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Entry
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- *300032 - ATRX CHROMATIN REMODELER; ATRX
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*300032</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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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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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="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#pathogenesis">Pathogenesis</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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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/300032">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>
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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>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000085224;t=ENST00000373344" 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=546" 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=300032" 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=ENSG00000085224;t=ENST00000373344" 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_000489,NM_138270,XM_005262153,XM_005262154,XM_005262156,XM_005262157,XM_006724666,XM_006724668,XM_017029601,XM_017029604,XM_047442191" 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_000489" 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=300032" 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=02069&isoform_id=02069_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/ATRX" 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/530788,606833,1333689,1778307,1778351,1778352,1778353,2306766,2306809,6960326,6960328,12803397,30583215,33352252,33352254,33352256,33352258,33352260,33352262,33352264,33352266,33352268,33352270,33352272,33352274,33352276,33352278,33352280,33352282,33352284,33352286,33352288,33352290,33354053,57208647,57208648,57210059,57210060,57210061,57284090,57284091,57284092,62087436,62088670,119619017,119619018,119619019,119619020,119619021,133923365,194379178,194384686,194386218,221039422,444737837,444737839,498923500,530788276,530788278,578838407,578838409,578838413,578838415,578838417,578838421,636629978,636629980,636629982,1034674574,1034674583,2203400840,2217392827,2462629899,2462629901,2462629903,2462629905,2462629907,2462629909,2462629911,2462629913,2462629915" 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/P46100" 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=546" 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=ENSG00000085224;t=ENST00000373344" 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=ATRX" 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=ATRX" 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+546" 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/ATRX" 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:546" 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/546" 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=chrX&hgg_gene=ENST00000373344.11&hgg_start=77504880&hgg_end=77786216&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:886" 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:886" 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/atrx" 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=300032[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=300032[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/ATRX/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/ENSG00000085224" 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=ATRX" 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=ATRX" 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=ATRX" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://lovd.bx.psu.edu/home.php?select_db=ATRX" title="alpha thalassemia/mental Retardation syndrome X-linked (ATRX) database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">alpha thalassemia/mental R…</a></div><div style="margin-left: 0.5em;"><a href="http://www.LOVD.nl/ATRX" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">ATRX database at LOVD</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ATRX&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/PA25179" 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:886" 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/FBgn0039338.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:103067" 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/ATRX#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:103067" 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/546/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=546" 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=WBGene00006961;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-030912-11" 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="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:300032" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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:546" 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=ATRX&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 715342005<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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300032
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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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ATRX CHROMATIN REMODELER; ATRX
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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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ATR-X GENE<br />
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HELICASE 2, X-LINKED; XH2<br />
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X-LINKED NUCLEAR PROTEIN GENE; XNP
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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=ATRX" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ATRX</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/X/447?start=-3&limit=10&highlight=447">Xq21.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chrX:77504880-77786216&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'})">X:77,504,880-77,786,216</a> </span>
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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Alpha-thalassemia/impaired intellectual development syndrome
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Intellectual disability-hypotonic facies syndrome, X-linked
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/300032" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/300032" 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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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<p><a href="#47" class="mim-tip-reference" title="Stayton, C. L., Dabovic, B., Gulisano, M., Gecz, J., Broccoli, V., Giovanazzi, S., Bossolasco, M., Monaco, L., Rastan, S., Boncinelli, E., Bianchi, M. E., Consalez, G. G. <strong>Cloning and characterization of a new human Xq13 gene, encoding a putative helicase.</strong> Hum. Molec. Genet. 3: 1957-1964, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874112</a>] [<a href="https://doi.org/10.1093/hmg/3.11.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874112">Stayton et al. (1994)</a> described the cloning and characterization of a gene, provisionally called X-linked helicase-2 (XH2), located on chromosome Xq13. The gene undergoes X inactivation, contains a 4-kb open reading frame, and encodes a putative NTP-binding nuclear protein homologous to several members of the helicase II superfamily. In situ hybridization studies in the mouse revealed precocious, widespread expression of the murine homolog of XH2 at early stages of embryogenesis, and more restricted expression during late developmental stages and at birth. XH2 shares 6 conserved, collinear domains with other members of the family of proven and putative helicases. In particular, the XH2 protein shows homology with RAD54. Type II helicases have been implicated in nucleotide excision repair and initiation of transcription. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874112" 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="#41" class="mim-tip-reference" title="Picketts, D. J., Higgs, D. R., Bachoo, S., Blake, D. J., Quarrell, O. W. J., Gibbons, R. J. <strong>ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome.</strong> Hum. Molec. Genet. 5: 1899-1907, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968741</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968741">Picketts et al. (1996)</a> established the full-length sequence of the ATRX cDNA and predicted the structure of the ATRX protein. Their comparative analysis showed that ATRX is a member of the SNF2-like subgroup of a superfamily of proteins with similar ATPase and helicase domains (see <a href="/entry/300012">300012</a>). The N-terminal region contains a nuclear localization signal and antibody studies indicated a nuclear localization of the protein. The C-terminal region is glutamine rich, a common attribute of other transcription factors. In addition, a 15-amino acid segment (the P element) in the C-terminal region shows 35 to 50% similarity to SNF2-like proteins which are involved in gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968741" 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="#54" class="mim-tip-reference" title="Villard, L., Lossi, A.-M., Cardoso, C., Proud, V., Chiaroni, P., Colleaux, L., Schwartz, C., Fontes, M. <strong>Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase.</strong> Genomics 43: 149-155, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9244431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9244431</a>] [<a href="https://doi.org/10.1006/geno.1997.4793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9244431">Villard et al. (1997)</a> determined that the ATRX gene encodes a predicted protein of 2,492 amino acids. Three zinc finger motifs were found within the 5-prime end of the gene. Expression analysis in different tissues identified an alternative splicing event that involves exon 6. One of these alternatively spliced transcripts is expressed predominantly in embryonic tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9244431" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Gibbons, R. J., Bachoo, S., Picketts, D. J., Aftimos, S., Asenbauer, B., Bergoffen, J., Berry, S. A., Dahl, N., Fryer, A., Keppler, K., Kurosawa, K., Levin, M. L., Masuno, M., Neri, G., Pierpont, M. E., Slaney, S. F., Higgs, D. R. <strong>Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain. (Letter)</strong> Nature Genet. 17: 146-148, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326931</a>] [<a href="https://doi.org/10.1038/ng1097-146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326931">Gibbons et al. (1997)</a> used the N-terminal sequence of ATRX, as identified by <a href="#41" class="mim-tip-reference" title="Picketts, D. J., Higgs, D. R., Bachoo, S., Blake, D. J., Quarrell, O. W. J., Gibbons, R. J. <strong>ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome.</strong> Hum. Molec. Genet. 5: 1899-1907, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968741</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968741">Picketts et al. (1996)</a>, to identify a cysteine-rich motif, similar to a putative zinc finger domain (cys4-his-cys3), called the PHD finger. PHD motifs span 50 to 80 amino acids and had been identified in more than 40 proteins, many of which are implicated in chromatin-mediated transcriptional control. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9326931+8968741" 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="#42" class="mim-tip-reference" title="Picketts, D. J., Tastan, A. O., Higgs, D. R., Gibbons, R. J. <strong>Comparison of the human and murine ATRX gene identifies highly conserved, functionally important domains.</strong> Mammalian Genome 9: 400-403, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9545503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9545503</a>] [<a href="https://doi.org/10.1007/s003359900781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9545503">Picketts et al. (1998)</a> showed that the mouse Atrx gene shows structural features similar to those of the human gene. Two highly conserved and functionally important regions were identified: a potential finger domain at the N terminus and a catalytic domain at the C terminus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9545503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Gibbons, R. J., Higgs, D. R. <strong>Molecular-clinical spectrum of the ATR-X syndrome.</strong> Am. J. Med. Genet. 97: 204-212, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11449489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11449489</a>] [<a href="https://doi.org/10.1002/1096-8628(200023)97:3<204::AID-AJMG1038>3.0.CO;2-X" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11449489">Gibbons and Higgs (2000)</a> stated that the XH2 gene encodes at least 2 alternatively spliced mRNA transcripts that differ at the 5-prime ends and give rise to slightly different proteins of 265 and 280 kD, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11449489" 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="#47" class="mim-tip-reference" title="Stayton, C. L., Dabovic, B., Gulisano, M., Gecz, J., Broccoli, V., Giovanazzi, S., Bossolasco, M., Monaco, L., Rastan, S., Boncinelli, E., Bianchi, M. E., Consalez, G. G. <strong>Cloning and characterization of a new human Xq13 gene, encoding a putative helicase.</strong> Hum. Molec. Genet. 3: 1957-1964, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874112</a>] [<a href="https://doi.org/10.1093/hmg/3.11.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874112">Stayton et al. (1994)</a> determined that the genomic length of XH2 is more than 220 kb. <a href="#41" class="mim-tip-reference" title="Picketts, D. J., Higgs, D. R., Bachoo, S., Blake, D. J., Quarrell, O. W. J., Gibbons, R. J. <strong>ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome.</strong> Hum. Molec. Genet. 5: 1899-1907, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968741</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968741">Picketts et al. (1996)</a> determined that the XH2 gene contains 36 exons and spans approximately 300 kb. Using a vectorette strategy, <a href="#54" class="mim-tip-reference" title="Villard, L., Lossi, A.-M., Cardoso, C., Proud, V., Chiaroni, P., Colleaux, L., Schwartz, C., Fontes, M. <strong>Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase.</strong> Genomics 43: 149-155, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9244431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9244431</a>] [<a href="https://doi.org/10.1006/geno.1997.4793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9244431">Villard et al. (1997)</a> identified and sequenced the intron/exon boundaries of the ATRX gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8968741+9244431+7874112" 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="#47" class="mim-tip-reference" title="Stayton, C. L., Dabovic, B., Gulisano, M., Gecz, J., Broccoli, V., Giovanazzi, S., Bossolasco, M., Monaco, L., Rastan, S., Boncinelli, E., Bianchi, M. E., Consalez, G. G. <strong>Cloning and characterization of a new human Xq13 gene, encoding a putative helicase.</strong> Hum. Molec. Genet. 3: 1957-1964, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874112</a>] [<a href="https://doi.org/10.1093/hmg/3.11.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874112">Stayton et al. (1994)</a> mapped the XH2 gene to chromosome Xq13, between the gene for Menkes disease (MNK; <a href="/entry/309400">309400</a>) and DXS56. They showed that the murine homolog maps to the homologous genetic interval between Pgk1 and Xist. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874112" 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="#23" class="mim-tip-reference" title="Gibbons, R. J., Picketts, D. J., Villard, L., Higgs, D. R. <strong>Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).</strong> Cell 80: 837-845, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7697714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7697714</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90287-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7697714">Gibbons et al. (1995)</a> showed that mutations in the XH2 gene cause the alpha-thalassemia/mental retardation syndrome (ATR-X; <a href="/entry/301040">301040</a>), an X-linked disorder comprising severe psychomotor retardation, characteristic facial features, genital abnormalities, and alpha-thalassemia. XH2 is a member of a subgroup of the helicase superfamily that includes proteins involved in a wide range of cellular functions, including DNA recombination and repair (e.g., ERCC6; <a href="/entry/609413">609413</a>) and transcription regulation. Because of the complex ATR-X phenotype, <a href="#23" class="mim-tip-reference" title="Gibbons, R. J., Picketts, D. J., Villard, L., Higgs, D. R. <strong>Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).</strong> Cell 80: 837-845, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7697714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7697714</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90287-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7697714">Gibbons et al. (1995)</a> suggested that a mutation in the XH2 gene results in transcriptional downregulation of several genes, including the alpha-globin genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7697714" 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="#41" class="mim-tip-reference" title="Picketts, D. J., Higgs, D. R., Bachoo, S., Blake, D. J., Quarrell, O. W. J., Gibbons, R. J. <strong>ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome.</strong> Hum. Molec. Genet. 5: 1899-1907, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968741</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968741">Picketts et al. (1996)</a> suggested that ATRX is most likely involved in the regulation of gene expression, a known function of helicases. They noted that ATRX downregulates alpha-globin (<a href="/entry/141800">141800</a>) but not beta-globin (<a href="/entry/141900">141900</a>). They postulated that this may be due to the fact that alpha- and beta-globin are contained within different chromosomal environments and are regulated differently because of the interaction of regulatory factors and chromatin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968741" 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>The SNF2-like family comprises numerous members involved in a broad range of biologic functions: transcriptional regulation, DNA repair, and chromosome segregation. Since experiments on fibroblasts from ATR-X patients provided no evidence for either a DNA repair defect or abnormal chromosome breakage segregation, <a href="#12" class="mim-tip-reference" title="Cardoso, C., Timsit, S., Villard, L., Khrestchatisky, M., Fontes, M., Colleaux, L. <strong>Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein.</strong> Hum. Molec. Genet. 7: 679-684, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9499421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9499421</a>] [<a href="https://doi.org/10.1093/hmg/7.4.679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9499421">Cardoso et al. (1998)</a> suspected that the XNP protein is somehow involved in regulation of gene expression. Genetic and biochemical studies had led to the emerging concept that SNF2-like proteins are components of a large protein complex that may exert its functions by modulating chromatin structure. <a href="#12" class="mim-tip-reference" title="Cardoso, C., Timsit, S., Villard, L., Khrestchatisky, M., Fontes, M., Colleaux, L. <strong>Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein.</strong> Hum. Molec. Genet. 7: 679-684, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9499421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9499421</a>] [<a href="https://doi.org/10.1093/hmg/7.4.679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9499421">Cardoso et al. (1998)</a> performed a yeast 2-hybrid analysis with XNP and several human heterochromatin-associated proteins. They found a specific interaction between XNP and the EZH2 (<a href="/entry/601573">601573</a>) proteins. In light of these observations, they discussed how the XNP protein may regulate gene transcription at the chromatin level. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9499421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using indirect immunofluorescence and confocal microscopy, <a href="#36" class="mim-tip-reference" title="McDowell, T. L., Gibbons, R. J., Sutherland, H., O'Rourke, D. M., Bickmore, W. A., Pombo, A., Turley, H., Gatter, K., Picketts, D. J., Buckle, V. J., Chapman, L., Rhodes, D., Higgs, D. R. <strong>Localization of a putative transcriptional regulator (ATRX) at pericentromeric heterochromatin and the short arms of acrocentric chromosomes.</strong> Proc. Nat. Acad. Sci. 96: 13983-13988, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10570185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10570185</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10570185[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.24.13983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10570185">McDowell et al. (1999)</a> showed that ATRX protein is associated with pericentromeric heterochromatin during interphase and mitosis. By coimmunofluorescence, they found that ATRX localizes with a mouse homolog of the Drosophila heterochromatic protein HP1 in vivo, consistent with a previous 2-hybrid screen identifying this interaction. From the analysis of a trap assay for nuclear proteins, <a href="#36" class="mim-tip-reference" title="McDowell, T. L., Gibbons, R. J., Sutherland, H., O'Rourke, D. M., Bickmore, W. A., Pombo, A., Turley, H., Gatter, K., Picketts, D. J., Buckle, V. J., Chapman, L., Rhodes, D., Higgs, D. R. <strong>Localization of a putative transcriptional regulator (ATRX) at pericentromeric heterochromatin and the short arms of acrocentric chromosomes.</strong> Proc. Nat. Acad. Sci. 96: 13983-13988, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10570185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10570185</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10570185[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.24.13983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10570185">McDowell et al. (1999)</a> showed that the localization of ATRX to heterochromatin is encoded by its N-terminal region, which contains a conserved plant homeodomain-like finger and a coiled-coil domain. In addition to its association with heterochromatin, at metaphase ATRX clearly binds to the short arms of human acrocentric chromosomes, where the arrays of ribosomal DNA are located. The unexpected association of a putative transcriptional regulator with highly repetitive DNA provides a potential explanation for the variability in phenotype of patients with identical mutations in the ATRX gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10570185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Berube, N. G., Smeenk, C. A., Picketts, D. J. <strong>Cell cycle-dependent phosphorylation of the ATRX protein correlates with changes in nuclear matrix and chromatin association.