, located in the 165-kb WHCR, with the SET domain (see <a href="/entry/600960">600960</a>) of the Drosophila protein ASH1 (<a href="/entry/607999">607999</a>). The SET domain is found in proteins that are involved in embryonic development. The WHSC1 gene was found to be expressed ubiquitously in early development and to undergo complex alternative splicing and differential polyadenylation. It encodes a 136-kD protein containing 4 domains present in other developmental proteins: a PWWP domain, an HMG box, a SET domain also found in the Drosophila dysmorphy gene ash-encoded protein, and a PHD-type zinc finger. It is expressed preferentially in rapidly growing embryonic tissues, in a pattern corresponding to affected organs in WHS patients. The nature of the protein motifs, the expression pattern, and its mapping to the critical region led <a href="#11" class="mim-tip-reference" title="Stec, I., Wright, T. J., van Ommen, G.-J. B., de Boer, P. A. J., van Haeringen, A., Moorman, A. F. M., Altherr, M. R., den Dunnen, J. T. <strong>WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma.</strong> Hum. Molec. Genet. 7: 1071-1082, 1998. Note: Erratum: Hum. Molec. Genet. 7: 1527-1528 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618163</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618163">Stec et al. (1998)</a> to propose WHSC1 as a good candidate gene to be responsible for many of the phenotypic features of WHS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8348156+9063753+9618163" 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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<h4 href="#mimGeneFunctionFold" id="mimGeneFunctionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<p><a href="#8" class="mim-tip-reference" title="Nimura, K., Ura, K., Shiratori, H., Ikawa, M., Okabe, M., Schwartz, R. J., Kaneda, Y. <strong>A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome.</strong> Nature 460: 287-291, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19483677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19483677</a>] [<a href="https://doi.org/10.1038/nature08086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19483677">Nimura et al. (2009)</a> showed that the H3K36me3-specific histone methyltransferase Whsc1 functions in transcriptional regulation together with developmental transcription factors whose defects overlap with the human disease Wolf-Hirschhorn syndrome (WHS). <a href="#8" class="mim-tip-reference" title="Nimura, K., Ura, K., Shiratori, H., Ikawa, M., Okabe, M., Schwartz, R. J., Kaneda, Y. <strong>A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome.</strong> Nature 460: 287-291, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19483677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19483677</a>] [<a href="https://doi.org/10.1038/nature08086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19483677">Nimura et al. (2009)</a> found that mouse Whsc1, 1 of 5 putative Set2 homologs, governed H3K36me3 along euchromatin by associating with the cell type-specific transcription factors Sall1 (<a href="/entry/602218">602218</a>), Sall4 (<a href="/entry/607343">607343</a>), and Nanog (<a href="/entry/607937">607937</a>) in embryonic stem cells, and Nkx2-5 (<a href="/entry/600584">600584</a>) in embryonic hearts, regulating the expression of their target genes. Whsc1-deficient mice showed growth retardation and various WHS-like midline defects, including congenital cardiovascular anomalies. The effects of Whsc1 haploinsufficiency were increased in Nkx2-5 heterozygous mutant hearts, indicating their functional link. <a href="#8" class="mim-tip-reference" title="Nimura, K., Ura, K., Shiratori, H., Ikawa, M., Okabe, M., Schwartz, R. J., Kaneda, Y. <strong>A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome.</strong> Nature 460: 287-291, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19483677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19483677</a>] [<a href="https://doi.org/10.1038/nature08086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19483677">Nimura et al. (2009)</a> proposed that WHSC1 functions together with developmental transcription factors to prevent the inappropriate transcription that can lead to various pathophysiologies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19483677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Pei, H., Zhang, L., Luo, K., Qin, Y., Chesi, M., Fei, F., Bergsagel, P. L., Wang, L., You, Z., Lou, Z. <strong>MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites.</strong> Nature 470: 124-128, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21293379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21293379</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21293379[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21293379">Pei et al. (2011)</a> found that H4K20 methylation actually increases locally upon the induction of double-strand breaks and that methylation of H4K20 at double-strand breaks is mediated by the histone methyltransferase MMSET in mammals. Downregulation of MMSET significantly decreases H4K20 methylation at double-strand breaks and the subsequent accumulation of 53BP1 (<a href="/entry/605230">605230</a>). Furthermore, <a href="#9" class="mim-tip-reference" title="Pei, H., Zhang, L., Luo, K., Qin, Y., Chesi, M., Fei, F., Bergsagel, P. L., Wang, L., You, Z., Lou, Z. <strong>MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites.</strong> Nature 470: 124-128, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21293379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21293379</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21293379[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21293379">Pei et al. (2011)</a> found that the recruitment of MMSET to double-strand breaks requires the gamma-H2AX (<a href="/entry/601772">601772</a>)-MDC1 (<a href="/entry/607593">607593</a>) pathway; specifically, the interaction between the MDC1 BRCT domain and phosphorylated ser102 of MMSET. Thus, <a href="#9" class="mim-tip-reference" title="Pei, H., Zhang, L., Luo, K., Qin, Y., Chesi, M., Fei, F., Bergsagel, P. L., Wang, L., You, Z., Lou, Z. <strong>MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites.</strong> Nature 470: 124-128, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21293379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21293379</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21293379[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21293379">Pei et al. (2011)</a> proposed that a pathway involving gamma-H2AX-MDC1-MMSET regulates the induction of H4K20 methylation on histones around double-strand breaks, which, in turn, facilitates 53BP1 recruitment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21293379" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The WHSC1 gene contains 25 exons (<a href="#11" class="mim-tip-reference" title="Stec, I., Wright, T. J., van Ommen, G.-J. B., de Boer, P. A. J., van Haeringen, A., Moorman, A. F. M., Altherr, M. R., den Dunnen, J. T. <strong>WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma.</strong> Hum. Molec. Genet. 7: 1071-1082, 1998. Note: Erratum: Hum. Molec. Genet. 7: 1527-1528 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618163</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618163">Stec et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9618163" 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="#11" class="mim-tip-reference" title="Stec, I., Wright, T. J., van Ommen, G.-J. B., de Boer, P. A. J., van Haeringen, A., Moorman, A. F. M., Altherr, M. R., den Dunnen, J. T. <strong>WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma.</strong> Hum. Molec. Genet. 7: 1071-1082, 1998. Note: Erratum: Hum. Molec. Genet. 7: 1527-1528 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618163</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618163">Stec et al. (1998)</a> mapped the WHSC1 gene to chromosome 4p16.3 based on genomic sequence analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9618163" 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="#11" class="mim-tip-reference" title="Stec, I., Wright, T. J., van Ommen, G.-J. B., de Boer, P. A. J., van Haeringen, A., Moorman, A. F. M., Altherr, M. R., den Dunnen, J. T. <strong>WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma.</strong> Hum. Molec. Genet. 7: 1071-1082, 1998. Note: Erratum: Hum. Molec. Genet. 7: 1527-1528 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618163</a>] [<a href="https://doi.org/10.1093/hmg/7.7.1071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9618163">Stec et al. (1998)</a> noted that the t(4;14)(p16.3;q32.3) translocations described in a significant fraction of multiple myelomas (<a href="#10" class="mim-tip-reference" title="Richelda, R., Ronchetti, D., Baldini, L., Cro, L., Viggiano, L., Marzella, R., Rocchi, M., Otsuki, T., Lombardi, L., Maiolo, A. T., Neri, A. <strong>A novel chromosomal translocation t(4;14)(p16.3;q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene.</strong> Blood 90: 4062-4070, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9354676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9354676</a>]" pmid="9354676">Richelda et al., 1997</a>; <a href="#3" class="mim-tip-reference" title="Chesi, M., Nardini, E., Brents, L. A., Schrock, E., Ried, T., Kuehl, W. M., Bergsagel, P. L. <strong>Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3.</strong> Nature Genet. 16: 260-264, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9207791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9207791</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9207791[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng0797-260" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9207791">Chesi et al., 1997</a>) have breakpoints located less than 100 kb centromeric of the FGFR3 gene (<a href="/entry/134934">134934</a>) on 4p16.3. They found that at least 3 of the breakpoints merged the immunoglobulin heavy-chain gene (IGHG1; <a href="/entry/147100">147100</a>) on chromosome 14 with the WHSC1 gene. This fusion of genes and their untimely expression in the myeloid lineage driven from the 5-prime IgH enhancer may indicate that WHSC1-encoded proteins are involved in the clinical heterogeneity of multiple myeloma. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9207791+9354676+9618163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#6" class="mim-tip-reference" title="Jaffe, J. D., Wang, Y., Chan, H. M., Zhang, J., Huether, R., Kryukov, G. V., Bhang, H. C., Taylor, J. E., Hu, M., Englund, N. P., Yan, F., Wang, Z., and 20 others. <strong>Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia.</strong> Nature Genet. 45: 1386-1391, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24076604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24076604</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24076604[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2777" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24076604">Jaffe et al. (2013)</a> profiled global histone modifications in 115 cancer cell lines from the Cancer Cell Line Encyclopedia. One signature was characterized by increased H3K36me2, exhibited by several lines harboring translocations in the NSD2 methyltransferase. An NSD2 glu1099-to-lys (E1099K) variant was identified in nontranslocated acute lymphoblastic leukemia (ALL; <a href="/entry/613065">613065</a>) cell lines sharing this signature. Ectopic expression of the variant induced a chromatin signature characteristic of NSD2 hyperactivation and promoted transformation. NSD2 knockdown selectively inhibited the proliferation of NSD2-mutant lines and impaired the in vivo growth of an NSD2-mutant ALL xenograft. Sequencing analysis of greater than 1,000 pediatric cancer genomes identified the NSD2 E1099K alteration in 14% of t(12;21) ETV6 (<a href="/entry/600618">600618</a>)-RUNX1 (<a href="/entry/151385">151385</a>)-containing ALLs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24076604" 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>Rauch-Steindl Syndrome</em></strong></p><p>
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In a 16-month-old boy with Rauch-Steindl syndrome (RAUST; <a href="/entry/619695">619695</a>), <a href="#7" class="mim-tip-reference" title="Lozier, E. R., Konovalov, F. A., Kanivets, I. V., Pyankov, D. V., Koshkin, P. A., Baleva, L. S., Sipyagina, A. E., Yakusheva, E. N., Kuchina, A. E., Korostelev, S. A. <strong>De novo nonsense mutation in WHSC1 (NSD2) in patient with intellectual disability and dysmorphic features.</strong> J. Hum. Genet. 63: 919-922, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29760529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29760529</a>] [<a href="https://doi.org/10.1038/s10038-018-0464-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29760529">Lozier et al. (2018)</a> identified a de novo heterozygous nonsense mutation in the NSD2 gene (R1138X; <a href="#0001">602952.0001</a>). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29760529" 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 2-year-old girl with RAUST, <a href="#2" class="mim-tip-reference" title="Boczek, N. J., Lahner, C. A., Nguyen, T., Ferber, M. J., Hasadsri, L., Thorland, E. C., Niu, Z., Gavrilova, R. H. <strong>Developmental delay and failure to thrive associated with a loss-of-function variant in WHSC1 (NSD2).</strong> Am. J. Med. Genet. 176A: 2798-2802, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30345613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30345613</a>] [<a href="https://doi.org/10.1002/ajmg.a.40498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30345613">Boczek et al. (2018)</a> identified a de novo heterozygous frameshift mutation in the NSD2 gene (<a href="#0002">602952.0002</a>). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30345613" 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 34-month-old boy (patient 2) with RAUST, <a href="#4" class="mim-tip-reference" title="Derar, N., Al-Hassnan, Z. N., Al-Owain, M., Monies, D., Abouelhoda, M., Meyer, B. F., Moghrabi, N., Alkuraya, F. S. <strong>De novo truncating variants in WHSC1 recapitulate the Wolf-Hirschhorn (4p16.3 microdeletion) syndrome phenotype.</strong> Genet. Med. 21: 185-188, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29892088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29892088</a>] [<a href="https://doi.org/10.1038/s41436-018-0014-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29892088">Derar et al. (2019)</a> identified a de novo heterozygous nonsense mutation in the NSD2 gene (<a href="#0003">602952.0003</a>). 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=29892088" 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 Chinese father and daughter with RAUST, <a href="#5" class="mim-tip-reference" title="Hu, X., Wu, D., Li, Y., Wei, L., Li, X., Qin, M., Li, H., Li, M., Chen, S., Gong, C., Shen, Y. <strong>The first familial NSD2 cases with a novel variant in a Chinese father and daughter with atypical WHS facial features and a 7.5-year follow-up of growth hormone therapy.</strong> BMC Med. Genomics 13: 181, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33276791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33276791</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33276791[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s12920-020-00831-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33276791">Hu et al. (2020)</a> identified a heterozygous frameshift mutation in the NSD2 gene (<a href="#0004">602952.0004</a>). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in the father, who transmitted it to his affected daughter. The variant, which was not present in public databases, was predicted to result in nonsense-mediated mRNA decay and a loss of function, although 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=33276791" 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 18 patients from 16 unrelated families with RAUST, <a href="#13" class="mim-tip-reference" title="Zanoni, P., Steindl, K., Sengupta, D., Joset, P., Bahr, A., Sticht, H., Lang-Muritano, M., van Ravenswaaij-Arts, C. M. A., Shinawi, M., Andrews, M., Attie-Bitach, T., Maystadt, I., and 22 others. <strong>Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype.</strong> Genet. Med. 23: 1474-1483, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33941880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33941880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33941880[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41436-021-01158-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33941880">Zanoni et al. (2021)</a> identified heterozygous variants in the NSD2 gene (see, e.g., <a href="#0005">602952.0005</a>-<a href="#0007">602952.0007</a>). The variants were found by exome sequencing. Most occurred de novo, although 2 were recurrent and 2 were inherited within families. There were 5 missense variants, 3 nonsense mutations, and 7 frameshift mutations. In vitro functional expression studies showed that some, but not all, of the tested missense variants caused reduced levels of H3K36me2, impaired NSD2 methylation activity, and were unable to fully rescue physiologic levels of H3K36me2 in NSD2-depleted cells. Notably, C869Y (patient 1) and E1091K (patient 5) yielded equivocal result in functional assays, whereas S1137F (<a href="#0006">602952.0006</a>) and K1019R (<a href="/entry/601952#0007">601952.0007</a>) significantly compromised NSD2 function. The nonsense and frameshift mutations were predicted to result in a loss of function, although functional studies of these variants were not performed. <a href="#13" class="mim-tip-reference" title="Zanoni, P., Steindl, K., Sengupta, D., Joset, P., Bahr, A., Sticht, H., Lang-Muritano, M., van Ravenswaaij-Arts, C. M. A., Shinawi, M., Andrews, M., Attie-Bitach, T., Maystadt, I., and 22 others. <strong>Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype.</strong> Genet. Med. 23: 1474-1483, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33941880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33941880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33941880[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41436-021-01158-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33941880">Zanoni et al. (2021)</a> concluded that the mutations result in a decrease or loss of NSD2 methyltransferase activity, which results in the developmental phenotype. While heterozygotes for missense variants were taller than those with nonsense or frameshift mutations, the overall clinical severity correlated only loosely with putative or demonstrated alterations in NSD2 enzymatic activity. Of note, several patients carried variants of uncertain significance in additional genes that could have contributed to the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33941880" 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">rs1726909627 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1726909627;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=rs1726909627" 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=rs1726909627" 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=RCV001807861" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001807861" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001807861</a>
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<p>In a 16-month-old boy with Rauch-Steindl syndrome (RAUST; <a href="/entry/619695">619695</a>), <a href="#7" class="mim-tip-reference" title="Lozier, E. R., Konovalov, F. A., Kanivets, I. V., Pyankov, D. V., Koshkin, P. A., Baleva, L. S., Sipyagina, A. E., Yakusheva, E. N., Kuchina, A. E., Korostelev, S. A. <strong>De novo nonsense mutation in WHSC1 (NSD2) in patient with intellectual disability and dysmorphic features.</strong> J. Hum. Genet. 63: 919-922, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29760529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29760529</a>] [<a href="https://doi.org/10.1038/s10038-018-0464-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29760529">Lozier et al. (2018)</a> identified a de novo heterozygous c.3412C-T transition (c.3412C-T, NM_001042424.2) in the NSD2 gene, resulting in an arg1138-to-ter (R1138X) substitution. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29760529" 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>.0002 RAUCH-STEINDL SYNDROME</strong>
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NSD2, 4-BP DEL, NT1676
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1553873247 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553873247;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=rs1553873247" 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=rs1553873247" 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=RCV000660609 OR RCV001008475 OR RCV001779037 OR RCV001809736 OR RCV002274084 OR RCV004735729" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000660609, RCV001008475, RCV001779037, RCV001809736, RCV002274084, RCV004735729" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000660609...</a>
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<p>In a 2-year-old girl with Rauch-Steindl syndrome (RAUST; <a href="/entry/619695">619695</a>), <a href="#2" class="mim-tip-reference" title="Boczek, N. J., Lahner, C. A., Nguyen, T., Ferber, M. J., Hasadsri, L., Thorland, E. C., Niu, Z., Gavrilova, R. H. <strong>Developmental delay and failure to thrive associated with a loss-of-function variant in WHSC1 (NSD2).</strong> Am. J. Med. Genet. 176A: 2798-2802, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30345613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30345613</a>] [<a href="https://doi.org/10.1002/ajmg.a.40498" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30345613">Boczek et al. (2018)</a> identified a de novo heterozygous 4-bp deletion (c.1676_1679del, NM_133330.2) in the NSD2 gene, predicted to result in a frameshift and premature termination (Arg559ThrfsTer38). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30345613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 RAUCH-STEINDL SYNDROME</strong>
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NSD2, ARG935TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2108959336 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2108959336;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=rs2108959336" 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=rs2108959336" 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=RCV001807862 OR RCV003442908" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001807862, RCV003442908" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001807862...</a>
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<p>In a 34-month-old boy (patient 2) with Rauch-Steindl syndrome (RAUST; <a href="/entry/619695">619695</a>), <a href="#4" class="mim-tip-reference" title="Derar, N., Al-Hassnan, Z. N., Al-Owain, M., Monies, D., Abouelhoda, M., Meyer, B. F., Moghrabi, N., Alkuraya, F. S. <strong>De novo truncating variants in WHSC1 recapitulate the Wolf-Hirschhorn (4p16.3 microdeletion) syndrome phenotype.</strong> Genet. Med. 21: 185-188, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29892088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29892088</a>] [<a href="https://doi.org/10.1038/s41436-018-0014-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29892088">Derar et al. (2019)</a> identified a de novo heterozygous c.2803C-T transition (c.2803C-T, NM_001042424) in exon 15 of the NSD2 gene, resulting in an arg935-to-ter (R935X) substitution. 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=29892088" 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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<h4>
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<span class="mim-font">
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<strong>.0004 RAUCH-STEINDL SYNDROME</strong>