</strong> Hum. Molec. Genet. 9: 539-547, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10699177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10699177</a>] [<a href="https://doi.org/10.1093/hmg/9.4.539" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10699177">Berube et al. (2000)</a> demonstrated that the association of the ATRX protein with chromosomes at mitosis is concomitant with phosphorylation and its association with HP1-alpha (<a href="/entry/604478">604478</a>). The authors proposed a dual role for ATRX, possibly involving gene regulation at interphase as well as chromosomal segregation at mitosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10699177" 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>XY patients with deletions or mutations in the ATRX gene display varying degrees of sex reversal, implicating ATRX in the development of the human testis (<a href="#44" class="mim-tip-reference" title="Reardon, W., Gibbons, R. J., Winter, R. M., Baraitser, M. <strong>Male pseudohermaphroditism in sibs with the alpha-thalassemia/mental retardation (ATR-X) syndrome.</strong> Am. J. Med. Genet. 55: 285-287, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726224</a>] [<a href="https://doi.org/10.1002/ajmg.1320550308" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7726224">Reardon et al., 1995</a>). To explore further the role of ATRX in mammalian sex differentiation, <a href="#40" class="mim-tip-reference" title="Pask, A., Renfree, M. B., Graves, J. A. M. <strong>The human sex-reversing ATRX gene has a homologue on the marsupial Y chromosome, ATRY: implications for the evolution of mammalian sex determination.</strong> Proc. Nat. Acad. Sci. 97: 13198-13202, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11069290/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11069290</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11069290[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.230424497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11069290">Pask et al. (2000)</a> cloned and characterized the homologous gene in a marsupial. To their surprise, active homologs of ATRX were detected on the marsupial Y as well as the X chromosome. The Y-borne copy (ATRY) displayed testis-specific expression. This, as well as the sex reversal of ATRX patients, suggested that ATRY is involved in testis development in marsupials and may represent an ancestral testis-determining mechanism that predated the evolution of SRY (<a href="/entry/480000">480000</a>) as the primary mammalian male sex-determining gene. The authors found no evidence for a Y-borne ATRX homolog in mouse or human, implying that this gene has been lost in eutherians and its role supplanted by the evolution of SRY from SOX3 (<a href="/entry/313430">313430</a>) as the dominant determiner of male differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11069290+7726224" 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="#22" class="mim-tip-reference" title="Gibbons, R. J., Pellagatti, A., Garrick, D., Wood, W. G., Malik, N., Ayyub, H., Langford, C., Boultwood, J., Wainscoat, J. S., Higgs, D. R. <strong>Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS).</strong> Nature Genet. 34: 446-449, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12858175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12858175</a>] [<a href="https://doi.org/10.1038/ng1213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12858175">Gibbons et al. (2003)</a> stated that like other members of the SWI2/SNF2 family of proteins, multiprotein complexes isolated by ATRX antibodies have ATP-dependent nucleosome remodeling and DNA translocase activities in vitro. ATRX is a nuclear protein that localizes to nuclear subcompartments called PML bodies and to pericentromeric heterochromatin, where it interacts with a known component of heterochromatin, HP1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12858175" 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="#39" class="mim-tip-reference" title="Nan, X., Hou, J., Maclean, A., Nasir, J., Lafuente, M. J., Shu, X., Kriaucionis, S., Bird, A. <strong>Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation.</strong> Proc. Nat. Acad. Sci. 104: 2709-2714, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17296936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17296936</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17296936[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0608056104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17296936">Nan et al. (2007)</a> found that ATRX interacts with MECP2 (<a href="/entry/300005">300005</a>), a methyl-CpG-binding protein that is mutated in Rett syndrome (RTT; <a href="/entry/312750">312750</a>) and some forms of mental retardation. Studies in cultured mouse cells showed that MECP2 targeted the C-terminal helicase domain of ATRX to heterochromatic foci. The heterochromatic localization of ATRX was disturbed in neurons from Mecp2-null mice. The findings suggested that disruption of MECP2-ATRX interaction leads to pathologic changes that contribute to mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17296936" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By immunofluorescence using ATRX deletion constructs in HeLa cells, <a href="#7" class="mim-tip-reference" title="Berube, N. G., Healy, J., Medina, C. F., Wu, S., Hodgson, T., Jagla, M., Picketts, D. J. <strong>Patient mutations alter ATRX targeting to PML nuclear bodies.</strong> Europ. J. Hum. Genet. 16: 192-201, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17957225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17957225</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201943" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17957225">Berube et al. (2008)</a> identified 2 nuclear localization signals and 2 C-terminal domains that targeted ATRX to nuclear speckles, including to promyelocytic leukemia (PML) nuclear bodies. The PML-targeting domain appeared to play a role in chromatin remodeling and subnuclear targeting. Mutant ATRX proteins with mutations in the C-terminal domain resulted an approximately 80% reduction in the number of transfected cells with ATRX colocalization to nuclear speckles. The findings showed that mutations have an effect on subnuclear targeting to PML nuclear bodies and can cause a loss of ATRX protein function, which may result in aberrant gene regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17957225" 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="#31" class="mim-tip-reference" title="Law, M. J., Lower, K. M., Voon, H. P. J., Hughes, J. R., Garrick, D., Viprakasit, V., Mitson, M., De Gobbi, M., Marra, M., Morris, A., Abbott, A., Wilder, S. P., and 10 others. <strong>ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner.</strong> Cell 143: 367-378, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21029860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21029860</a>] [<a href="https://doi.org/10.1016/j.cell.2010.09.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21029860">Law et al. (2010)</a> examined the genomewide distribution of ATRX protein and found that it was enriched at telomeres and subtelomeric regions of human chromosomes. Chromatin immunoprecipitation and sequence analysis identified 917 ATRX targets in primary human erythroid cells and 1,305 targets in mouse embryonic stem cells. The most prominent feature of the targets in both human and mouse is the presence of variable number tandem repeats, many of which are G and C rich, contain a high proportion of CpG dinucleotides, and/or have the potential to form G-quadruplex structures, particularly when single stranded. A subtelomeric region of chromosome 16 (16p13.3) contains 2 ATRX targets, alpha-globin and NME4 (<a href="/entry/601818">601818</a>), and each has the potential to form G-quadruplex structures. The beta-globin locus does not contain likely ATRX target sequences. Quantitative PCR analysis showed that all peaks of ATRX binding localized at or very close to regions of G-rich tandemly repetitive DNA, and the degree of downregulation of each alpha-like globin gene was related to its proximity to the major peak of ATRX binding 1 kb upstream from the hemoglobin mu gene (HBM; <a href="/entry/609639">609639</a>). Gel-shift assays confirmed that ATRX bound G-quadruplex DNA in vitro. <a href="#31" class="mim-tip-reference" title="Law, M. J., Lower, K. M., Voon, H. P. J., Hughes, J. R., Garrick, D., Viprakasit, V., Mitson, M., De Gobbi, M., Marra, M., Morris, A., Abbott, A., Wilder, S. P., and 10 others. <strong>ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner.</strong> Cell 143: 367-378, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21029860/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21029860</a>] [<a href="https://doi.org/10.1016/j.cell.2010.09.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21029860">Law et al. (2010)</a> noted that a number of ATRX targets are highly polymorphic, suggesting that the degree to which gene expression is altered by ATRX may relate to the size of the tandem repeat. This variability in ATRX targets may also explain incomplete penetrance of alpha-thalassemia in individuals with identical ATRX mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21029860" 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="#17" class="mim-tip-reference" title="Elsasser, S. J., Noh, K.-M., Diaz, N., Allis, C. D., Banaszynski, L. A. <strong>Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells.</strong> Nature 522: 240-244, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25938714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25938714</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25938714[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/nature14345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25938714">Elsasser et al. (2015)</a> showed that the replacement histone variant H3.3 (<a href="/entry/601128">601128</a>) is enriched at class I and class II endogenous retroviral elements (ERVs), notably those of the early transposon/MusD family and intracisternal A-type particles. Deposition at a subset of these elements is dependent on the H3.3 chaperone complex containing ATRX and DAXX (<a href="/entry/603186">603186</a>). <a href="#17" class="mim-tip-reference" title="Elsasser, S. J., Noh, K.-M., Diaz, N., Allis, C. D., Banaszynski, L. A. <strong>Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells.</strong> Nature 522: 240-244, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25938714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25938714</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25938714[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/nature14345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25938714">Elsasser et al. (2015)</a> demonstrated that recruitment of DAXX, H3.3, and KAP1 (TRIM28; <a href="/entry/601742">601742</a>) to ERVs is codependent and occurs upstream of ESET (SETDB1; <a href="/entry/604396">604396</a>), linking H3.3 to ERV-associated H3K9me3. Importantly, H3K9me3 is reduced at ERVs upon H3.3 deletion, resulting in derepression and dysregulation of adjacent, endogenous genes, along with increased retrotransposition of intracisternal A-type particles. <a href="#17" class="mim-tip-reference" title="Elsasser, S. J., Noh, K.-M., Diaz, N., Allis, C. D., Banaszynski, L. A. <strong>Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells.</strong> Nature 522: 240-244, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25938714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25938714</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25938714[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/nature14345" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25938714">Elsasser et al. (2015)</a> concluded that their study identifies a unique heterochromatin state marked by the presence of both H3.3 and H3K9me3, and establishes an important role for H3.3 in control of ERV retrotransposition in embryonic stem cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25938714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Flynn, R. L., Cox, K. E., Jeitany, M., Wakimoto, H., Bryll, A. R., Ganem, N. J., Bersani, F., Pineda, J. R., Suva, M. L., Benes, C. H., Haber, D. A., Boussin, F. D., Zou, L. <strong>Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors.</strong> Science 347: 273-277, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25593184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25593184</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25593184[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/10.1126/science.1257216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25593184">Flynn et al. (2015)</a> showed that loss of ATRX compromises cell-cycle regulation of the telomeric noncoding RNA TERRA and leads to persistent association of replication protein A (RPA; see <a href="/entry/179835">179835</a>) with telomeres after DNA replication, creating a recombinogenic nucleoprotein structure. Inhibition of the protein kinase ATR (<a href="/entry/601215">601215</a>), a critical regulator of recombination recruited by RPA, disrupts alternative lengthening of telomeres (ALT) and triggers chromosome fragmentation and apoptosis in ALT cells. The cell death induced by ATR inhibitors is highly selective for cancer cells that rely on ALT, suggesting that such inhibitors may be useful for treatment of ALT-positive cancers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25593184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Alpha-Thalassemia/Impaired Intellectual Development Syndrome</em></strong></p><p>
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In patients with the ATRX syndrome (<a href="/entry/301040">301040</a>), an X-linked disorder comprising severe psychomotor retardation, characteristic facial features, genital abnormalities, and alpha-thalassemia, <a href="#23" class="mim-tip-reference" title="Gibbons, R. J., Picketts, D. J., Villard, L., Higgs, D. R. <strong>Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).</strong> Cell 80: 837-845, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7697714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7697714</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90287-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7697714">Gibbons et al. (1995)</a> identified mutations in the XH2 gene (<a href="#0001">300032.0001</a>-<a href="#0009">300032.0009</a>). They identified 2 premature in-frame stop mutations, 7 missense mutations, and a small deletion that reduced expression of the gene in ATRX patients to less than 1% of that of controls. A clue to the presence of mutations in XH2 associated with ATRX syndrome was the absence of a hybridization signal with an XH2 probe in the patient with the deletion. The 9 other mutations were identified by single-strand conformation polymorphism analysis followed by sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7697714" 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="#41" class="mim-tip-reference" title="Picketts, D. J., Higgs, D. R., Bachoo, S., Blake, D. J., Quarrell, O. W. J., Gibbons, R. J. <strong>ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome.</strong> Hum. Molec. Genet. 5: 1899-1907, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968741</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968741">Picketts et al. (1996)</a> screened 52 individuals with ATRX syndrome and identified 4 novel splicing defects in the ATRX gene. They reported sites of mutation in 27 different cases of ATRX. <a href="#41" class="mim-tip-reference" title="Picketts, D. J., Higgs, D. R., Bachoo, S., Blake, D. J., Quarrell, O. W. J., Gibbons, R. J. <strong>ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome.</strong> Hum. Molec. Genet. 5: 1899-1907, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968741</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968741">Picketts et al. (1996)</a> noted that mutations associated with the severe urogenital abnormalities which may occur in ATRX have primarily been mutations that lead to severe truncation of the protein with loss of the C-terminal region, which includes both the P element and the polyglutamine tract. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968741" 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="#54" class="mim-tip-reference" title="Villard, L., Lossi, A.-M., Cardoso, C., Proud, V., Chiaroni, P., Colleaux, L., Schwartz, C., Fontes, M. <strong>Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase.</strong> Genomics 43: 149-155, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9244431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9244431</a>] [<a href="https://doi.org/10.1006/geno.1997.4793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9244431">Villard et al. (1997)</a> searched for mutations in the 5-prime region of the ATRX gene in ATRX patients who did not have mutations in the 3-prime region. In 1 patient, they found that part of exon 7 was removed from the XNP transcript as a result of a mutation creating a novel splice site that was substituted for the natural splice site (<a href="#0013">300032.0013</a>). The new splicing event removed 1 zinc finger motif, suggesting that mutations in both the helicase and zinc finger regions result in disease manifestations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9244431" 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>Extending the mutation analysis of the ATRX gene to include the PHD zinc finger region, <a href="#19" class="mim-tip-reference" title="Gibbons, R. J., Bachoo, S., Picketts, D. J., Aftimos, S., Asenbauer, B., Bergoffen, J., Berry, S. A., Dahl, N., Fryer, A., Keppler, K., Kurosawa, K., Levin, M. L., Masuno, M., Neri, G., Pierpont, M. E., Slaney, S. F., Higgs, D. R. <strong>Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain. (Letter)</strong> Nature Genet. 17: 146-148, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326931</a>] [<a href="https://doi.org/10.1038/ng1097-146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326931">Gibbons et al. (1997)</a> identified 10 different mutations within a 294-bp segment (see, e.g., <a href="#0014">300032.0014</a>; <a href="#0018">300032.0018</a>). Family studies confirmed de novo mutations at 4 of these sites. In 15 unrelated individuals, a C-to-T transition at a single CpG dinucleotide, presumably a deamination 'hotspot,' changed arg to cys, which had the potential to disrupt the putative zinc finger. Similarly, 3 mutations affected conserved cys residues, which could coordinate zinc binding in this region. Finally, in 4 unrelated individuals, an identical splice site mutation removed 21 amino acids, which would disrupt the putative zinc finger located upstream of the PHD-like domain. Although the clinical phenotype of particular ATRX mutations was similar, there was a wide range in the perturbation of alpha-globin expression as reflected by the proportion of cells with Hb H inclusions, suggesting that the effect of ATRX protein on gene expression, as for other chromatin-associated regulators, may be modified by other genetic factors. Variation was observed even within the same family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9326931" 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="#50" class="mim-tip-reference" title="Villard, L., Bonino, M.-C., Abidi, F., Ragusa, A., Belougne, J., Lossi, A.-M., Seaver, L., Bonnefont, J.-P., Romano, C., Fichera, M., Lacombe, D., Hanauer, A., Philip, N., Schwartz, C., Fontes, M. <strong>Evaluation of a mutation screening strategy for sporadic cases of ATR-X syndrome.</strong> J. Med. Genet. 36: 183-186, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10204841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10204841</a>]" pmid="10204841">Villard et al. (1999)</a> reported mutation analysis of the XNP gene using direct sequencing of PCR products derived from primers amplifying the 300-bp zinc finger coding region spanning exons 7, 8, and 9. In 21 mentally retarded male patients with facial appearance typical of ATRX, but not necessarily having urogenital abnormalities or hemoglobin H inclusions, 6 mutations (28%) were detected. <a href="#50" class="mim-tip-reference" title="Villard, L., Bonino, M.-C., Abidi, F., Ragusa, A., Belougne, J., Lossi, A.-M., Seaver, L., Bonnefont, J.-P., Romano, C., Fichera, M., Lacombe, D., Hanauer, A., Philip, N., Schwartz, C., Fontes, M. <strong>Evaluation of a mutation screening strategy for sporadic cases of ATR-X syndrome.</strong> J. Med. Genet. 36: 183-186, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10204841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10204841</a>]" pmid="10204841">Villard et al. (1999)</a> concluded that this method was suitable for screening individuals in this population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10204841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bachoo, S., Gibbons, R. J. <strong>Germline and gonosomal mosaicism in the ATR-X syndrome.</strong> Europ. J. Hum. Genet. 7: 933-936, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10602370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10602370</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10602370">Bachoo and Gibbons (1999)</a> identified 2 women who were each mosaic for an ATRX mutation. One of them, whose mutation was undetectable in peripheral blood and buccal cells, had 2 affected sons and was therefore presumed to be a germline mosaic. In the other woman, the ATRX mutation was weakly detectable in the peripheral blood, but only 1 of her 3 children who shared the disease-associated haplotype carried the mutation. Therefore, the authors concluded that she represented a gonosomal mosaic. These cases provided the first molecular evidence for the occurrence of postzygotic mutations in ATRX syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10602370" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Gibbons, R. J., McDowell, T. L., Raman, S., O'Rourke, D. M., Garrick, D., Ayyub, H., Higgs, D. R. <strong>Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation.</strong> Nature Genet. 24: 368-371, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742099</a>] [<a href="https://doi.org/10.1038/74191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742099">Gibbons et al. (2000)</a> demonstrated that mutations in the ATRX gene give rise to changes in the methylation pattern of several highly repeated sequences, including the rDNA arrays, a Y-specific satellite, and subtelomeric repeats. Using methylation-sensitive restriction endonucleases, they noted differences in the pattern of rDNA methylation by comparing genomic DNA from EBV-transformed B cells or the peripheral blood of normal individuals with that from patients with ATRX syndrome. In normal individuals, approximately 20% of rDNA repeats were methylated within most CpG-rich regions. In ATRX patients, rDNA genes were substantially unmethylated. These differences were present in a variety of tissues from the fetal stage of development onwards. The Y-specific repeat DYZ2 makes up 10 to 20% of the Y chromosome, distributed along the entire heterochromatic band Yq12. <a href="#21" class="mim-tip-reference" title="Gibbons, R. J., McDowell, T. L., Raman, S., O'Rourke, D. M., Garrick, D., Ayyub, H., Higgs, D. R. <strong>Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation.</strong> Nature Genet. 24: 368-371, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742099</a>] [<a href="https://doi.org/10.1038/74191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742099">Gibbons et al. (2000)</a> discovered that approximately 6% of DYZ2 repeats were unmethylated on the Y chromosomes in the peripheral blood of normal individuals, but almost all were methylated in ATRX patients. These results differed from those identified in the rDNA repeats, suggesting that the effect of ATRX mutations on Y-chromosome repeats is different from their effect on rDNA repeats. <a href="#21" class="mim-tip-reference" title="Gibbons, R. J., McDowell, T. L., Raman, S., O'Rourke, D. M., Garrick, D., Ayyub, H., Higgs, D. R. <strong>Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation.</strong> Nature Genet. 24: 368-371, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742099</a>] [<a href="https://doi.org/10.1038/74191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742099">Gibbons et al. (2000)</a> concluded that their findings provide a potential link between the processes of chromatin remodeling, DNA methylation, and gene expression in mammalian development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10742099" 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 study of 8 unrelated Japanese families, <a href="#56" class="mim-tip-reference" title="Wada, T., Kubota, T., Fukushima, Y., Saitoh, S. <strong>Molecular genetic study of Japanese patients with X-linked alpha-thalassemia/mental retardation syndrome (ATR-X).</strong> Am. J. Med. Genet. 94: 242-248, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10995512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10995512</a>]" pmid="10995512">Wada et al. (2000)</a> found 7 missense mutations, including 6 novel mutations, as the cause of the ATRX syndrome. One mutation, arg246-to-cys (<a href="#0018">300032.0018</a>), was found in 2 unrelated patients. All mutations were located either in the N-terminal region corresponding to the putative zinc finger domain or in the C-terminal region corresponding to the helicase domain. The clinical manifestations were the same with mutations of either group, suggesting that the putative zinc finger and helicase domains have similar functional significance for the ATRX gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10995512" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a broad range denaturing gel gradient electrophoresis (DGGE) method for single-step mutation scanning of the entire open reading frame and canonical splice sites of the ATRX gene, <a href="#11" class="mim-tip-reference" title="Borgione, E., Sturnio, M., Spalletta, A., Lo Giudice, M. A., Castiglia, L., Galesi, O., Ragusa, A., Fichera, M. <strong>Mutational analysis of the ATRX gene by DGGE: a powerful diagnostic approach for the ATRX syndrome.</strong> Hum. Mutat. 21: 529-534, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12673795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12673795</a>] [<a href="https://doi.org/10.1002/humu.10183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12673795">Borgione et al. (2003)</a> identified 5 novel sequence changes (4 missense mutations and 1 polymorphism). All 4 mutations occurred in the helicase domain region of the gene in patients with typical features of ATRX syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12673795" 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>Partial Duplication of the ATRX Gene</em></strong></p><p>
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<a href="#49" class="mim-tip-reference" title="Thienpont, B., de Ravel, T., Van Esch, H., Van Schoubroeck, D., Moerman, P., Vermeesch, J. R., Fryns, J.-P., Froyen, G., Lacoste, C., Badens, C., Devriendt, K. <strong>Partial duplications of the ATRX gene cause the ATR-X syndrome.</strong> Europ. J. Hum. Genet. 15: 1094-1097, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17579672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17579672</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17579672">Thienpont et al. (2007)</a> reported 3 patients, including 2 sibs, with the ATRX syndrome due to partial duplications of the ATRX gene. In 1 family, the duplication included exons 2 to 35; in the other family, exons 2 to 29. Further analysis showed that both mothers carried the duplication and both had skewed X inactivation. In 1 patient, ATRX mRNA levels were about 3% of normal values. <a href="#49" class="mim-tip-reference" title="Thienpont, B., de Ravel, T., Van Esch, H., Van Schoubroeck, D., Moerman, P., Vermeesch, J. R., Fryns, J.-P., Froyen, G., Lacoste, C., Badens, C., Devriendt, K. <strong>Partial duplications of the ATRX gene cause the ATR-X syndrome.</strong> Europ. J. Hum. Genet. 15: 1094-1097, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17579672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17579672</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201878" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17579672">Thienpont et al. (2007)</a> noted that the duplications were not identified by sequence analysis and suggested that quantitative analysis to detect copy numbers of the ATRX gene may be required in some cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17579672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Cohn, D. M., Pagon, R. A., Hudgins, L., Schwartz, C. E., Stevenson, R. E., Friez, M. J. <strong>Partial ATRX gene duplication causes ATR-X syndrome. (Letter)</strong> Am. J. Med. Genet. 149A: 2317-2320, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19764021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19764021</a>] [<a href="https://doi.org/10.1002/ajmg.a.33006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19764021">Cohn et al. (2009)</a> reported a family in which 3 males had ATRX syndrome due to a partial intragenic duplication of the ATRX gene that spanned exons 2 to 31. Northern blot analysis failed to identify a full-length transcript, but cDNA sequencing was consistent with some level of expression. The authors noted that complete loss of ATRX is most likely lethal, suggesting that the mutation was likely hypomorphic and associated with some residual protein function. Unaffected obligate carrier females in the family had highly skewed X inactivation. The phenotype was typical for the disorder, although the facial features were not as readily apparent in the 2 older affected individuals. The proband was identified from 2 larger cohorts comprising 300 males with mental retardation. <a href="#16" class="mim-tip-reference" title="Cohn, D. M., Pagon, R. A., Hudgins, L., Schwartz, C. E., Stevenson, R. E., Friez, M. J. <strong>Partial ATRX gene duplication causes ATR-X syndrome. (Letter)</strong> Am. J. Med. Genet. 149A: 2317-2320, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19764021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19764021</a>] [<a href="https://doi.org/10.1002/ajmg.a.33006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19764021">Cohn et al. (2009)</a> did not find ATRX duplications in 29 additional males with ATRX syndrome who were negative on sequence analysis, suggesting that duplications are a rare cause of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19764021" 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>Intellectual Disability-Hypotonic Facies Syndrome, X-linked</em></strong></p><p>
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In a family with intellectual disability-hypotonic facies syndrome (MRXHF1; <a href="/entry/309580">309580</a>), in which affected members were originally diagnosed with Juberg-Marsidi syndrome by <a href="#35" class="mim-tip-reference" title="Mattei, J. F., Collignon, P., Ayme, S., Giraud, F. <strong>X-linked mental retardation, growth retardation, deafness and microgenitalism: a second familial report.</strong> Clin. Genet. 23: 70-74, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6682021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6682021</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1983.tb00439.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6682021">Mattei et al. (1983)</a>, <a href="#52" class="mim-tip-reference" title="Villard, L., Gecz, J., Mattei, J. F., Fontes, M., Saugier-Veber, P., Munnich, A., Lyonnet, S. <strong>XNP mutation in a large family with Juberg-Marsidi syndrome. (Letter)</strong> Nature Genet. 12: 359-360, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8630485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8630485</a>] [<a href="https://doi.org/10.1038/ng0496-359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8630485">Villard et al. (1996)</a> identified a mutation in the ATRX gene (<a href="#0011">300032.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8630485+6682021" 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 4 male cousins with MRXHF1, <a href="#24" class="mim-tip-reference" title="Guerrini, R., Shanahan, J. L., Carrozzo, R., Bonanni, P., Higgs, D. R., Gibbons, R. J. <strong>A nonsense mutation of the ATRX gene causing mild mental retardation and epilepsy.</strong> Ann. Neurol. 47: 117-121, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10632111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10632111</a>]" pmid="10632111">Guerrini et al. (2000)</a> identified a hemizygous nonsense mutation in the ATRX gene (R37X; <a href="#0022">300032.0022</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10632111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Abidi, F. E., Cardoso, C., Lossi, A.-M., Lowry, R. B., Depetris, D., Mattei, M.-G., Lubs, H. A., Stevenson, R. E., Fontes, M., Chudley, A. E., Schwartz, C. E. <strong>Mutation in the 5-prime alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome.</strong> Europ. J. Hum. Genet. 13: 176-183, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15508018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15508018</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15508018">Abidi et al. (2005)</a> identified the R37X mutation in 3 affected males with MRXHF1 who were originally reported by Chudley et al. (1988) as having Chudley-Lowry syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15508018" 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 several members of a family with MRXHF1, <a href="#58" class="mim-tip-reference" title="Wieland, H., Sabathil, J., Ostendorf, A., Rittinger, O., Ropke, A., Winnepenninckx, B., Kooy, F., Holinski-Feder, E., Wieacker, P. <strong>A missense mutation in the coiled-coil motif of the HP1-interacting domain of ATR-X in a family with X-linked mental retardation.</strong> Neurogenetics 6: 45-47, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15565397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15565397</a>] [<a href="https://doi.org/10.1007/s10048-004-0190-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15565397">Wieland et al. (2005)</a> identified a missense mutation in the ATRX gene (L409S; <a href="#0023">300032.0023</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15565397" 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>Alpha-Thalassemia Myelodysplasia Syndrome, Somatic</em></strong></p><p>
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Rarely, alpha-thalassemia occurs as an acquired abnormality in individuals with various types of multilineage myelodysplasia (<a href="#57" class="mim-tip-reference" title="Weatherall, D. J., Old, J., Longley, J., Wood, W. G., Clegg, J. B., Pollock, A., Lewis, M. J. <strong>Acquired haemoglobin H disease in leukaemia: pathophysiology and molecular basis.</strong> Brit. J. Haemat. 38: 305-322, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/273430/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">273430</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1978.tb01049.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="273430">Weatherall et al., 1978</a>; <a href="#26" class="mim-tip-reference" title="Higgs, D. R., Wood, W. G., Barton, C., Weatherall, D. J. <strong>Clinical features and molecular analysis of acquired hemoglobin H disease.</strong> Am. J. Med. 75: 181-191, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6881169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6881169</a>] [<a href="https://doi.org/10.1016/0002-9343(83)91189-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6881169">Higgs et al., 1983</a>). <a href="#22" class="mim-tip-reference" title="Gibbons, R. J., Pellagatti, A., Garrick, D., Wood, W. G., Malik, N., Ayyub, H., Langford, C., Boultwood, J., Wainscoat, J. S., Higgs, D. R. <strong>Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS).</strong> Nature Genet. 34: 446-449, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12858175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12858175</a>] [<a href="https://doi.org/10.1038/ng1213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12858175">Gibbons et al. (2003)</a> stated that 71 individuals with alpha-thalassemia myelodysplasia syndrome (ATMDS; <a href="/entry/300448">300448</a>) had been identified, of whom 62 (87%) were males who had a de novo, acquired form of alpha-thalassemia with hypochromic microcytic anemia. In these individuals, a reduction in alpha-globin expression leads to an excess of beta-globin chains, which form an abnormal hemoglobin (HbH, or beta-4) that is readily detectable in peripheral blood. In the most severely affected individuals, alpha-chain synthesis is almost abolished, implying that all 4 alpha genes are downregulated. This degree of alpha-thalassemia would be lethal during development if it resulted from an inherited mutation. No structural abnormalities in cis to the alpha-globin genes had been detected, and the downregulation of alpha-globin appeared to be associated with a trans-acting mutation. ATRX was a plausible candidate for harboring mutations associated with this syndrome. Because of the large size of the gene (300 kb) and the failure of previous direct mutational searches, <a href="#22" class="mim-tip-reference" title="Gibbons, R. J., Pellagatti, A., Garrick, D., Wood, W. G., Malik, N., Ayyub, H., Langford, C., Boultwood, J., Wainscoat, J. S., Higgs, D. R. <strong>Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS).</strong> Nature Genet. 34: 446-449, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12858175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12858175</a>] [<a href="https://doi.org/10.1038/ng1213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12858175">Gibbons et al. (2003)</a> chose microarray analysis to search for genes whose expression might be perturbed in ATMDS. In purified granulocytes from the peripheral blood they found that ATRX expression was 3 to 4% of that in normal controls. In contrast, there was no significant reduction in ATRX expression in 13 individuals with myelodysplasia syndrome with alpha-thalassemia. Sequence analysis identified a G-to-A mutation in the canonic splice donor site (GT) of intron 1 of ATRX (<a href="#0020">300032.0020</a>). This mutation was present in granulocytes but absent in DNA from both buccal cells and a lymphoblastoid cell line derived from the patient. The finding suggested that this pleiotropic cofactor is an essential component rather than a mere facilitator of globin gene expression. For many important genes, inherited null mutations are lethal early in development. The only viable manifestations of such mutations in these genes will be seen in diseases associated with acquired somatic mutations. Other examples of this, in addition to ATRX, include mutations of PIGA (<a href="/entry/311770">311770</a>) in paroxysmal nocturnal hemoglobinuria (<a href="/entry/300818">300818</a>), and GNAS1 (<a href="/entry/139320">139320</a>) in McCune-Albright syndrome (<a href="/entry/174800">174800</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=273430+12858175+6881169" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Pancreatic Neuroendocrine Tumors</em></strong></p><p>
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<a href="#29" class="mim-tip-reference" title="Jiao, Y., Shi, C., Edil, B. H., de Wilde, R. F., Klimstra, D. S., Maitra, A., Schulick, R. D., Tang, L. H., Wolfgang, C. L., Choti, M. A., Velculescu, V. E., Diaz, L. A., Jr., Vogelstein, B., Kinzler, K. W., Hruban, R. H., Papadopoulos, N. <strong>DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors.</strong> Science 331: 1199-1203, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21252315/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21252315</a>] [<a href="https://doi.org/10.1126/science.1200609" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21252315">Jiao et al. (2011)</a> explored the genetic basis of pancreatic neuroendocrine tumors (PanNETs) by determining the exomic sequence of 10 nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN1 (<a href="/entry/613733">613733</a>), and 43% had mutations in genes encoding either of the 2 subunits of a transcription/chromatin remodeling complex consisting of DAXX (death domain-associated protein, <a href="/entry/603186">603186</a>) and ATRX. Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. <a href="#29" class="mim-tip-reference" title="Jiao, Y., Shi, C., Edil, B. H., de Wilde, R. F., Klimstra, D. S., Maitra, A., Schulick, R. D., Tang, L. H., Wolfgang, C. L., Choti, M. A., Velculescu, V. E., Diaz, L. A., Jr., Vogelstein, B., Kinzler, K. W., Hruban, R. H., Papadopoulos, N. <strong>DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors.</strong> Science 331: 1199-1203, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21252315/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21252315</a>] [<a href="https://doi.org/10.1126/science.1200609" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21252315">Jiao et al. (2011)</a> also found mutations in genes in the mTOR (<a href="/entry/601231">601231</a>) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatments with mTOR inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21252315" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Heaphy, C. M., de Wilde, R. F., Jiao, Y., Klein, A. P., Edil, B. H., Shi, C., Bettegowda, C., Rodriguez, F. J., Eberhart, C. G., Hebbar, S., Offerhaus, G. J., McLendon, R., and 13 others. <strong>Altered telomeres in tumors with ATRX and DAXX mutations.</strong> Science 333: 425 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21719641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21719641</a>] [<a href="https://doi.org/10.1126/science.1207313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21719641">Heaphy et al. (2011)</a> evaluated telomere status in PanNETs in which ATRX and DAXX mutational status had been determined through Sanger sequencing. Telomere-specific FISH revealed that 25 of 41 (61%) PanNETs displayed large, ultrabright telomere FISH signals, a nearly universal feature of the telomerase-independent telomere maintenance mechanism termed alternative lengthening of telomeres. ATRX and DAXX gene mutations both were significantly correlated with ALT positivity (P less than 0.008 for each gene). All 19 (100%) PanNETs with ATRX or DAXX gene mutations were ALT-positive, whereas 6 of 20 cases without detectable mutations were ALT-positive. To ascertain whether ATRX and DAXX gene mutations might be more generally associated with the ALT phenotype, <a href="#25" class="mim-tip-reference" title="Heaphy, C. M., de Wilde, R. F., Jiao, Y., Klein, A. P., Edil, B. H., Shi, C., Bettegowda, C., Rodriguez, F. J., Eberhart, C. G., Hebbar, S., Offerhaus, G. J., McLendon, R., and 13 others. <strong>Altered telomeres in tumors with ATRX and DAXX mutations.</strong> Science 333: 425 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21719641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21719641</a>] [<a href="https://doi.org/10.1126/science.1207313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21719641">Heaphy et al. (2011)</a> examined 439 tumors of other types and found a strong correlation between inactivation of ATRX or DAXX and the ALT phenotype in unrelated tumor types. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21719641" 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>Pediatric Glioblastoma</em></strong></p><p>
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<a href="#45" class="mim-tip-reference" title="Schwartzentruber, J., Korshunov, A, Liu, X.-Y., Jones, D. T. W., Pfaff, E., Jacob, K., Sturm, D., Fontebasso, A. M., Quang, D.-A. K., Tonjes, M., Hovestadt, V., Albrecht, S., and 50 others. <strong>Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.</strong> Nature 482: 226-231, 2012. Note: Erratum: Nature 484: 130 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22286061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22286061</a>] [<a href="https://doi.org/10.1038/nature10833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22286061">Schwartzentruber et al. (2012)</a> sequenced the exomes of 48 pediatric glioblastoma (<a href="/entry/137800">137800</a>) samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodeling pathway were identified in 44% of tumors (21 of 48). Recurrent mutations in H3F3A (<a href="/entry/601128">601128</a>), which encodes the replication-independent histone-3 variant H3.3, were observed in 31% of tumors, and led to amino acid substitutions at 2 critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory posttranslational modifications. Mutations in ATRX and DAXX, encoding 2 subunits of a chromatin remodeling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumors harboring a G34R or G34V H3.3 mutation. Somatic TP53 (<a href="/entry/191170">191170</a>) mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to glioblastoma multiforme and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. <a href="#45" class="mim-tip-reference" title="Schwartzentruber, J., Korshunov, A, Liu, X.-Y., Jones, D. T. W., Pfaff, E., Jacob, K., Sturm, D., Fontebasso, A. M., Quang, D.-A. K., Tonjes, M., Hovestadt, V., Albrecht, S., and 50 others. <strong>Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.</strong> Nature 482: 226-231, 2012. Note: Erratum: Nature 484: 130 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22286061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22286061</a>] [<a href="https://doi.org/10.1038/nature10833" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22286061">Schwartzentruber et al. (2012)</a> stated that this was the first report to highlight recurrent mutations in a regulatory histone in humans, and that their data suggested that defects of the chromatin architecture underlie pediatric and young adult glioblastoma multiforme pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22286061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a review article, <a href="#20" class="mim-tip-reference" title="Gibbons, R. J., Higgs, D. R. <strong>Molecular-clinical spectrum of the ATR-X syndrome.</strong> Am. J. Med. Genet. 97: 204-212, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11449489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11449489</a>] [<a href="https://doi.org/10.1002/1096-8628(200023)97:3<204::AID-AJMG1038>3.0.CO;2-X" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11449489">Gibbons and Higgs (2000)</a> noted that mutations resulting in the loss of the C-terminal domain are associated with the most severe urogenital abnormalities. However, at other sites, there is no obvious link between genotype and phenotype, and there is considerable variation in the degree of abnormalities seen in individuals with the same mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11449489" 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>Among 22 ATRX patients from 16 families, <a href="#5" class="mim-tip-reference" title="Badens, C., Lacoste, C., Philip, N., Martini, N., Courrier, S., Giuliano, F., Verloes, A., Munnich, A., Leheup, B., Burglen, L., Odent, S., Van Esch, H., Levy, N. <strong>Mutations in PHD-like domain of the ATRX gene correlate with severe psychomotor impairment and severe urogenital abnormalities in patients with ATRX syndrome.</strong> Clin. Genet. 70: 57-62, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16813605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16813605</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00641.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16813605">Badens et al. (2006)</a> found that those with mutations in the PHD-like domain of the ATRX protein had significantly more severe and permanent psychomotor retardation and significantly more severe urogenital anomalies compared to those with mutations in the helicase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16813605" 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>Extreme skewing of X-chromosome inactivation (XCI) is rare in the normal female population but is observed frequently in carriers of some X-linked mutations. <a href="#43" class="mim-tip-reference" title="Plenge, R. M., Stevenson, R. A., Lubs, H. A., Schwartz, C. E., Willard, H. F. <strong>Skewed X-chromosome inactivation is a common feature of X-linked mental retardation disorders.</strong> Am. J. Hum. Genet. 71: 168-173, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12068376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12068376</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12068376[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/341123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12068376">Plenge et al. (2002)</a> showed that various forms of X-linked mental retardation (XLMR) have a strong association with skewed XCI in female carriers. The ATRX syndrome is one such disorder; phenotypically normal female carriers virtually all have highly skewed XCI biased against the X chromosome that harbors the mutant allele. <a href="#38" class="mim-tip-reference" title="Muers, M. R., Sharpe, J. A., Garrick, D., Sloane-Stanley, J., Nolan, P. M., Hacker, T., Wood, W. G., Higgs, D. R., Gibbons, R. J. <strong>Defining the cause of skewed X-chromosome inactivation in X-linked mental retardation by use of a mouse model.</strong> Am. J. Hum. Genet. 80: 1138-1149, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17503331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17503331</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17503331[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/518369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17503331">Muers et al. (2007)</a> used a mouse model to understand the processes causing skewed XCI. In female mice heterozygous for a null Atrx allele, they found that XCI is balanced early in embryogenesis but becomes skewed over the course of development, because of selection favoring cells expressing the wildtype Atrx allele. Unexpectedly, selection did not appear to be the result of general cellular viability defects in Atrx-deficient cells, since it was restricted to specific stages of development and was not ongoing throughout the life of the animal. Instead, there was evidence that selection results from independent tissue-specific effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12068376+17503331" 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>Although the ATRX protein is a member of the SWI/SNF family of chromatin remodeling proteins, little is known about the biochemical activity of the ATRX protein or its in vivo function during development. <a href="#8" class="mim-tip-reference" title="Berube, N. G., Jagla, M., Smeenk, C., De Repentigny, Y., Kothary, R., Picketts, D. J. <strong>Neurodevelopmental defects resulting from ATRX overexpression in transgenic mice.</strong> Hum. Molec. Genet. 11: 253-261, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823444</a>] [<a href="https://doi.org/10.1093/hmg/11.3.253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11823444">Berube et al. (2002)</a> demonstrated that ATRX is part of a large multiprotein complex similar in size to the SWI/SNF complex. Overexpression of ATRX in transgenic mice was associated with growth retardation, neural tube defects, and a high incidence of embryonic death. Moreover, brains from E10.5 transgenic embryos displayed abnormal growth and organization of the ventricular zone that was highly convoluted in the most severely affected embryos. Transgenic mice that survived to birth exhibited a high incidence of perinatal death as well as seizures, mild craniofacial anomalies, and abnormal behavior. The authors concluded that ATRX dosage is crucial for normal development and organization of the cortex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11823444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By immunostaining for Atrx in mouse brain, <a href="#9" class="mim-tip-reference" title="Berube, N. G., Mangelsdorf, M., Jagla, M., Vanderluit, J., Garrick, D., Gibbons, R. J., Higgs, D. R., Slack, R. S., Picketts, D. J. <strong>The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis.</strong> J. Clin. Invest. 115: 258-267, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15668733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15668733</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15668733[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/10.1172/JCI22329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15668733">Berube et al. (2005)</a> found that Atrx expression was nuclear in all cells and coincided with regions of intense DAPI staining, consistent with a heterochromatin colocalization. The temporal pattern of Atrx expression followed the process of neuroprogenitor differentiation. To circumvent early lethality in Atrx-null mice, <a href="#9" class="mim-tip-reference" title="Berube, N. G., Mangelsdorf, M., Jagla, M., Vanderluit, J., Garrick, D., Gibbons, R. J., Higgs, D. R., Slack, R. S., Picketts, D. J. <strong>The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis.</strong> J. Clin. Invest. 115: 258-267, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15668733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15668733</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15668733[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/10.1172/JCI22329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15668733">Berube et al. (2005)</a> developed mice with forebrain-targeted conditional loss of Atrx expression. Targeted loss of Atrx caused widespread hypocellularity in the neocortex and hippocampus and a pronounced reduction in forebrain size. Neuronal 'birthdating' confirmed that fewer neurons reached the superficial cortical layers, despite normal progenitor cell proliferation. The loss of cortical mass resulted from a 12-fold increase in neuronal apoptosis during early stages of corticogenesis in the mutant animals. Cultured cortical progenitor cells isolated from Atrx-null mice underwent enhanced apoptosis upon differentiation. <a href="#9" class="mim-tip-reference" title="Berube, N. G., Mangelsdorf, M., Jagla, M., Vanderluit, J., Garrick, D., Gibbons, R. J., Higgs, D. R., Slack, R. S., Picketts, D. J. <strong>The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis.</strong> J. Clin. Invest. 115: 258-267, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15668733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15668733</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15668733[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/10.1172/JCI22329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15668733">Berube et al. (2005)</a> concluded that Atrx is a critical mediator of cell survival during early neuronal differentiation and that neuronal loss may contribute to the mental retardation observed in ATRX syndrome patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15668733" 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="#37" class="mim-tip-reference" title="Medina, C. F., Mazerolle, C., Wang, Y., Berube, N. G., Coupland, S., Gibbons, R. J., Wallace, V. A., Picketts, D. J. <strong>Altered visual function and interneuron survival in Atrx knockout mice: inference for the human syndrome.</strong> Hum. Molec. Genet. 18: 966-977, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19088125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19088125</a>] [<a href="https://doi.org/10.1093/hmg/ddn424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19088125">Medina et al. (2009)</a> surveyed ATRX syndrome clinical findings and noted that ocular defects were present in 47 (23%) of 202 patients. They showed that Atrx was expressed in the neuroprogenitor pool in embryonic mouse retina and in all cell types of adult mouse retina except rod photoreceptors. Conditional inactivation of Atrx in mouse retina during embryogenesis resulted in loss of only 2 types of neurons, amacrine and horizontal cells. This defect did not arise from a failure to specify these cells, but rather a defect in interneuron differentiation and survival postnatally. The timing of cell loss was concomitant with light-dependent changes in synaptic organization in mouse retina and with a change in Atrx subnuclear localization within these interneurons. The interneuron defects were associated with functional deficits as demonstrated by reduced b-wave amplitudes upon electroretinogram analysis. <a href="#37" class="mim-tip-reference" title="Medina, C. F., Mazerolle, C., Wang, Y., Berube, N. G., Coupland, S., Gibbons, R. J., Wallace, V. A., Picketts, D. J. <strong>Altered visual function and interneuron survival in Atrx knockout mice: inference for the human syndrome.</strong> Hum. Molec. Genet. 18: 966-977, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19088125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19088125</a>] [<a href="https://doi.org/10.1093/hmg/ddn424" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19088125">Medina et al. (2009)</a> proposed a role for Atrx in interneuron survival and differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19088125" 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">rs122445093 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445093;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=rs122445093" 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=rs122445093" 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=RCV000012487 OR RCV002285255" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012487, RCV002285255" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012487...</a>
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<p>In a patient with the ATRX syndrome (<a href="/entry/301040">301040</a>), <a href="#23" class="mim-tip-reference" title="Gibbons, R. J., Picketts, D. J., Villard, L., Higgs, D. R. <strong>Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).</strong> Cell 80: 837-845, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7697714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7697714</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90287-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7697714">Gibbons et al. (1995)</a> identified a 2302A-G transition in the XH2 gene, resulting in a his750-to-arg (H750R) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7697714" 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 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</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">rs122445094 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445094;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=rs122445094" 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=rs122445094" 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=RCV000012488" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012488" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012488</a>
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<p>In a patient with the ATRX syndrome (<a href="/entry/301040">301040</a>), <a href="#23" class="mim-tip-reference" title="Gibbons, R. J., Picketts, D. J., Villard, L., Higgs, D. R. <strong>Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).</strong> Cell 80: 837-845, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7697714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7697714</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90287-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7697714">Gibbons et al. (1995)</a> identified a 2316T-C transition in the XH2 gene, resulting in a cys755-to-arg (C755R) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7697714" 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 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
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ATRX, LYS792ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs122445095 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445095;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=rs122445095" 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=rs122445095" 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=RCV000012489" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012489" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012489</a>
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<span class="mim-text-font">
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<p>In a patient with the ATRX syndrome (<a href="/entry/301040">301040</a>), <a href="#23" class="mim-tip-reference" title="Gibbons, R. J., Picketts, D. J., Villard, L., Higgs, D. R. <strong>Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).</strong> Cell 80: 837-845, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7697714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7697714</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90287-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7697714">Gibbons et al. (1995)</a> identified a 2429G-T transversion in the XH2 gene, resulting in a lys792-to-asn (K792N) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7697714" 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>.0004 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
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ATRX, ASN1002SER
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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> rs45439799 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs45439799;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/rs45439799?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=rs45439799" 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=rs45439799" 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=RCV000012490 OR RCV000078966 OR RCV000428077 OR RCV000588578 OR RCV000590248 OR RCV002311512 OR RCV004593961" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012490, RCV000078966, RCV000428077, RCV000588578, RCV000590248, RCV002311512, RCV004593961" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012490...</a>
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<span class="mim-text-font">
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<p>In a patient with the ATRX syndrome (<a href="/entry/301040">301040</a>), <a href="#23" class="mim-tip-reference" title="Gibbons, R. J., Picketts, D. J., Villard, L., Higgs, D. R. <strong>Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).</strong> Cell 80: 837-845, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7697714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7697714</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90287-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7697714">Gibbons et al. (1995)</a> identified a 3058A-G transition in the XH2 gene, resulting in an asn1002-to-ser (N1002S) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7697714" 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>.0005 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
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ATRX, ASP1177VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs122445096 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445096;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=rs122445096" 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=rs122445096" 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=RCV000012491" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012491" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012491</a>
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<p>In a patient with the ATRX syndrome (<a href="/entry/301040">301040</a>), <a href="#23" class="mim-tip-reference" title="Gibbons, R. J., Picketts, D. J., Villard, L., Higgs, D. R. <strong>Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).</strong> Cell 80: 837-845, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7697714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7697714</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90287-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7697714">Gibbons et al. (1995)</a> identified a 3583A-T transversion in the XH2 gene, leading to an asp1177-to-val (D1177V) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7697714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
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ATRX, TYR1226HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs122445097 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445097;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=rs122445097" 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=rs122445097" 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=RCV000012492" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012492" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012492</a>
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<p>In a patient with the ATRX syndrome (<a href="/entry/301040">301040</a>), <a href="#23" class="mim-tip-reference" title="Gibbons, R. J., Picketts, D. J., Villard, L., Higgs, D. R. <strong>Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).</strong> Cell 80: 837-845, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7697714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7697714</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90287-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7697714">Gibbons et al. (1995)</a> identified a 3729T-C transition in the XH2 gene, leading to a tyr1226-to-his (Y1226H) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7697714" 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 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</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">rs122445098 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445098;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=rs122445098" 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=rs122445098" 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=RCV000012493" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012493" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012493</a>
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<p>In a patient with the ATRX syndrome (<a href="/entry/301040">301040</a>), <a href="#23" class="mim-tip-reference" title="Gibbons, R. J., Picketts, D. J., Villard, L., Higgs, D. R. <strong>Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).</strong> Cell 80: 837-845, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7697714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7697714</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90287-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7697714">Gibbons et al. (1995)</a> identified a 3967A-G transition in the XH2 gene, leading to a tyr1305-to-cys (Y1305C) amino acid change. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7697714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
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ATRX, ARG1528TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs122445099 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445099;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=rs122445099" 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=rs122445099" 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=RCV000012494 OR RCV000723525 OR RCV002283442 OR RCV004532323 OR RCV005055347" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012494, RCV000723525, RCV002283442, RCV004532323, RCV005055347" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012494...</a>
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<p>In a patient with the ATRX syndrome (<a href="/entry/301040">301040</a>), <a href="#23" class="mim-tip-reference" title="Gibbons, R. J., Picketts, D. J., Villard, L., Higgs, D. R. <strong>Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).</strong> Cell 80: 837-845, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7697714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7697714</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90287-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7697714">Gibbons et al. (1995)</a> identified a 4635C-T transition in the XH2 gene, leading to premature termination of the polypeptide at codon 1528 (R1528X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7697714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
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ATRX, GLU1530TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs122445100 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445100;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=rs122445100" 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=rs122445100" 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=RCV000012495" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012495" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012495</a>
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<p>In a patient with the ATRX syndrome (<a href="/entry/301040">301040</a>), <a href="#23" class="mim-tip-reference" title="Gibbons, R. J., Picketts, D. J., Villard, L., Higgs, D. R. <strong>Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome).</strong> Cell 80: 837-845, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7697714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7697714</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90287-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7697714">Gibbons et al. (1995)</a> identified a 4641G-T transversion in the XH2 gene, resulting in a glu1530-to-ter (E1530X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7697714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