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NSD2, 1-BP DUP, 1577G
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2108877068 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2108877068;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=rs2108877068" 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=rs2108877068" 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=RCV001807863" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001807863" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001807863</a>
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<span class="mim-text-font">
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<p>In a Chinese father and daughter with Rauch-Steindl syndrome (RAUST; <a href="/entry/619695">619695</a>), <a href="#5" class="mim-tip-reference" title="Hu, X., Wu, D., Li, Y., Wei, L., Li, X., Qin, M., Li, H., Li, M., Chen, S., Gong, C., Shen, Y. <strong>The first familial NSD2 cases with a novel variant in a Chinese father and daughter with atypical WHS facial features and a 7.5-year follow-up of growth hormone therapy.</strong> BMC Med. Genomics 13: 181, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33276791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33276791</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33276791[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s12920-020-00831-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33276791">Hu et al. (2020)</a> identified a heterozygous 1-bp duplication (c.1577dupG, NM_001042424) in the NSD2 gene, predicted to result in a frameshift and premature termination (Asn527LysfsTer14). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in the father, who transmitted it to his affected daughter. The variant, which was not present in public databases, was predicted to result in nonsense-mediated mRNA decay and a loss of function, although functional studies of the variant and studies of patient cells were not performed. The patients had mildly dysmorphic facial features and mild intellectual disability, although only the daughter had short stature, suggesting incomplete penetrance or variable expressivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33276791" 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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<span class="mim-font">
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<strong>.0005 RAUCH-STEINDL SYNDROME</strong>
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NSD2, 1-BP DEL, 4028C
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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> rs752037034 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs752037034;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/rs752037034?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=rs752037034" 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=rs752037034" 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=RCV001807864" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001807864" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001807864</a>
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<p>In 2 unrelated boys (patients 11 and 15) with Rauch-Steindl syndrome (RAUST; <a href="/entry/619695">619695</a>), <a href="#13" class="mim-tip-reference" title="Zanoni, P., Steindl, K., Sengupta, D., Joset, P., Bahr, A., Sticht, H., Lang-Muritano, M., van Ravenswaaij-Arts, C. M. A., Shinawi, M., Andrews, M., Attie-Bitach, T., Maystadt, I., and 22 others. <strong>Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype.</strong> Genet. Med. 23: 1474-1483, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33941880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33941880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33941880[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41436-021-01158-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33941880">Zanoni et al. (2021)</a> identified a de novo heterozygous 1-bp deletion (c.4028delC, NM_133330.2) in the NSD2 gene, predicted to result in a frameshift with elongation of the protein (Pro1343GlnfsTer49). The mutation was found by exome sequencing. Functional studies of the variant were not performed, but it was predicted to result in a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33941880" 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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<strong>.0006 RAUCH-STEINDL SYNDROME</strong>
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NSD2, SER1137PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2109020378 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2109020378;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=rs2109020378" 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=rs2109020378" 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=RCV001807865 OR RCV004728828" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001807865, RCV004728828" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001807865...</a>
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<p>In a 12-year-old Caucasian boy (patient 10) with Rauch-Steindl syndrome (RAUST; <a href="/entry/619695">619695</a>), <a href="#13" class="mim-tip-reference" title="Zanoni, P., Steindl, K., Sengupta, D., Joset, P., Bahr, A., Sticht, H., Lang-Muritano, M., van Ravenswaaij-Arts, C. M. A., Shinawi, M., Andrews, M., Attie-Bitach, T., Maystadt, I., and 22 others. <strong>Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype.</strong> Genet. Med. 23: 1474-1483, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33941880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33941880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33941880[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41436-021-01158-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33941880">Zanoni et al. (2021)</a> identified a de novo heterozygous c.3410C-T transition (c.3410C-T, NM_133330.2) in the NSD2 gene, resulting in a ser1137-to-phe (S1137F) substitution in the core of the methyltransferase domain. The variant was found by exome sequencing. In vitro functional expression studies showed that the variant caused reduced levels of H3K36me2, impaired NSD2 methylation activity, and was unable to fully rescue physiologic levels of H3K36me2 in NSD2-depleted cells. The findings were consistent with NSD2 deficiency. Exome sequencing showed that the patient carried variants of uncertain significance in other genes (HUWE1, <a href="/entry/300697">300697</a> and RNF38, <a href="/entry/612488">612488</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33941880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 RAUCH-STEINDL SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2108971327 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2108971327;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=rs2108971327" 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=rs2108971327" 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=RCV001807866" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001807866" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001807866</a>
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<p>In a 26-year-old man (patient 12) with Rauch-Steindl syndrome (RAUST; <a href="/entry/619695">619695</a>), <a href="#13" class="mim-tip-reference" title="Zanoni, P., Steindl, K., Sengupta, D., Joset, P., Bahr, A., Sticht, H., Lang-Muritano, M., van Ravenswaaij-Arts, C. M. A., Shinawi, M., Andrews, M., Attie-Bitach, T., Maystadt, I., and 22 others. <strong>Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype.</strong> Genet. Med. 23: 1474-1483, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33941880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33941880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33941880[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41436-021-01158-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33941880">Zanoni et al. (2021)</a> identified a de novo heterozygous c.3056A-G transition (c.3056A-G, NM_133330.2) in the NSD2 domain, resulting in a lys1019-to-arg (K1019R) substitution in the methyltransferase domain. The variant was found by exome sequencing. In vitro functional expression studies showed that the variant caused reduced levels of H3K36me2, impaired NSD2 methylation activity, and was unable to fully rescue physiologic levels of H3K36me2 in NSD2-depleted cells. The findings were consistent with NSD2 deficiency. Exome sequencing showed that the patient carried a variant of uncertain significance in the AGO2 gene (<a href="/entry/606229">606229</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33941880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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Derar, N., Al-Hassnan, Z. N., Al-Owain, M., Monies, D., Abouelhoda, M., Meyer, B. F., Moghrabi, N., Alkuraya, F. S.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29892088/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29892088</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29892088" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Hu, X., Wu, D., Li, Y., Wei, L., Li, X., Qin, M., Li, H., Li, M., Chen, S., Gong, C., Shen, Y.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33276791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33276791</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33276791[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=33276791" 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/s10038-018-0464-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature09658" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="Richelda1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Richelda, R., Ronchetti, D., Baldini, L., Cro, L., Viggiano, L., Marzella, R., Rocchi, M., Otsuki, T., Lombardi, L., Maiolo, A. T., Neri, A.
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<strong>A novel chromosomal translocation t(4;14)(p16.3;q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene.</strong>
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Blood 90: 4062-4070, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9354676/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9354676</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9354676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Stec1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stec, I., Wright, T. J., van Ommen, G.-J. B., de Boer, P. A. J., van Haeringen, A., Moorman, A. F. M., Altherr, M. R., den Dunnen, J. T.
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<strong>WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma.</strong>
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Hum. Molec. Genet. 7: 1071-1082, 1998. Note: Erratum: Hum. Molec. Genet. 7: 1527-1528 only, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9618163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9618163</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9618163" 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/7.7.1071" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
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<a id="Wright1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wright, T. J., Ricke, D. O., Denison, K., Abmayr, S., Cotter, P. D., Hirschhorn, K., Keinanen, M., McDonald-McGinn, D., Somer, M., Spinner, N., Yang-Feng, T., Zackai, E., Altherr, M. R.
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<strong>A transcript map of the newly defined 165 kb Wolf-Hirschhorn syndrome critical region.</strong>
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Hum. Molec. Genet. 6: 317-324, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063753</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9063753" 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/6.2.317" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Zanoni2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zanoni, P., Steindl, K., Sengupta, D., Joset, P., Bahr, A., Sticht, H., Lang-Muritano, M., van Ravenswaaij-Arts, C. M. A., Shinawi, M., Andrews, M., Attie-Bitach, T., Maystadt, I., and 22 others.
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<strong>Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype.</strong>
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Genet. Med. 23: 1474-1483, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33941880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33941880</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33941880[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=33941880" 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/s41436-021-01158-1" target="_blank">Full Text</a>]
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</ol>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 01/07/2022
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 01/08/2014<br>Ada Hamosh - updated : 6/22/2011<br>Ada Hamosh - updated : 8/27/2009
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 8/7/1998
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 01/18/2022
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</span>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 01/11/2022<br>ckniffin : 01/07/2022<br>carol : 04/19/2017<br>alopez : 01/08/2014<br>terry : 9/17/2012<br>carol : 7/5/2012<br>alopez : 6/22/2011<br>carol : 6/10/2010<br>carol : 6/10/2010<br>alopez : 9/30/2009<br>alopez : 9/8/2009<br>terry : 8/27/2009<br>wwang : 4/20/2005<br>terry : 4/11/2005<br>mgross : 7/30/2003<br>cwells : 7/31/2002<br>terry : 7/2/2002<br>carol : 8/7/1998
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<h3>
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<span class="mim-font">
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<strong>*</strong> 602952
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<div>
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<h3>
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<span class="mim-font">
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NUCLEAR RECEPTOR-BINDING SET DOMAIN PROTEIN 2; NSD2
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</h3>
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</div>
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<div>
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<br />
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<div>
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<div >
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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WOLF-HIRSCHHORN SYNDROME CANDIDATE 1; WHSC1<br />
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MULTIPLE MYELOMA SET DOMAIN; MMSET
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</span>
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</h4>
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</div>
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<div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: NSD2</em></strong>
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</span>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 4p16.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 4:1,871,393-1,982,192 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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4p16.3
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</td>
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<td>
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<span class="mim-font">
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Rauch-Steindl syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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619695