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ATRX, IVSAS, T-A, -10
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2148261114 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2148261114;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=rs2148261114" 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=rs2148261114" 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=RCV000012496" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012496" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012496</a>
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<p>In affected members of a family with ATRX syndrome (<a href="/entry/301040">301040</a>), <a href="#55" class="mim-tip-reference" title="Villard, L., Toutain, A., Lossi, A.-M., Gecz, J., Houdayer, C., Moraine, C., Fontes, M. <strong>Splicing mutation in the ATR-X gene can lead to a dysmorphic mental retardation phenotype without alpha-thalassemia.</strong> Am. J. Hum. Genet. 58: 499-505, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644709</a>]" pmid="8644709">Villard et al. (1996)</a> identified a T-to-A transversion in the XH2 gene in the consensus splice acceptor site at position -10 on the upstream side of the deleted 176-bp exon, resulting in a premature stop codon and a shortened protein with 638 amino acids. In 2 first cousins presenting the classic ATRX phenotype with alpha-thalassemia and Hb H inclusions, only the abnormal transcript was expressed. In a distant cousin presenting with a similar dysmorphic mental retardation phenotype, but without thalassemia, they found that approximately 30% of the XH2 transcripts were normal. These data suggested that the mode of action of the XH2 gene product on globin expression is distinct from its mode of action in brain development and facial morphogenesis. The mothers of the patients were found to be heterozygotes. It appeared that the mutated splice site could be used with varying efficiency in different individuals. <a href="#30" class="mim-tip-reference" title="Kiesewetter, S., Macek, M., Jr., Davis, C., Curristin, S. M., Chu, C.-S., Graham, C., Shrimpton, A. E., Cashman, S. M., Tsui, L.-C., Mickle, J., Amos, J., Highsmith, W. E., Shuber, A., Witt, D. R., Crystal, R. G., Cutting, G. R. <strong>A mutation in CFTR produces different phenotypes depending on chromosomal background.</strong> Nature Genet. 5: 274-278, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7506096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7506096</a>] [<a href="https://doi.org/10.1038/ng1193-274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7506096">Kiesewetter et al. (1993)</a> reported the same missense mutation in the cystic fibrosis gene, in which it leads to different phenotypes, depending on the genetic background in which the mutation was segregating. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8644709+7506096" 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="0011" class="mim-anchor"></a>
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<strong>.0011 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</strong>
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ATRX, ARG1272GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs122445101 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445101;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=rs122445101" 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=rs122445101" 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=RCV000012497 OR RCV000199096 OR RCV002272014 OR RCV004528102" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012497, RCV000199096, RCV002272014, RCV004528102" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012497...</a>
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<p>In affected members of a large family with intellectual disability-hypotonic facies syndrome (MRXHF1; <a href="/entry/309580">309580</a>), who originally had a diagnosis of Juberg-Marsidi syndrome (<a href="#35" class="mim-tip-reference" title="Mattei, J. F., Collignon, P., Ayme, S., Giraud, F. <strong>X-linked mental retardation, growth retardation, deafness and microgenitalism: a second familial report.</strong> Clin. Genet. 23: 70-74, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6682021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6682021</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1983.tb00439.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6682021">Mattei et al., 1983</a>), <a href="#52" class="mim-tip-reference" title="Villard, L., Gecz, J., Mattei, J. F., Fontes, M., Saugier-Veber, P., Munnich, A., Lyonnet, S. <strong>XNP mutation in a large family with Juberg-Marsidi syndrome. (Letter)</strong> Nature Genet. 12: 359-360, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8630485/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8630485</a>] [<a href="https://doi.org/10.1038/ng0496-359" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8630485">Villard et al. (1996)</a> identified a mutation in the XH2 gene, resulting in an arg1272-to-gln (R1272Q) substitution in the highly conserved helicase V domain. The helicase V domain was known to be involved in transcriptional control in yeast. Furthermore, the change of amino acid arg1272, which is highly conserved among species from yeast to human, alters the overall charge of the domain. In the family studied, the mutant X chromosome was consistently inactivated in carriers as it is in the ATRX syndrome. This suggested to the authors that the XNP protein either plays a role in a fundamental cellular process, such as X inactivation or cell division, or has a nonspecific deleterious effect with clonal selection of the normal XNP allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8630485+6682021" 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="0012" class="mim-anchor"></a>
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<strong>.0012 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</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">rs122445102 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445102;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=rs122445102" 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=rs122445102" 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=RCV000012498" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012498" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012498</a>
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<p>In a proband and a maternal uncle with X-linked intellectual disability-hypotonic face syndrome (MRXHF1; <a href="/entry/309580">309580</a>), <a href="#53" class="mim-tip-reference" title="Villard, L., Lacombe, D., Fontes, M. <strong>A point mutation in the XNP gene, associated with an ATR-X phenotype without alpha-thalassemia.</strong> Europ. J. Hum. Genet. 4: 316-320, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9043863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9043863</a>] [<a href="https://doi.org/10.1159/000472225" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9043863">Villard et al. (1996)</a> identified a pro852-to-ser (P852S) substitution in the ATRX gene in a highly-conserved region of helicase domain II. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9043863" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</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">rs1569539477 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569539477;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=rs1569539477" 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=rs1569539477" 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=RCV000012499" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012499" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012499</a>
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<p>In a sporadic case presenting with a typical ATRX phenotype (<a href="/entry/301040">301040</a>), <a href="#54" class="mim-tip-reference" title="Villard, L., Lossi, A.-M., Cardoso, C., Proud, V., Chiaroni, P., Colleaux, L., Schwartz, C., Fontes, M. <strong>Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase.</strong> Genomics 43: 149-155, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9244431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9244431</a>] [<a href="https://doi.org/10.1006/geno.1997.4793" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9244431">Villard et al. (1997)</a> found that the 2 alternatively spliced transcripts of ATRX were smaller than expected. DNA sequencing identified a 751A-G transition in the ATRX gene. This mutation created an effective splicing site with a consensus value (<a href="#46" class="mim-tip-reference" title="Shapiro, M. B., Senapathy, P. <strong>RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression.</strong> Nucleic Acids Res. 15: 7155-7174, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3658675/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3658675</a>] [<a href="https://doi.org/10.1093/nar/15.17.7155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3658675">Shapiro and Senapathy, 1987</a>) of 0.9, which is a higher value than that for the usual donor splicing site (0.85) or the nonmutated cryptic site (0.77), probably allowing it to be more efficiently used in vivo than the normal donor site. The event leads to a potential protein missing 21 amino acids. The missing part of the transcript corresponded to the first zinc finger of the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9244431+3658675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
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ATRX, PRO73ALA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs122445103 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445103;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=rs122445103" 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=rs122445103" 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=RCV000012500 OR RCV000197579" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012500, RCV000197579" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012500...</a>
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<p>In a patient with ATRX syndrome (<a href="/entry/301040">301040</a>), <a href="#19" class="mim-tip-reference" title="Gibbons, R. J., Bachoo, S., Picketts, D. J., Aftimos, S., Asenbauer, B., Bergoffen, J., Berry, S. A., Dahl, N., Fryer, A., Keppler, K., Kurosawa, K., Levin, M. L., Masuno, M., Neri, G., Pierpont, M. E., Slaney, S. F., Higgs, D. R. <strong>Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain. (Letter)</strong> Nature Genet. 17: 146-148, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326931</a>] [<a href="https://doi.org/10.1038/ng1097-146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326931">Gibbons et al. (1997)</a> identified a 901C-G transversion in the XH2 gene, resulting in a pro73-to-ala (P73A) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9326931" 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>.0015 MOVED TO <a href="/entry/300032#0018">300032.0018</a></strong>
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<strong>.0016 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
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ATRX, ARG1742LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs122445104 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445104;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=rs122445104" 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=rs122445104" 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=RCV000012502" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012502" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012502</a>
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<p>In affected patients from a family with ATRX syndrome (<a href="/entry/301040">301040</a>) reported by <a href="#34" class="mim-tip-reference" title="Martinez, F., Tomas, M., Millan, J. M., Fernandez, A., Palau, F., Prieto, F. <strong>Genetic localisation of mental retardation with spastic diplegia to the pericentromeric region of the X chromosome: X inactivation in female carriers.</strong> J. Med. Genet. 35: 284-287, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9598720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9598720</a>] [<a href="https://doi.org/10.1136/jmg.35.4.284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9598720">Martinez et al. (1998)</a>, <a href="#33" class="mim-tip-reference" title="Lossi, A. M., Millan, J. M., Villard, L., Orellana, C., Cardoso, C., Prieto, F., Fontes, M., Martinez, F. <strong>Mutation of the XNP/ATR-X gene in a family with severe mental retardation, spastic paraplegia and skewed pattern of X inactivation: demonstration that the mutation is involved in the inactivation bias. (Letter)</strong> Am. J. Hum. Genet. 65: 558-562, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10417298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10417298</a>] [<a href="https://doi.org/10.1086/302499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10417298">Lossi et al. (1999)</a> identified a 5459G-A transition in the XH2 gene, resulting in an arg1742-to-lys (R1742K) substitution in the conserved helicase domain III. Affected patients showed hypertonia from birth and spasticity, which are unusual findings in ATRX syndrome. Haplotype analysis identified 2 females who shared the disease-associated haplotype, spanning both the ATRX gene and the X-inactivation center, but lacking the R1742K mutation. <a href="#33" class="mim-tip-reference" title="Lossi, A. M., Millan, J. M., Villard, L., Orellana, C., Cardoso, C., Prieto, F., Fontes, M., Martinez, F. <strong>Mutation of the XNP/ATR-X gene in a family with severe mental retardation, spastic paraplegia and skewed pattern of X inactivation: demonstration that the mutation is involved in the inactivation bias. (Letter)</strong> Am. J. Hum. Genet. 65: 558-562, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10417298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10417298</a>] [<a href="https://doi.org/10.1086/302499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10417298">Lossi et al. (1999)</a> deduced that the mutation arose de novo in the germline of 1 member of the founding couple. Furthermore, the fact that females in the nonmutated branch of the family did not exhibit a skewed pattern of X inactivation demonstrated that the skewing in carrier females was directly linked to the presence of the mutation in the gene. <a href="#33" class="mim-tip-reference" title="Lossi, A. M., Millan, J. M., Villard, L., Orellana, C., Cardoso, C., Prieto, F., Fontes, M., Martinez, F. <strong>Mutation of the XNP/ATR-X gene in a family with severe mental retardation, spastic paraplegia and skewed pattern of X inactivation: demonstration that the mutation is involved in the inactivation bias. (Letter)</strong> Am. J. Hum. Genet. 65: 558-562, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10417298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10417298</a>] [<a href="https://doi.org/10.1086/302499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10417298">Lossi et al. (1999)</a> stated that this was the first reported instance in which negative selection against the cells expressing an abnormal gene product in females did not imply a male lethal condition. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10417298+9598720" 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>.0017 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</strong>
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ATRX, IVS34, A-G, -2
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1569513021 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1569513021;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=rs1569513021" 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=rs1569513021" 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=RCV000012503" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012503" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012503</a>
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<p><a href="#51" class="mim-tip-reference" title="Villard, L., Fontes, M., Ades, L. C., Gecz, J. <strong>Identification of a mutation in the XNP/ATR-X gene in a family reported as Smith-Fineman-Myers syndrome. (Letter)</strong> Am. J. Med. Genet. 91: 83-85, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10751095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10751095</a>]" pmid="10751095">Villard et al. (2000)</a> demonstrated that 2 brothers reported by <a href="#3" class="mim-tip-reference" title="Ades, L. C., Kerr, B., Turner, G., Wise, G. <strong>Smith-Fineman-Myers syndrome in two brothers.</strong> Am. J. Med. Genet. 40: 467-470, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684092</a>] [<a href="https://doi.org/10.1002/ajmg.1320400419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1684092">Ades et al. (1991)</a> as having the Smith-Fineman-Myers type of mental retardation (MRXHF1; <a href="/entry/309580">309580</a>) had a mutation in the ATRX gene: the acceptor splice site of intron 34 was affected, causing a frameshift and the replacement of the 92 amino acids encoded by exon 35 in the wildtype transcript by 46 different amino acids. Three previous mutations had been reported to affect this last exon of the gene. In 2 of the 3, the affected patients presented severe urogenital anomalies which led to female gender assignment. The brothers reported by <a href="#3" class="mim-tip-reference" title="Ades, L. C., Kerr, B., Turner, G., Wise, G. <strong>Smith-Fineman-Myers syndrome in two brothers.</strong> Am. J. Med. Genet. 40: 467-470, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684092</a>] [<a href="https://doi.org/10.1002/ajmg.1320400419" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1684092">Ades et al. (1991)</a> and <a href="#51" class="mim-tip-reference" title="Villard, L., Fontes, M., Ades, L. C., Gecz, J. <strong>Identification of a mutation in the XNP/ATR-X gene in a family reported as Smith-Fineman-Myers syndrome. (Letter)</strong> Am. J. Med. Genet. 91: 83-85, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10751095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10751095</a>]" pmid="10751095">Villard et al. (2000)</a> had bilateral cryptorchidism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10751095+1684092" 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">rs122445105 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445105;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=rs122445105" 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=rs122445105" 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=RCV000012501 OR RCV000078972 OR RCV000190796 OR RCV000763634 OR RCV001249275 OR RCV001252427" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012501, RCV000078972, RCV000190796, RCV000763634, RCV001249275, RCV001252427" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012501...</a>
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<p>In 2 presumably unrelated Japanese patients with ATRX syndrome (<a href="/entry/301040">301040</a>), <a href="#56" class="mim-tip-reference" title="Wada, T., Kubota, T., Fukushima, Y., Saitoh, S. <strong>Molecular genetic study of Japanese patients with X-linked alpha-thalassemia/mental retardation syndrome (ATR-X).</strong> Am. J. Med. Genet. 94: 242-248, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10995512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10995512</a>]" pmid="10995512">Wada et al. (2000)</a> identified a mutation in the ATRX gene, resulting in an arg246-to-cys (R246C) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10995512" 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="#56" class="mim-tip-reference" title="Wada, T., Kubota, T., Fukushima, Y., Saitoh, S. <strong>Molecular genetic study of Japanese patients with X-linked alpha-thalassemia/mental retardation syndrome (ATR-X).</strong> Am. J. Med. Genet. 94: 242-248, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10995512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10995512</a>]" pmid="10995512">Wada et al. (2000)</a> noted that the R246C mutation had previously been reported by <a href="#19" class="mim-tip-reference" title="Gibbons, R. J., Bachoo, S., Picketts, D. J., Aftimos, S., Asenbauer, B., Bergoffen, J., Berry, S. A., Dahl, N., Fryer, A., Keppler, K., Kurosawa, K., Levin, M. L., Masuno, M., Neri, G., Pierpont, M. E., Slaney, S. F., Higgs, D. R. <strong>Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain. (Letter)</strong> Nature Genet. 17: 146-148, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326931</a>] [<a href="https://doi.org/10.1038/ng1097-146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326931">Gibbons et al. (1997)</a> in 15 pedigrees. <a href="#19" class="mim-tip-reference" title="Gibbons, R. J., Bachoo, S., Picketts, D. J., Aftimos, S., Asenbauer, B., Bergoffen, J., Berry, S. A., Dahl, N., Fryer, A., Keppler, K., Kurosawa, K., Levin, M. L., Masuno, M., Neri, G., Pierpont, M. E., Slaney, S. F., Higgs, D. R. <strong>Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain. (Letter)</strong> Nature Genet. 17: 146-148, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9326931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9326931</a>] [<a href="https://doi.org/10.1038/ng1097-146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9326931">Gibbons et al. (1997)</a> reported the mutation as a 1069C-T transition, resulting in an arg129-to-cys (R129C) substitution. The mutation was de novo in 3 cases. The proportion of cells with Hb H inclusions ranged from 0.006 to 14% in these pedigrees with an identical mutation. The mutation occurred in a CpG dinucleotide. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9326931+10995512" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Badens, C., Martini, N., Courrier, S., DesPortes, V., Touraine, R., Levy, N., Edery, P. <strong>ATRX syndrome in a girl with a heterozygous mutation in the ATRX Zn finger domain and a totally skewed X-inactivation pattern.</strong> Am. J. Med. Genet. 140A: 2212-2215, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16955409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16955409</a>] [<a href="https://doi.org/10.1002/ajmg.a.31400" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16955409">Badens et al. (2006)</a> reported a 4-year-old girl with typical features of the ATRX syndrome. Molecular studies showed a totally skewed X-inactivation pattern with the active chromosome carrying a heterozygous R246C mutation, resulting from a 951C-T transition in the zinc finger domain-coding region of the ATRX gene. Neither parent had the mutation in peripheral blood leukocytes, but SNP analysis indicated that the mutation occurred on the maternal chromosome. The child was conceived with assisted reproduction technologies (ART) due to micropolycystic ovaries and endometriosis in the mother. <a href="#6" class="mim-tip-reference" title="Badens, C., Martini, N., Courrier, S., DesPortes, V., Touraine, R., Levy, N., Edery, P. <strong>ATRX syndrome in a girl with a heterozygous mutation in the ATRX Zn finger domain and a totally skewed X-inactivation pattern.</strong> Am. J. Med. Genet. 140A: 2212-2215, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16955409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16955409</a>] [<a href="https://doi.org/10.1002/ajmg.a.31400" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16955409">Badens et al. (2006)</a> suggested that some aspect of ART may have disturbed imprinting in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16955409" 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>.0019 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</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"><span class="text-primary">●</span> rs122445106 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445106;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/rs122445106?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=rs122445106" 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=rs122445106" 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=RCV000012505 OR RCV003128081 OR RCV004734510" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012505, RCV003128081, RCV004734510" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012505...</a>
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<p><a href="#59" class="mim-tip-reference" title="Yntema, H. G., Poppelaars, F. A., Derksen, E., Oudakker, A. R., van Roosmalen, T., Jacobs, A., Obbema, H., Brunner, H. G., Hamel, B. C. J., van Bokhoven, H. <strong>Expanding phenotype of XNP mutations: mild to moderate mental retardation.</strong> Am. J. Med. Genet. 110: 243-247, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12116232/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12116232</a>] [<a href="https://doi.org/10.1002/ajmg.10446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12116232">Yntema et al. (2002)</a> identified a thr1621-to-met (T1621M) missense mutation in the ATRX gene in a patient from a family in which most affected members had only mild mental retardation and no obvious facial dysmorphisms. Linkage analysis showed a maximum lod score of 3.9 at theta = 0.0 for linkage to the ATRX locus. Subsequent analysis of red blood cells revealed hemoglobin H inclusion bodies. Furthermore, X-inactivation studies revealed extreme skewing of X-inactivation in carrier females. In retrospect, facial hypotonia was recognized in pictures taken in childhood, a usual finding in the ATRX syndrome (<a href="/entry/301040">301040</a>), but this feature was not seen in adulthood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12116232" 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>.0020 ALPHA-THALASSEMIA MYELODYSPLASIA SYNDROME, SOMATIC</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">rs587776756 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776756;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=rs587776756" 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=rs587776756" 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=RCV000012506" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012506" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012506</a>
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<p>In a case of alpha-thalassemia myelodysplasia syndrome (ATMDS; <a href="/entry/300448">300448</a>), <a href="#22" class="mim-tip-reference" title="Gibbons, R. J., Pellagatti, A., Garrick, D., Wood, W. G., Malik, N., Ayyub, H., Langford, C., Boultwood, J., Wainscoat, J. S., Higgs, D. R. <strong>Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS).</strong> Nature Genet. 34: 446-449, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12858175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12858175</a>] [<a href="https://doi.org/10.1038/ng1213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12858175">Gibbons et al. (2003)</a> identified a G-to-A transition in the canonic splice donor site (GT) of intron 1 of the ATRX gene. The mutation was present in granulocytes but absent in DNA from both buccal cells and a lymphoblastoid cell line derived from the patient. Because ATMDS is a clonal disorder affecting myeloid progenitors, DNA isolated from the unfractionated white cells (granulocytes and lymphocytes) in peripheral blood had a mixture of mutant and wildtype sequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12858175" 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">rs122445107 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445107;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=rs122445107" 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=rs122445107" 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=RCV000012507" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012507" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012507</a>
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<p>In bone marrow cDNA from a patient with alpha-thalassemia myelodysplasia syndrome (ATMDS; <a href="/entry/300448">300448</a>), <a href="#22" class="mim-tip-reference" title="Gibbons, R. J., Pellagatti, A., Garrick, D., Wood, W. G., Malik, N., Ayyub, H., Langford, C., Boultwood, J., Wainscoat, J. S., Higgs, D. R. <strong>Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS).</strong> Nature Genet. 34: 446-449, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12858175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12858175</a>] [<a href="https://doi.org/10.1038/ng1213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12858175">Gibbons et al. (2003)</a> found a C-to-G transversion in exon 4 of the ATRX gene, resulting in a ser79-to-ter (S79X) substitution. A mixture of mutant and wildtype sequence in DNA from bone marrow and peripheral blood was found. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12858175" 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>.0022 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</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">rs122445108 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445108;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=rs122445108" 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=rs122445108" 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=RCV000012508 OR RCV000148028 OR RCV000224314 OR RCV000680146 OR RCV002444427 OR RCV003151722 OR RCV004795394" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012508, RCV000148028, RCV000224314, RCV000680146, RCV002444427, RCV003151722, RCV004795394" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012508...</a>
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<p>In 4 male cousins with the X-linked intellectual disability-hypotonic facies syndrome (MRXHF1; <a href="/entry/309580">309580</a>), <a href="#24" class="mim-tip-reference" title="Guerrini, R., Shanahan, J. L., Carrozzo, R., Bonanni, P., Higgs, D. R., Gibbons, R. J. <strong>A nonsense mutation of the ATRX gene causing mild mental retardation and epilepsy.</strong> Ann. Neurol. 47: 117-121, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10632111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10632111</a>]" pmid="10632111">Guerrini et al. (2000)</a> identified a 109C-T transition in exon 2 of the ATRX gene, resulting in an arg37-to-ter (R37X) substitution. Two patients had moderate to profound mental retardation and the typical facial features of the syndrome, whereas the other 2 patients presented with mild mental retardation and epilepsy, but without the characteristic facial dysmorphism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10632111" 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="#28" class="mim-tip-reference" title="Howard, M. T., Malik, N., Anderson, C. B., Voskuil, J. L. A., Atkins, J. F., Gibbons, R. J. <strong>Attenuation of an amino-terminal premature stop codon mutation in the ATRX gene by an alternative mode of translational initiation. (Letter)</strong> J. Med. Genet. 41: 951-956, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15591283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15591283</a>] [<a href="https://doi.org/10.1136/jmg.2004.020248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15591283">Howard et al. (2004)</a> found that human embryonic kidney cells carrying the R37X mutation expressed approximately 20% of a slightly shortened ATRX protein compared to controls. Analysis of the 5-prime end of the ATRX gene revealed a downstream AUG start codon at residue 40, suggesting an alternative initiation event. <a href="#28" class="mim-tip-reference" title="Howard, M. T., Malik, N., Anderson, C. B., Voskuil, J. L. A., Atkins, J. F., Gibbons, R. J. <strong>Attenuation of an amino-terminal premature stop codon mutation in the ATRX gene by an alternative mode of translational initiation. (Letter)</strong> J. Med. Genet. 41: 951-956, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15591283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15591283</a>] [<a href="https://doi.org/10.1136/jmg.2004.020248" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15591283">Howard et al. (2004)</a> suggested that 'phenotypic rescue' due to the expression of a truncated ATRX protein using the alternative downstream initiation site underlies the relatively mild phenotype seen in some patients with the R37X mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15591283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Abidi, F. E., Cardoso, C., Lossi, A.-M., Lowry, R. B., Depetris, D., Mattei, M.-G., Lubs, H. A., Stevenson, R. E., Fontes, M., Chudley, A. E., Schwartz, C. E. <strong>Mutation in the 5-prime alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome.</strong> Europ. J. Hum. Genet. 13: 176-183, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15508018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15508018</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15508018">Abidi et al. (2005)</a> identified the R37X mutation in 3 affected males originally reported by <a href="#15" class="mim-tip-reference" title="Chudley, A. E., Lowry, R. B., Hoar, D. I. <strong>Mental retardation, distinct facial changes, short stature, obesity, and hypogonadism: a new X-linked mental retardation syndrome.</strong> Am. J. Med. Genet. 31: 741-751, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3239563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3239563</a>] [<a href="https://doi.org/10.1002/ajmg.1320310404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3239563">Chudley et al. (1988)</a> as having Chudley-Lowry syndrome. Western blot and immunocytochemical analyses using a specific monoclonal antibody directed against ATRX showed the protein to be present in lymphoblastoid cells, despite the premature stop codon. <a href="#1" class="mim-tip-reference" title="Abidi, F. E., Cardoso, C., Lossi, A.-M., Lowry, R. B., Depetris, D., Mattei, M.-G., Lubs, H. A., Stevenson, R. E., Fontes, M., Chudley, A. E., Schwartz, C. E. <strong>Mutation in the 5-prime alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome.</strong> Europ. J. Hum. Genet. 13: 176-183, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15508018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15508018</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15508018">Abidi et al. (2005)</a> suggested that the less severe phenotype was due to the presence of some residual ATRX protein. The phenotypic variation between patients with the same mutation suggested that the ATRX gene may influence the expression of several genes in multiple tissues during development. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15508018+3239563" 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>.0023 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</strong>
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ATRX, LEU409SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs122445109 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445109;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=rs122445109" 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=rs122445109" 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=RCV000012509" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012509" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012509</a>
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<p>In several members of a family with X-linked intellectual disability-hypotonic facies syndrome (MRXHF1; <a href="/entry/309580">309580</a>), <a href="#58" class="mim-tip-reference" title="Wieland, H., Sabathil, J., Ostendorf, A., Rittinger, O., Ropke, A., Winnepenninckx, B., Kooy, F., Holinski-Feder, E., Wieacker, P. <strong>A missense mutation in the coiled-coil motif of the HP1-interacting domain of ATR-X in a family with X-linked mental retardation.</strong> Neurogenetics 6: 45-47, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15565397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15565397</a>] [<a href="https://doi.org/10.1007/s10048-004-0190-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15565397">Wieland et al. (2005)</a> identified a 1226T-C transition in the ATRX gene, resulting in a leu409-to-ser (L409S) substitution in a conserved residue within the coiled-coil motif of the heterochromatin protein-1 (HP1; <a href="/entry/604478">604478</a>)-interacting domain of the ATRX protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15565397" 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>.0024 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</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">rs122445110 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445110;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=rs122445110" 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=rs122445110" 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=RCV000012510 OR RCV000190781 OR RCV000717338 OR RCV003144106" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012510, RCV000190781, RCV000717338, RCV003144106" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012510...</a>
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<p>In affected members of a family with X-linked intellectual disability-hypotonic facies syndrome (MRXHF1; <a href="/entry/309580">309580</a>) originally reported by Carpenter et al. (<a href="#14" class="mim-tip-reference" title="Carpenter, N. J., Waziri, M., Liston, J., Patil, S. R. <strong>Studies on X-linked mental retardation: evidence for a gene in the region Xq11-q22. (Abstract)</strong> Am. J. Hum. Genet. 43 (suppl.): A139 only, 1988."None>1988</a>, <a href="#13" class="mim-tip-reference" title="Carpenter, N. J., Qu, Y., Curtis, M., Patil, S. R. <strong>X-linked mental retardation syndrome with characteristic 'coarse' facial appearance, brachydactyly, and short stature maps to proximal Xq.</strong> Am. J. Med. Genet. 85: 230-235, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10398234/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10398234</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19990730)85:3<230::aid-ajmg9>3.0.co;2-o" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10398234">1999</a>), <a href="#2" class="mim-tip-reference" title="Abidi, F., Schwartz, C. E., Carpenter, N. J., Villard, L., Fontes, M., Curtis, M. <strong>Carpenter-Waziri syndrome results from a mutation in XNP. (Letter)</strong> Am. J. Med. Genet. 85: 249-251, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10398237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10398237</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19990730)85:3<249::aid-ajmg12>3.0.co;2-u" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10398237">Abidi et al. (1999)</a> identified a c.6356T-C transition in the ATRX gene, resulting in an ile2052-to-thr (I2052T) substitution in the helicase IV domain. <a href="#2" class="mim-tip-reference" title="Abidi, F., Schwartz, C. E., Carpenter, N. J., Villard, L., Fontes, M., Curtis, M. <strong>Carpenter-Waziri syndrome results from a mutation in XNP. (Letter)</strong> Am. J. Med. Genet. 85: 249-251, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10398237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10398237</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19990730)85:3<249::aid-ajmg12>3.0.co;2-u" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10398237">Abidi et al. (1999)</a> referred to the disorder as the Carpenter-Waziri syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10398237+10398234" 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>.0025 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</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">rs122445111 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445111;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=rs122445111" 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=rs122445111" 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=RCV000012511 OR RCV000624600 OR RCV001582475" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012511, RCV000624600, RCV001582475" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012511...</a>
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<p>In 2 obligate carriers from a family with intellectual disability-hypotonic facies syndrome (MRXHF1; <a href="/entry/309580">309580</a>) originally reported by <a href="#27" class="mim-tip-reference" title="Holmes, L. B., Gang, D. L. <strong>An X-linked mental retardation syndrome with craniofacial abnormalities, microcephaly and club foot.</strong> Am. J. Med. Genet. 17: 375-382, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6711605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6711605</a>] [<a href="https://doi.org/10.1002/ajmg.1320170131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6711605">Holmes and Gang (1984)</a>, <a href="#48" class="mim-tip-reference" title="Stevenson, R. E., Abidi, F., Schwartz, C. E., Lubs, H. A., Holmes, L. B. <strong>Holmes-Gang syndrome is allelic with XLMR-hypotonic face syndrome. (Letter)</strong> Am. J. Med. Genet. 94: 383-385, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11050622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11050622</a>] [<a href="https://doi.org/10.1002/1096-8628(20001023)94:5<383::aid-ajmg7>3.0.co;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11050622">Stevenson et al. (2000)</a> identified an 866G-A transition in the XH2 gene, resulting in a cys220-to-tyr (C220Y) substitution in the second zinc finger domain. Carriers in this family, who had no clinical manifestations, showed the typical marked skewing of X inactivation, consistent with a mutation in the XH2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11050622+6711605" 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>.0026 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</strong>
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ATRX, ARG2271GLY
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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> rs122445112 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs122445112;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/rs122445112?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=rs122445112" 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=rs122445112" 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=RCV000012512" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000012512" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000012512</a>
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<p>In a 3-year-old boy with intellectual disability-hypotonic facies syndrome (MRXHF1; <a href="/entry/309580">309580</a>), a history of hypotonia followed by hypertonia, and asplenia, <a href="#32" class="mim-tip-reference" title="Leahy, R. T., Philip, R. K., Gibbons, R. J., Fisher, C., Suri, M., Reardon, W. <strong>Asplenia in ATR-X syndrome: a second report.</strong> Am. J. Med. Genet. 139A: 37-39, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16222662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16222662</a>] [<a href="https://doi.org/10.1002/ajmg.a.30990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16222662">Leahy et al. (2005)</a> identified a 6811A-G transition in exon 32 of the ATRX gene, resulting in an arg2271-to-gly (R2271G) substitution. The mother was a carrier of the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16222662" 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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Abidi, F. E., Cardoso, C., Lossi, A.-M., Lowry, R. B., Depetris, D., Mattei, M.-G., Lubs, H. A., Stevenson, R. E., Fontes, M., Chudley, A. E., Schwartz, C. E.
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<strong>Mutation in the 5-prime alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome.</strong>
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Europ. J. Hum. Genet. 13: 176-183, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15508018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15508018</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15508018" 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/sj.ejhg.5201303" target="_blank">Full Text</a>]
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Abidi, F., Schwartz, C. E., Carpenter, N. J., Villard, L., Fontes, M., Curtis, M.
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<strong>Carpenter-Waziri syndrome results from a mutation in XNP. (Letter)</strong>
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Am. J. Med. Genet. 85: 249-251, 1999.
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[<a href="https://doi.org/10.1002/(sici)1096-8628(19990730)85:3<249::aid-ajmg12>3.0.co;2-u" target="_blank">Full Text</a>]
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Ades, L. C., Kerr, B., Turner, G., Wise, G.
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<strong>Smith-Fineman-Myers syndrome in two brothers.</strong>
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Am. J. Med. Genet. 40: 467-470, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1684092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1684092</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1684092" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320400419" target="_blank">Full Text</a>]
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Bachoo, S., Gibbons, R. J.
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<strong>Germline and gonosomal mosaicism in the ATR-X syndrome.</strong>
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Europ. J. Hum. Genet. 7: 933-936, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10602370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10602370</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10602370" 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/sj.ejhg.5200387" target="_blank">Full Text</a>]
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Badens, C., Lacoste, C., Philip, N., Martini, N., Courrier, S., Giuliano, F., Verloes, A., Munnich, A., Leheup, B., Burglen, L., Odent, S., Van Esch, H., Levy, N.