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The NSD2 gene encodes a SET domain-containing transcriptional regulatory protein with histone methyltransferase activity associated with actively transcribed regions of the genome during embryonic development. NSD2 is the principal enzyme that dimethylates histone H3 at lysine 36 (H3K36me2) in most cells and tissues (summary by Boczek et al., 2018 and Zanoni et al., 2021). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Wolf-Hirschhorn syndrome (WHS; 194190) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4 (4p16.3). The shortest region of overlap of the deletions observed in WHS patients, the WHS critical region, has been confined to a region of 165 kb (Wright et al., 1997). This region was sequenced completely during the search for the Huntington disease gene (Baxendale et al., 1993). Stec et al. (1998) described a novel developmental gene, two-thirds of which maps in the distal part of the WHS critical region. They designated the gene WHSC1 (Wolf-Hirschhorn syndrome candidate-1). The WHSC1 gene was identified initially through its high similarity to the translation product of an expressed sequence tag, located in the 165-kb WHCR, with the SET domain (see 600960) of the Drosophila protein ASH1 (607999). The SET domain is found in proteins that are involved in embryonic development. The WHSC1 gene was found to be expressed ubiquitously in early development and to undergo complex alternative splicing and differential polyadenylation. It encodes a 136-kD protein containing 4 domains present in other developmental proteins: a PWWP domain, an HMG box, a SET domain also found in the Drosophila dysmorphy gene ash-encoded protein, and a PHD-type zinc finger. It is expressed preferentially in rapidly growing embryonic tissues, in a pattern corresponding to affected organs in WHS patients. The nature of the protein motifs, the expression pattern, and its mapping to the critical region led Stec et al. (1998) to propose WHSC1 as a good candidate gene to be responsible for many of the phenotypic features of WHS. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Nimura et al. (2009) showed that the H3K36me3-specific histone methyltransferase Whsc1 functions in transcriptional regulation together with developmental transcription factors whose defects overlap with the human disease Wolf-Hirschhorn syndrome (WHS). Nimura et al. (2009) found that mouse Whsc1, 1 of 5 putative Set2 homologs, governed H3K36me3 along euchromatin by associating with the cell type-specific transcription factors Sall1 (602218), Sall4 (607343), and Nanog (607937) in embryonic stem cells, and Nkx2-5 (600584) in embryonic hearts, regulating the expression of their target genes. Whsc1-deficient mice showed growth retardation and various WHS-like midline defects, including congenital cardiovascular anomalies. The effects of Whsc1 haploinsufficiency were increased in Nkx2-5 heterozygous mutant hearts, indicating their functional link. Nimura et al. (2009) proposed that WHSC1 functions together with developmental transcription factors to prevent the inappropriate transcription that can lead to various pathophysiologies. </p><p>Pei et al. (2011) found that H4K20 methylation actually increases locally upon the induction of double-strand breaks and that methylation of H4K20 at double-strand breaks is mediated by the histone methyltransferase MMSET in mammals. Downregulation of MMSET significantly decreases H4K20 methylation at double-strand breaks and the subsequent accumulation of 53BP1 (605230). Furthermore, Pei et al. (2011) found that the recruitment of MMSET to double-strand breaks requires the gamma-H2AX (601772)-MDC1 (607593) pathway; specifically, the interaction between the MDC1 BRCT domain and phosphorylated ser102 of MMSET. Thus, Pei et al. (2011) proposed that a pathway involving gamma-H2AX-MDC1-MMSET regulates the induction of H4K20 methylation on histones around double-strand breaks, which, in turn, facilitates 53BP1 recruitment. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The WHSC1 gene contains 25 exons (Stec et al., 1998). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Stec et al. (1998) mapped the WHSC1 gene to chromosome 4p16.3 based on genomic sequence analysis. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</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>Stec et al. (1998) noted that the t(4;14)(p16.3;q32.3) translocations described in a significant fraction of multiple myelomas (Richelda et al., 1997; Chesi et al., 1997) have breakpoints located less than 100 kb centromeric of the FGFR3 gene (134934) on 4p16.3. They found that at least 3 of the breakpoints merged the immunoglobulin heavy-chain gene (IGHG1; 147100) on chromosome 14 with the WHSC1 gene. This fusion of genes and their untimely expression in the myeloid lineage driven from the 5-prime IgH enhancer may indicate that WHSC1-encoded proteins are involved in the clinical heterogeneity of multiple myeloma. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Somatic Mutations in Cancer</em></strong></p><p>
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Jaffe et al. (2013) profiled global histone modifications in 115 cancer cell lines from the Cancer Cell Line Encyclopedia. One signature was characterized by increased H3K36me2, exhibited by several lines harboring translocations in the NSD2 methyltransferase. An NSD2 glu1099-to-lys (E1099K) variant was identified in nontranslocated acute lymphoblastic leukemia (ALL; 613065) cell lines sharing this signature. Ectopic expression of the variant induced a chromatin signature characteristic of NSD2 hyperactivation and promoted transformation. NSD2 knockdown selectively inhibited the proliferation of NSD2-mutant lines and impaired the in vivo growth of an NSD2-mutant ALL xenograft. Sequencing analysis of greater than 1,000 pediatric cancer genomes identified the NSD2 E1099K alteration in 14% of t(12;21) ETV6 (600618)-RUNX1 (151385)-containing ALLs. </p><p><strong><em>Rauch-Steindl Syndrome</em></strong></p><p>
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In a 16-month-old boy with Rauch-Steindl syndrome (RAUST; 619695), Lozier et al. (2018) identified a de novo heterozygous nonsense mutation in the NSD2 gene (R1138X; 602952.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function. </p><p>In a 2-year-old girl with RAUST, Boczek et al. (2018) identified a de novo heterozygous frameshift mutation in the NSD2 gene (602952.0002). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function. </p><p>In a 34-month-old boy (patient 2) with RAUST, Derar et al. (2019) identified a de novo heterozygous nonsense mutation in the NSD2 gene (602952.0003). Functional studies of the variant and studies of patient cells were not performed. </p><p>In a Chinese father and daughter with RAUST, Hu et al. (2020) identified a heterozygous frameshift mutation in the NSD2 gene (602952.0004). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in the father, who transmitted it to his affected daughter. The variant, which was not present in public databases, was predicted to result in nonsense-mediated mRNA decay and a loss of function, although functional studies of the variant and studies of patient cells were not performed. </p><p>In 18 patients from 16 unrelated families with RAUST, Zanoni et al. (2021) identified heterozygous variants in the NSD2 gene (see, e.g., 602952.0005-602952.0007). The variants were found by exome sequencing. Most occurred de novo, although 2 were recurrent and 2 were inherited within families. There were 5 missense variants, 3 nonsense mutations, and 7 frameshift mutations. In vitro functional expression studies showed that some, but not all, of the tested missense variants caused reduced levels of H3K36me2, impaired NSD2 methylation activity, and were unable to fully rescue physiologic levels of H3K36me2 in NSD2-depleted cells. Notably, C869Y (patient 1) and E1091K (patient 5) yielded equivocal result in functional assays, whereas S1137F (602952.0006) and K1019R (601952.0007) significantly compromised NSD2 function. The nonsense and frameshift mutations were predicted to result in a loss of function, although functional studies of these variants were not performed. Zanoni et al. (2021) concluded that the mutations result in a decrease or loss of NSD2 methyltransferase activity, which results in the developmental phenotype. While heterozygotes for missense variants were taller than those with nonsense or frameshift mutations, the overall clinical severity correlated only loosely with putative or demonstrated alterations in NSD2 enzymatic activity. Of note, several patients carried variants of uncertain significance in additional genes that could have contributed to the phenotype. </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>7 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 RAUCH-STEINDL 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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NSD2, ARG1138TER