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<strong>Mutations in PHD-like domain of the ATRX gene correlate with severe psychomotor impairment and severe urogenital abnormalities in patients with ATRX syndrome.</strong>
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Clin. Genet. 70: 57-62, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16813605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16813605</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16813605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Badens, C., Martini, N., Courrier, S., DesPortes, V., Touraine, R., Levy, N., Edery, P.
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<strong>ATRX syndrome in a girl with a heterozygous mutation in the ATRX Zn finger domain and a totally skewed X-inactivation pattern.</strong>
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Am. J. Med. Genet. 140A: 2212-2215, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16955409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16955409</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16955409" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31400" target="_blank">Full Text</a>]
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Berube, N. G., Healy, J., Medina, C. F., Wu, S., Hodgson, T., Jagla, M., Picketts, D. J.
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<strong>Patient mutations alter ATRX targeting to PML nuclear bodies.</strong>
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Europ. J. Hum. Genet. 16: 192-201, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17957225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17957225</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17957225" 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/sj.ejhg.5201943" target="_blank">Full Text</a>]
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Berube, N. G., Jagla, M., Smeenk, C., De Repentigny, Y., Kothary, R., Picketts, D. J.
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<strong>Neurodevelopmental defects resulting from ATRX overexpression in transgenic mice.</strong>
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Hum. Molec. Genet. 11: 253-261, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11823444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11823444</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11823444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Berube, N. G., Mangelsdorf, M., Jagla, M., Vanderluit, J., Garrick, D., Gibbons, R. J., Higgs, D. R., Slack, R. S., Picketts, D. J.
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<strong>The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis.</strong>
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J. Clin. Invest. 115: 258-267, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15668733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15668733</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15668733[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=15668733" 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/10.1172/JCI22329" target="_blank">Full Text</a>]
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Berube, N. G., Smeenk, C. A., Picketts, D. J.
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<strong>Cell cycle-dependent phosphorylation of the ATRX protein correlates with changes in nuclear matrix and chromatin association.</strong>
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Hum. Molec. Genet. 9: 539-547, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10699177/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10699177</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10699177" 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/9.4.539" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320550308" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000472225" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1997.4793" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10048-004-0190-3" target="_blank">Full Text</a>]
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Yntema, H. G., Poppelaars, F. A., Derksen, E., Oudakker, A. R., van Roosmalen, T., Jacobs, A., Obbema, H., Brunner, H. G., Hamel, B. C. J., van Bokhoven, H.
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[<a href="https://doi.org/10.1002/ajmg.10446" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 2/1/2016
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Ada Hamosh - updated : 6/24/2015<br>Ada Hamosh - updated : 3/7/2012<br>Ada Hamosh - updated : 9/2/2011<br>Ada Hamosh - updated : 6/6/2011<br>Patricia A. Hartz - updated : 2/17/2011<br>Cassandra L. Kniffin - updated : 10/13/2010<br>Cassandra L. Kniffin - updated : 1/26/2010<br>George E. Tiller - updated : 8/12/2009<br>Cassandra L. Kniffin - updated : 10/16/2007<br>Victor A. McKusick - updated : 5/23/2007<br>Cassandra L. Kniffin - updated : 4/27/2007<br>Cassandra L. Kniffin - updated : 12/18/2006<br>Cassandra L. Kniffin - updated : 8/24/2006<br>Marla J. F. O'Neill - updated : 11/17/2005<br>Cassandra L. Kniffin - updated : 6/23/2005<br>Cassandra L. Kniffin - updated : 5/12/2005<br>Victor A. McKusick - updated : 4/11/2005<br>Patricia A. Hartz - updated : 2/25/2005<br>Cassandra L. Kniffin - updated : 1/25/2005<br>Victor A. McKusick - updated : 7/30/2003<br>Victor A. McKusick - updated : 6/11/2003<br>George E. Tiller - updated : 9/19/2002<br>Victor A. McKusick - updated : 7/2/2002<br>Victor A. McKusick - updated : 1/3/2001<br>George E. Tiller - updated : 4/14/2000<br>Ada Hamosh - updated : 3/29/2000<br>Victor A. McKusick - updated : 3/1/2000<br>Victor A. McKusick - updated : 2/16/2000<br>Victor A. McKusick - updated : 12/8/1999<br>Michael J. Wright - updated : 11/3/1999<br>Victor A. McKusick - updated : 10/6/1998<br>Victor A. McKusick - updated : 5/8/1998<br>Victor A. McKusick - updated : 4/20/1998<br>Victor A. McKusick - updated : 1/21/1998<br>Moyra Smith - updated : 1/24/1997
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Creation Date:
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Victor A. McKusick : 2/25/1996
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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alopez : 01/25/2024
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carol : 08/15/2023<br>carol : 08/15/2023<br>carol : 12/18/2022<br>alopez : 11/16/2022<br>carol : 04/01/2022<br>carol : 04/01/2022<br>carol : 03/31/2022<br>carol : 03/05/2021<br>carol : 02/08/2016<br>carol : 2/2/2016<br>alopez : 2/1/2016<br>alopez : 6/24/2015<br>carol : 4/11/2012<br>alopez : 3/12/2012<br>terry : 3/7/2012<br>alopez : 9/2/2011<br>terry : 9/2/2011<br>alopez : 6/14/2011<br>terry : 6/6/2011<br>carol : 6/1/2011<br>alopez : 3/30/2011<br>mgross : 3/14/2011<br>mgross : 3/14/2011<br>terry : 2/17/2011<br>wwang : 10/20/2010<br>ckniffin : 10/13/2010<br>mgross : 7/1/2010<br>wwang : 2/5/2010<br>ckniffin : 1/26/2010<br>wwang : 8/24/2009<br>terry : 8/12/2009<br>carol : 6/13/2008<br>carol : 10/17/2007<br>ckniffin : 10/16/2007<br>alopez : 5/23/2007<br>terry : 5/23/2007<br>wwang : 5/9/2007<br>ckniffin : 4/27/2007<br>wwang : 12/21/2006<br>ckniffin : 12/18/2006<br>wwang : 9/1/2006<br>ckniffin : 8/24/2006<br>wwang : 11/23/2005<br>terry : 11/17/2005<br>ckniffin : 7/19/2005<br>carol : 7/15/2005<br>ckniffin : 6/23/2005<br>ckniffin : 5/12/2005<br>wwang : 4/28/2005<br>wwang : 4/20/2005<br>terry : 4/11/2005<br>mgross : 2/25/2005<br>tkritzer : 1/27/2005<br>ckniffin : 1/25/2005<br>alopez : 1/23/2004<br>carol : 12/15/2003<br>ckniffin : 12/11/2003<br>tkritzer : 10/13/2003<br>alopez : 9/17/2003<br>alopez : 8/11/2003<br>alopez : 7/31/2003<br>terry : 7/30/2003<br>tkritzer : 6/24/2003<br>terry : 6/11/2003<br>cwells : 9/19/2002<br>ckniffin : 8/28/2002<br>cwells : 7/15/2002<br>terry : 7/2/2002<br>mcapotos : 1/10/2001<br>mcapotos : 1/9/2001<br>terry : 1/3/2001<br>carol : 10/4/2000<br>terry : 10/4/2000<br>alopez : 4/14/2000<br>terry : 4/14/2000<br>carol : 4/4/2000<br>mgross : 3/29/2000<br>carol : 3/29/2000<br>mgross : 3/1/2000<br>mgross : 2/16/2000<br>terry : 12/8/1999<br>alopez : 11/10/1999<br>alopez : 11/10/1999<br>terry : 11/3/1999<br>carol : 9/14/1999<br>carol : 8/4/1999<br>carol : 8/4/1999<br>carol : 8/4/1999<br>carol : 10/9/1998<br>terry : 10/6/1998<br>dkim : 9/10/1998<br>carol : 8/18/1998<br>carol : 5/9/1998<br>terry : 5/8/1998<br>carol : 5/6/1998<br>terry : 4/20/1998<br>mark : 1/25/1998<br>terry : 1/21/1998<br>mark : 1/25/1997<br>mark : 1/25/1997<br>terry : 1/24/1997<br>mark : 1/24/1997<br>mark : 4/9/1996<br>mark : 4/9/1996<br>terry : 4/5/1996<br>mark : 3/8/1996<br>mark : 3/7/1996<br>terry : 3/4/1996<br>joanna : 2/25/1996
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<span class="mim-font">
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<strong>*</strong> 300032
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ATRX CHROMATIN REMODELER; ATRX
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<em>Alternative titles; symbols</em>
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ATR-X GENE<br />
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HELICASE 2, X-LINKED; XH2<br />
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X-LINKED NUCLEAR PROTEIN GENE; XNP
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<strong><em>HGNC Approved Gene Symbol: ATRX</em></strong>
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<strong>SNOMEDCT:</strong> 715342005;
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Cytogenetic location: Xq21.1
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Genomic coordinates <span class="small">(GRCh38)</span> : X:77,504,880-77,786,216 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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Xq21.1
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<span class="mim-font">
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Alpha-thalassemia myelodysplasia syndrome, somatic
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<span class="mim-font">
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300448
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<span class="mim-font">
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<span class="mim-font">
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3
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<span class="mim-font">
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Alpha-thalassemia/impaired intellectual development syndrome
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<span class="mim-font">
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301040
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<span class="mim-font">
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X-linked dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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Intellectual disability-hypotonic facies syndrome, X-linked
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<span class="mim-font">
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309580
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<span class="mim-font">
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X-linked recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Cloning and Expression</strong>
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<p>Stayton et al. (1994) described the cloning and characterization of a gene, provisionally called X-linked helicase-2 (XH2), located on chromosome Xq13. The gene undergoes X inactivation, contains a 4-kb open reading frame, and encodes a putative NTP-binding nuclear protein homologous to several members of the helicase II superfamily. In situ hybridization studies in the mouse revealed precocious, widespread expression of the murine homolog of XH2 at early stages of embryogenesis, and more restricted expression during late developmental stages and at birth. XH2 shares 6 conserved, collinear domains with other members of the family of proven and putative helicases. In particular, the XH2 protein shows homology with RAD54. Type II helicases have been implicated in nucleotide excision repair and initiation of transcription. </p><p>Picketts et al. (1996) established the full-length sequence of the ATRX cDNA and predicted the structure of the ATRX protein. Their comparative analysis showed that ATRX is a member of the SNF2-like subgroup of a superfamily of proteins with similar ATPase and helicase domains (see 300012). The N-terminal region contains a nuclear localization signal and antibody studies indicated a nuclear localization of the protein. The C-terminal region is glutamine rich, a common attribute of other transcription factors. In addition, a 15-amino acid segment (the P element) in the C-terminal region shows 35 to 50% similarity to SNF2-like proteins which are involved in gene expression. </p><p>Villard et al. (1997) determined that the ATRX gene encodes a predicted protein of 2,492 amino acids. Three zinc finger motifs were found within the 5-prime end of the gene. Expression analysis in different tissues identified an alternative splicing event that involves exon 6. One of these alternatively spliced transcripts is expressed predominantly in embryonic tissues. </p><p>Gibbons et al. (1997) used the N-terminal sequence of ATRX, as identified by Picketts et al. (1996), to identify a cysteine-rich motif, similar to a putative zinc finger domain (cys4-his-cys3), called the PHD finger. PHD motifs span 50 to 80 amino acids and had been identified in more than 40 proteins, many of which are implicated in chromatin-mediated transcriptional control. </p><p>Picketts et al. (1998) showed that the mouse Atrx gene shows structural features similar to those of the human gene. Two highly conserved and functionally important regions were identified: a potential finger domain at the N terminus and a catalytic domain at the C terminus. </p><p>Gibbons and Higgs (2000) stated that the XH2 gene encodes at least 2 alternatively spliced mRNA transcripts that differ at the 5-prime ends and give rise to slightly different proteins of 265 and 280 kD, respectively. </p>
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<strong>Gene Structure</strong>
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</div>
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<span class="mim-text-font">
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<p>Stayton et al. (1994) determined that the genomic length of XH2 is more than 220 kb. Picketts et al. (1996) determined that the XH2 gene contains 36 exons and spans approximately 300 kb. Using a vectorette strategy, Villard et al. (1997) identified and sequenced the intron/exon boundaries of the ATRX gene. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</div>
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<span class="mim-text-font">
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<p>Stayton et al. (1994) mapped the XH2 gene to chromosome Xq13, between the gene for Menkes disease (MNK; 309400) and DXS56. They showed that the murine homolog maps to the homologous genetic interval between Pgk1 and Xist. </p>
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<strong>Gene Function</strong>
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</span>
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</div>
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<p>Gibbons et al. (1995) showed that mutations in the XH2 gene cause the alpha-thalassemia/mental retardation syndrome (ATR-X; 301040), an X-linked disorder comprising severe psychomotor retardation, characteristic facial features, genital abnormalities, and alpha-thalassemia. XH2 is a member of a subgroup of the helicase superfamily that includes proteins involved in a wide range of cellular functions, including DNA recombination and repair (e.g., ERCC6; 609413) and transcription regulation. Because of the complex ATR-X phenotype, Gibbons et al. (1995) suggested that a mutation in the XH2 gene results in transcriptional downregulation of several genes, including the alpha-globin genes. </p><p>Picketts et al. (1996) suggested that ATRX is most likely involved in the regulation of gene expression, a known function of helicases. They noted that ATRX downregulates alpha-globin (141800) but not beta-globin (141900). They postulated that this may be due to the fact that alpha- and beta-globin are contained within different chromosomal environments and are regulated differently because of the interaction of regulatory factors and chromatin. </p><p>The SNF2-like family comprises numerous members involved in a broad range of biologic functions: transcriptional regulation, DNA repair, and chromosome segregation. Since experiments on fibroblasts from ATR-X patients provided no evidence for either a DNA repair defect or abnormal chromosome breakage segregation, Cardoso et al. (1998) suspected that the XNP protein is somehow involved in regulation of gene expression. Genetic and biochemical studies had led to the emerging concept that SNF2-like proteins are components of a large protein complex that may exert its functions by modulating chromatin structure. Cardoso et al. (1998) performed a yeast 2-hybrid analysis with XNP and several human heterochromatin-associated proteins. They found a specific interaction between XNP and the EZH2 (601573) proteins. In light of these observations, they discussed how the XNP protein may regulate gene transcription at the chromatin level. </p><p>Using indirect immunofluorescence and confocal microscopy, McDowell et al. (1999) showed that ATRX protein is associated with pericentromeric heterochromatin during interphase and mitosis. By coimmunofluorescence, they found that ATRX localizes with a mouse homolog of the Drosophila heterochromatic protein HP1 in vivo, consistent with a previous 2-hybrid screen identifying this interaction. From the analysis of a trap assay for nuclear proteins, McDowell et al. (1999) showed that the localization of ATRX to heterochromatin is encoded by its N-terminal region, which contains a conserved plant homeodomain-like finger and a coiled-coil domain. In addition to its association with heterochromatin, at metaphase ATRX clearly binds to the short arms of human acrocentric chromosomes, where the arrays of ribosomal DNA are located. The unexpected association of a putative transcriptional regulator with highly repetitive DNA provides a potential explanation for the variability in phenotype of patients with identical mutations in the ATRX gene. </p><p>Berube et al. (2000) demonstrated that the association of the ATRX protein with chromosomes at mitosis is concomitant with phosphorylation and its association with HP1-alpha (604478). The authors proposed a dual role for ATRX, possibly involving gene regulation at interphase as well as chromosomal segregation at mitosis. </p><p>XY patients with deletions or mutations in the ATRX gene display varying degrees of sex reversal, implicating ATRX in the development of the human testis (Reardon et al., 1995). To explore further the role of ATRX in mammalian sex differentiation, Pask et al. (2000) cloned and characterized the homologous gene in a marsupial. To their surprise, active homologs of ATRX were detected on the marsupial Y as well as the X chromosome. The Y-borne copy (ATRY) displayed testis-specific expression. This, as well as the sex reversal of ATRX patients, suggested that ATRY is involved in testis development in marsupials and may represent an ancestral testis-determining mechanism that predated the evolution of SRY (480000) as the primary mammalian male sex-determining gene. The authors found no evidence for a Y-borne ATRX homolog in mouse or human, implying that this gene has been lost in eutherians and its role supplanted by the evolution of SRY from SOX3 (313430) as the dominant determiner of male differentiation. </p><p>Gibbons et al. (2003) stated that like other members of the SWI2/SNF2 family of proteins, multiprotein complexes isolated by ATRX antibodies have ATP-dependent nucleosome remodeling and DNA translocase activities in vitro. ATRX is a nuclear protein that localizes to nuclear subcompartments