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<br />
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SNP: rs1726909627,
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ClinVar: RCV001807861
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 16-month-old boy with Rauch-Steindl syndrome (RAUST; 619695), Lozier et al. (2018) identified a de novo heterozygous c.3412C-T transition (c.3412C-T, NM_001042424.2) in the NSD2 gene, resulting in an arg1138-to-ter (R1138X) substitution. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 RAUCH-STEINDL 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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NSD2, 4-BP DEL, NT1676
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<br />
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SNP: rs1553873247,
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ClinVar: RCV000660609, RCV001008475, RCV001779037, RCV001809736, RCV002274084, RCV004735729
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 2-year-old girl with Rauch-Steindl syndrome (RAUST; 619695), Boczek et al. (2018) identified a de novo heterozygous 4-bp deletion (c.1676_1679del, NM_133330.2) in the NSD2 gene, predicted to result in a frameshift and premature termination (Arg559ThrfsTer38). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in a loss of function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 RAUCH-STEINDL 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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NSD2, ARG935TER
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<br />
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SNP: rs2108959336,
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ClinVar: RCV001807862, RCV003442908
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 34-month-old boy (patient 2) with Rauch-Steindl syndrome (RAUST; 619695), Derar et al. (2019) identified a de novo heterozygous c.2803C-T transition (c.2803C-T, NM_001042424) in exon 15 of the NSD2 gene, resulting in an arg935-to-ter (R935X) substitution. 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>
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<span class="mim-font">
|
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<strong>.0004 RAUCH-STEINDL 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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NSD2, 1-BP DUP, 1577G
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<br />
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SNP: rs2108877068,
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ClinVar: RCV001807863
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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 Chinese father and daughter with Rauch-Steindl syndrome (RAUST; 619695), Hu et al. (2020) identified a heterozygous 1-bp duplication (c.1577dupG, NM_001042424) in the NSD2 gene, predicted to result in a frameshift and premature termination (Asn527LysfsTer14). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in the father, who transmitted it to his affected daughter. The variant, which was not present in public databases, was predicted to result in nonsense-mediated mRNA decay and a loss of function, although functional studies of the variant and studies of patient cells were not performed. The patients had mildly dysmorphic facial features and mild intellectual disability, although only the daughter had short stature, suggesting incomplete penetrance or variable expressivity. </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>.0005 RAUCH-STEINDL 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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NSD2, 1-BP DEL, 4028C
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<br />
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SNP: rs752037034,
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gnomAD: rs752037034,
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ClinVar: RCV001807864
|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated boys (patients 11 and 15) with Rauch-Steindl syndrome (RAUST; 619695), Zanoni et al. (2021) identified a de novo heterozygous 1-bp deletion (c.4028delC, NM_133330.2) in the NSD2 gene, predicted to result in a frameshift with elongation of the protein (Pro1343GlnfsTer49). The mutation was found by exome sequencing. Functional studies of the variant were not performed, but it was predicted to result in a loss of function. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 RAUCH-STEINDL 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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|
NSD2, SER1137PHE
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<br />
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|
|
SNP: rs2109020378,
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|
|
ClinVar: RCV001807865, RCV004728828
|
|
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 12-year-old Caucasian boy (patient 10) with Rauch-Steindl syndrome (RAUST; 619695), Zanoni et al. (2021) identified a de novo heterozygous c.3410C-T transition (c.3410C-T, NM_133330.2) in the NSD2 gene, resulting in a ser1137-to-phe (S1137F) substitution in the core of the methyltransferase domain. The variant was found by exome sequencing. In vitro functional expression studies showed that the variant caused reduced levels of H3K36me2, impaired NSD2 methylation activity, and was unable to fully rescue physiologic levels of H3K36me2 in NSD2-depleted cells. The findings were consistent with NSD2 deficiency. Exome sequencing showed that the patient carried variants of uncertain significance in other genes (HUWE1, 300697 and RNF38, 612488). </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 RAUCH-STEINDL SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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|
NSD2, LYS1019ARG
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<br />
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|
|
SNP: rs2108971327,
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|
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ClinVar: RCV001807866
|
|
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|
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 26-year-old man (patient 12) with Rauch-Steindl syndrome (RAUST; 619695), Zanoni et al. (2021) identified a de novo heterozygous c.3056A-G transition (c.3056A-G, NM_133330.2) in the NSD2 domain, resulting in a lys1019-to-arg (K1019R) substitution in the methyltransferase domain. The variant was found by exome sequencing. In vitro functional expression studies showed that the variant caused reduced levels of H3K36me2, impaired NSD2 methylation activity, and was unable to fully rescue physiologic levels of H3K36me2 in NSD2-depleted cells. The findings were consistent with NSD2 deficiency. Exome sequencing showed that the patient carried a variant of uncertain significance in the AGO2 gene (606229). </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>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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Baxendale, S., MacDonald, M. E., Mott, R., Francis, F., Lin, C., Kirby, S. F., James, M., Zehetner, G., Hummerich, H., Valdes, J., Collins, F. S., Deaven, L. J., Gusella, J. F., Lehrach, H., Bates, G. P.
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<strong>A cosmid contig and high resolution restriction map of the 2 megabase region containing the Huntington's disease gene.</strong>
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Nature Genet. 4: 181-186, 1993.
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[PubMed: 8348156]
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[Full Text: https://doi.org/10.1038/ng0693-181]
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</li>
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<li>
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<p class="mim-text-font">
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Boczek, N. J., Lahner, C. A., Nguyen, T., Ferber, M. J., Hasadsri, L., Thorland, E. C., Niu, Z., Gavrilova, R. H.
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<strong>Developmental delay and failure to thrive associated with a loss-of-function variant in WHSC1 (NSD2).</strong>
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Am. J. Med. Genet. 176A: 2798-2802, 2018.
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[PubMed: 30345613]
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<li>
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<p class="mim-text-font">
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Chesi, M., Nardini, E., Brents, L. A., Schrock, E., Ried, T., Kuehl, W. M., Bergsagel, P. L.
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<strong>Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3.</strong>
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Nature Genet. 16: 260-264, 1997.
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[PubMed: 9207791]
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[Full Text: https://doi.org/10.1038/ng0797-260]
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<li>
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<p class="mim-text-font">
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Derar, N., Al-Hassnan, Z. N., Al-Owain, M., Monies, D., Abouelhoda, M., Meyer, B. F., Moghrabi, N., Alkuraya, F. S.
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<strong>De novo truncating variants in WHSC1 recapitulate the Wolf-Hirschhorn (4p16.3 microdeletion) syndrome phenotype.</strong>
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Genet. Med. 21: 185-188, 2019.
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[PubMed: 29892088]
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<p class="mim-text-font">
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Hu, X., Wu, D., Li, Y., Wei, L., Li, X., Qin, M., Li, H., Li, M., Chen, S., Gong, C., Shen, Y.
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<strong>The first familial NSD2 cases with a novel variant in a Chinese father and daughter with atypical WHS facial features and a 7.5-year follow-up of growth hormone therapy.</strong>
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BMC Med. Genomics 13: 181, 2020.
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[PubMed: 33276791]
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[Full Text: https://doi.org/10.1186/s12920-020-00831-9]
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<p class="mim-text-font">
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Jaffe, J. D., Wang, Y., Chan, H. M., Zhang, J., Huether, R., Kryukov, G. V., Bhang, H. C., Taylor, J. E., Hu, M., Englund, N. P., Yan, F., Wang, Z., and 20 others.
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<strong>Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia.</strong>
|
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Nature Genet. 45: 1386-1391, 2013.
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[PubMed: 24076604]
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<p class="mim-text-font">
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Lozier, E. R., Konovalov, F. A., Kanivets, I. V., Pyankov, D. V., Koshkin, P. A., Baleva, L. S., Sipyagina, A. E., Yakusheva, E. N., Kuchina, A. E., Korostelev, S. A.
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<strong>De novo nonsense mutation in WHSC1 (NSD2) in patient with intellectual disability and dysmorphic features.</strong>
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[PubMed: 29760529]
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[Full Text: https://doi.org/10.1038/s10038-018-0464-5]
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<li>
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<p class="mim-text-font">
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Nimura, K., Ura, K., Shiratori, H., Ikawa, M., Okabe, M., Schwartz, R. J., Kaneda, Y.
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<strong>A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome.</strong>
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Nature 460: 287-291, 2009.
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[PubMed: 19483677]
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[Full Text: https://doi.org/10.1038/nature08086]
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Pei, H., Zhang, L., Luo, K., Qin, Y., Chesi, M., Fei, F., Bergsagel, P. L., Wang, L., You, Z., Lou, Z.
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Richelda, R., Ronchetti, D., Baldini, L., Cro, L., Viggiano, L., Marzella, R., Rocchi, M., Otsuki, T., Lombardi, L., Maiolo, A. T., Neri, A.
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Stec, I., Wright, T. J., van Ommen, G.-J. B., de Boer, P. A. J., van Haeringen, A., Moorman, A. F. M., Altherr, M. R., den Dunnen, J. T.
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<strong>WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma.</strong>
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Hum. Molec. Genet. 7: 1071-1082, 1998. Note: Erratum: Hum. Molec. Genet. 7: 1527-1528 only, 1998.
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Wright, T. J., Ricke, D. O., Denison, K., Abmayr, S., Cotter, P. D., Hirschhorn, K., Keinanen, M., McDonald-McGinn, D., Somer, M., Spinner, N., Yang-Feng, T., Zackai, E., Altherr, M. R.
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Zanoni, P., Steindl, K., Sengupta, D., Joset, P., Bahr, A., Sticht, H., Lang-Muritano, M., van Ravenswaaij-Arts, C. M. A., Shinawi, M., Andrews, M., Attie-Bitach, T., Maystadt, I., and 22 others.
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<strong>Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype.</strong>
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Cassandra L. Kniffin - updated : 01/07/2022<br>Ada Hamosh - updated : 01/08/2014<br>Ada Hamosh - updated : 6/22/2011<br>Ada Hamosh - updated : 8/27/2009
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