called PML bodies and to pericentromeric heterochromatin, where it interacts with a known component of heterochromatin, HP1. </p><p>Nan et al. (2007) found that ATRX interacts with MECP2 (300005), a methyl-CpG-binding protein that is mutated in Rett syndrome (RTT; 312750) and some forms of mental retardation. Studies in cultured mouse cells showed that MECP2 targeted the C-terminal helicase domain of ATRX to heterochromatic foci. The heterochromatic localization of ATRX was disturbed in neurons from Mecp2-null mice. The findings suggested that disruption of MECP2-ATRX interaction leads to pathologic changes that contribute to mental retardation. </p><p>By immunofluorescence using ATRX deletion constructs in HeLa cells, Berube et al. (2008) identified 2 nuclear localization signals and 2 C-terminal domains that targeted ATRX to nuclear speckles, including to promyelocytic leukemia (PML) nuclear bodies. The PML-targeting domain appeared to play a role in chromatin remodeling and subnuclear targeting. Mutant ATRX proteins with mutations in the C-terminal domain resulted an approximately 80% reduction in the number of transfected cells with ATRX colocalization to nuclear speckles. The findings showed that mutations have an effect on subnuclear targeting to PML nuclear bodies and can cause a loss of ATRX protein function, which may result in aberrant gene regulation. </p><p>Law et al. (2010) examined the genomewide distribution of ATRX protein and found that it was enriched at telomeres and subtelomeric regions of human chromosomes. Chromatin immunoprecipitation and sequence analysis identified 917 ATRX targets in primary human erythroid cells and 1,305 targets in mouse embryonic stem cells. The most prominent feature of the targets in both human and mouse is the presence of variable number tandem repeats, many of which are G and C rich, contain a high proportion of CpG dinucleotides, and/or have the potential to form G-quadruplex structures, particularly when single stranded. A subtelomeric region of chromosome 16 (16p13.3) contains 2 ATRX targets, alpha-globin and NME4 (601818), and each has the potential to form G-quadruplex structures. The beta-globin locus does not contain likely ATRX target sequences. Quantitative PCR analysis showed that all peaks of ATRX binding localized at or very close to regions of G-rich tandemly repetitive DNA, and the degree of downregulation of each alpha-like globin gene was related to its proximity to the major peak of ATRX binding 1 kb upstream from the hemoglobin mu gene (HBM; 609639). Gel-shift assays confirmed that ATRX bound G-quadruplex DNA in vitro. Law et al. (2010) noted that a number of ATRX targets are highly polymorphic, suggesting that the degree to which gene expression is altered by ATRX may relate to the size of the tandem repeat. This variability in ATRX targets may also explain incomplete penetrance of alpha-thalassemia in individuals with identical ATRX mutations. </p><p>Elsasser et al. (2015) showed that the replacement histone variant H3.3 (601128) is enriched at class I and class II endogenous retroviral elements (ERVs), notably those of the early transposon/MusD family and intracisternal A-type particles. Deposition at a subset of these elements is dependent on the H3.3 chaperone complex containing ATRX and DAXX (603186). Elsasser et al. (2015) demonstrated that recruitment of DAXX, H3.3, and KAP1 (TRIM28; 601742) to ERVs is codependent and occurs upstream of ESET (SETDB1; 604396), linking H3.3 to ERV-associated H3K9me3. Importantly, H3K9me3 is reduced at ERVs upon H3.3 deletion, resulting in derepression and dysregulation of adjacent, endogenous genes, along with increased retrotransposition of intracisternal A-type particles. Elsasser et al. (2015) concluded that their study identifies a unique heterochromatin state marked by the presence of both H3.3 and H3K9me3, and establishes an important role for H3.3 in control of ERV retrotransposition in embryonic stem cells. </p><p>Flynn et al. (2015) showed that loss of ATRX compromises cell-cycle regulation of the telomeric noncoding RNA TERRA and leads to persistent association of replication protein A (RPA; see 179835) with telomeres after DNA replication, creating a recombinogenic nucleoprotein structure. Inhibition of the protein kinase ATR (601215), a critical regulator of recombination recruited by RPA, disrupts alternative lengthening of telomeres (ALT) and triggers chromosome fragmentation and apoptosis in ALT cells. The cell death induced by ATR inhibitors is highly selective for cancer cells that rely on ALT, suggesting that such inhibitors may be useful for treatment of ALT-positive cancers. </p>
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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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</h4>
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<p><strong><em>Alpha-Thalassemia/Impaired Intellectual Development Syndrome</em></strong></p><p>
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In patients with the ATRX syndrome (301040), an X-linked disorder comprising severe psychomotor retardation, characteristic facial features, genital abnormalities, and alpha-thalassemia, Gibbons et al. (1995) identified mutations in the XH2 gene (300032.0001-300032.0009). They identified 2 premature in-frame stop mutations, 7 missense mutations, and a small deletion that reduced expression of the gene in ATRX patients to less than 1% of that of controls. A clue to the presence of mutations in XH2 associated with ATRX syndrome was the absence of a hybridization signal with an XH2 probe in the patient with the deletion. The 9 other mutations were identified by single-strand conformation polymorphism analysis followed by sequencing. </p><p>Picketts et al. (1996) screened 52 individuals with ATRX syndrome and identified 4 novel splicing defects in the ATRX gene. They reported sites of mutation in 27 different cases of ATRX. Picketts et al. (1996) noted that mutations associated with the severe urogenital abnormalities which may occur in ATRX have primarily been mutations that lead to severe truncation of the protein with loss of the C-terminal region, which includes both the P element and the polyglutamine tract. </p><p>Villard et al. (1997) searched for mutations in the 5-prime region of the ATRX gene in ATRX patients who did not have mutations in the 3-prime region. In 1 patient, they found that part of exon 7 was removed from the XNP transcript as a result of a mutation creating a novel splice site that was substituted for the natural splice site (300032.0013). The new splicing event removed 1 zinc finger motif, suggesting that mutations in both the helicase and zinc finger regions result in disease manifestations. </p><p>Extending the mutation analysis of the ATRX gene to include the PHD zinc finger region, Gibbons et al. (1997) identified 10 different mutations within a 294-bp segment (see, e.g., 300032.0014; 300032.0018). Family studies confirmed de novo mutations at 4 of these sites. In 15 unrelated individuals, a C-to-T transition at a single CpG dinucleotide, presumably a deamination 'hotspot,' changed arg to cys, which had the potential to disrupt the putative zinc finger. Similarly, 3 mutations affected conserved cys residues, which could coordinate zinc binding in this region. Finally, in 4 unrelated individuals, an identical splice site mutation removed 21 amino acids, which would disrupt the putative zinc finger located upstream of the PHD-like domain. Although the clinical phenotype of particular ATRX mutations was similar, there was a wide range in the perturbation of alpha-globin expression as reflected by the proportion of cells with Hb H inclusions, suggesting that the effect of ATRX protein on gene expression, as for other chromatin-associated regulators, may be modified by other genetic factors. Variation was observed even within the same family. </p><p>Villard et al. (1999) reported mutation analysis of the XNP gene using direct sequencing of PCR products derived from primers amplifying the 300-bp zinc finger coding region spanning exons 7, 8, and 9. In 21 mentally retarded male patients with facial appearance typical of ATRX, but not necessarily having urogenital abnormalities or hemoglobin H inclusions, 6 mutations (28%) were detected. Villard et al. (1999) concluded that this method was suitable for screening individuals in this population. </p><p>Bachoo and Gibbons (1999) identified 2 women who were each mosaic for an ATRX mutation. One of them, whose mutation was undetectable in peripheral blood and buccal cells, had 2 affected sons and was therefore presumed to be a germline mosaic. In the other woman, the ATRX mutation was weakly detectable in the peripheral blood, but only 1 of her 3 children who shared the disease-associated haplotype carried the mutation. Therefore, the authors concluded that she represented a gonosomal mosaic. These cases provided the first molecular evidence for the occurrence of postzygotic mutations in ATRX syndrome. </p><p>Gibbons et al. (2000) demonstrated that mutations in the ATRX gene give rise to changes in the methylation pattern of several highly repeated sequences, including the rDNA arrays, a Y-specific satellite, and subtelomeric repeats. Using methylation-sensitive restriction endonucleases, they noted differences in the pattern of rDNA methylation by comparing genomic DNA from EBV-transformed B cells or the peripheral blood of normal individuals with that from patients with ATRX syndrome. In normal individuals, approximately 20% of rDNA repeats were methylated within most CpG-rich regions. In ATRX patients, rDNA genes were substantially unmethylated. These differences were present in a variety of tissues from the fetal stage of development onwards. The Y-specific repeat DYZ2 makes up 10 to 20% of the Y chromosome, distributed along the entire heterochromatic band Yq12. Gibbons et al. (2000) discovered that approximately 6% of DYZ2 repeats were unmethylated on the Y chromosomes in the peripheral blood of normal individuals, but almost all were methylated in ATRX patients. These results differed from those identified in the rDNA repeats, suggesting that the effect of ATRX mutations on Y-chromosome repeats is different from their effect on rDNA repeats. Gibbons et al. (2000) concluded that their findings provide a potential link between the processes of chromatin remodeling, DNA methylation, and gene expression in mammalian development. </p><p>In a study of 8 unrelated Japanese families, Wada et al. (2000) found 7 missense mutations, including 6 novel mutations, as the cause of the ATRX syndrome. One mutation, arg246-to-cys (300032.0018), was found in 2 unrelated patients. All mutations were located either in the N-terminal region corresponding to the putative zinc finger domain or in the C-terminal region corresponding to the helicase domain. The clinical manifestations were the same with mutations of either group, suggesting that the putative zinc finger and helicase domains have similar functional significance for the ATRX gene. </p><p>Using a broad range denaturing gel gradient electrophoresis (DGGE) method for single-step mutation scanning of the entire open reading frame and canonical splice sites of the ATRX gene, Borgione et al. (2003) identified 5 novel sequence changes (4 missense mutations and 1 polymorphism). All 4 mutations occurred in the helicase domain region of the gene in patients with typical features of ATRX syndrome. </p><p><strong><em>Partial Duplication of the ATRX Gene</em></strong></p><p>
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Thienpont et al. (2007) reported 3 patients, including 2 sibs, with the ATRX syndrome due to partial duplications of the ATRX gene. In 1 family, the duplication included exons 2 to 35; in the other family, exons 2 to 29. Further analysis showed that both mothers carried the duplication and both had skewed X inactivation. In 1 patient, ATRX mRNA levels were about 3% of normal values. Thienpont et al. (2007) noted that the duplications were not identified by sequence analysis and suggested that quantitative analysis to detect copy numbers of the ATRX gene may be required in some cases. </p><p>Cohn et al. (2009) reported a family in which 3 males had ATRX syndrome due to a partial intragenic duplication of the ATRX gene that spanned exons 2 to 31. Northern blot analysis failed to identify a full-length transcript, but cDNA sequencing was consistent with some level of expression. The authors noted that complete loss of ATRX is most likely lethal, suggesting that the mutation was likely hypomorphic and associated with some residual protein function. Unaffected obligate carrier females in the family had highly skewed X inactivation. The phenotype was typical for the disorder, although the facial features were not as readily apparent in the 2 older affected individuals. The proband was identified from 2 larger cohorts comprising 300 males with mental retardation. Cohn et al. (2009) did not find ATRX duplications in 29 additional males with ATRX syndrome who were negative on sequence analysis, suggesting that duplications are a rare cause of the disorder. </p><p><strong><em>Intellectual Disability-Hypotonic Facies Syndrome, X-linked</em></strong></p><p>
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In a family with intellectual disability-hypotonic facies syndrome (MRXHF1; 309580), in which affected members were originally diagnosed with Juberg-Marsidi syndrome by Mattei et al. (1983), Villard et al. (1996) identified a mutation in the ATRX gene (300032.0011). </p><p>In 4 male cousins with MRXHF1, Guerrini et al. (2000) identified a hemizygous nonsense mutation in the ATRX gene (R37X; 300032.0022). </p><p>Abidi et al. (2005) identified the R37X mutation in 3 affected males with MRXHF1 who were originally reported by Chudley et al. (1988) as having Chudley-Lowry syndrome. </p><p>In several members of a family with MRXHF1, Wieland et al. (2005) identified a missense mutation in the ATRX gene (L409S; 300032.0023). </p><p><strong><em>Alpha-Thalassemia Myelodysplasia Syndrome, Somatic</em></strong></p><p>
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Rarely, alpha-thalassemia occurs as an acquired abnormality in individuals with various types of multilineage myelodysplasia (Weatherall et al., 1978; Higgs et al., 1983). Gibbons et al. (2003) stated that 71 individuals with alpha-thalassemia myelodysplasia syndrome (ATMDS; 300448) had been identified, of whom 62 (87%) were males who had a de novo, acquired form of alpha-thalassemia with hypochromic microcytic anemia. In these individuals, a reduction in alpha-globin expression leads to an excess of beta-globin chains, which form an abnormal hemoglobin (HbH, or beta-4) that is readily detectable in peripheral blood. In the most severely affected individuals, alpha-chain synthesis is almost abolished, implying that all 4 alpha genes are downregulated. This degree of alpha-thalassemia would be lethal during development if it resulted from an inherited mutation. No structural abnormalities in cis to the alpha-globin genes had been detected, and the downregulation of alpha-globin appeared to be associated with a trans-acting mutation. ATRX was a plausible candidate for harboring mutations associated with this syndrome. Because of the large size of the gene (300 kb) and the failure of previous direct mutational searches, Gibbons et al. (2003) chose microarray analysis to search for genes whose expression might be perturbed in ATMDS. In purified granulocytes from the peripheral blood they found that ATRX expression was 3 to 4% of that in normal controls. In contrast, there was no significant reduction in ATRX expression in 13 individuals with myelodysplasia syndrome with alpha-thalassemia. Sequence analysis identified a G-to-A mutation in the canonic splice donor site (GT) of intron 1 of ATRX (300032.0020). This mutation was present in granulocytes but absent in DNA from both buccal cells and a lymphoblastoid cell line derived from the patient. The finding suggested that this pleiotropic cofactor is an essential component rather than a mere facilitator of globin gene expression. For many important genes, inherited null mutations are lethal early in development. The only viable manifestations of such mutations in these genes will be seen in diseases associated with acquired somatic mutations. Other examples of this, in addition to ATRX, include mutations of PIGA (311770) in paroxysmal nocturnal hemoglobinuria (300818), and GNAS1 (139320) in McCune-Albright syndrome (174800). </p>
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<h4>
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<span class="mim-font">
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<strong>Pathogenesis</strong>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Pancreatic Neuroendocrine Tumors</em></strong></p><p>
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Jiao et al. (2011) explored the genetic basis of pancreatic neuroendocrine tumors (PanNETs) by determining the exomic sequence of 10 nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN1 (613733), and 43% had mutations in genes encoding either of the 2 subunits of a transcription/chromatin remodeling complex consisting of DAXX (death domain-associated protein, 603186) and ATRX. Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. Jiao et al. (2011) also found mutations in genes in the mTOR (601231) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatments with mTOR inhibitors. </p><p>Heaphy et al. (2011) evaluated telomere status in PanNETs in which ATRX and DAXX mutational status had been determined through Sanger sequencing. Telomere-specific FISH revealed that 25 of 41 (61%) PanNETs displayed large, ultrabright telomere FISH signals, a nearly universal feature of the telomerase-independent telomere maintenance mechanism termed alternative lengthening of telomeres. ATRX and DAXX gene mutations both were significantly correlated with ALT positivity (P less than 0.008 for each gene). All 19 (100%) PanNETs with ATRX or DAXX gene mutations were ALT-positive, whereas 6 of 20 cases without detectable mutations were ALT-positive. To ascertain whether ATRX and DAXX gene mutations might be more generally associated with the ALT phenotype, Heaphy et al. (2011) examined 439 tumors of other types and found a strong correlation between inactivation of ATRX or DAXX and the ALT phenotype in unrelated tumor types. </p><p><strong><em>Pediatric Glioblastoma</em></strong></p><p>
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Schwartzentruber et al. (2012) sequenced the exomes of 48 pediatric glioblastoma (137800) samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodeling pathway were identified in 44% of tumors (21 of 48). Recurrent mutations in H3F3A (601128), which encodes the replication-independent histone-3 variant H3.3, were observed in 31% of tumors, and led to amino acid substitutions at 2 critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory posttranslational modifications. Mutations in ATRX and DAXX, encoding 2 subunits of a chromatin remodeling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres, were identified in 31% of samples overall, and in 100% of tumors harboring a G34R or G34V H3.3 mutation. Somatic TP53 (191170) mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to glioblastoma multiforme and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. Schwartzentruber et al. (2012) stated that this was the first report to highlight recurrent mutations in a regulatory histone in humans, and that their data suggested that defects of the chromatin architecture underlie pediatric and young adult glioblastoma multiforme pathogenesis. </p>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</h4>
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<span class="mim-text-font">
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<p>In a review article, Gibbons and Higgs (2000) noted that mutations resulting in the loss of the C-terminal domain are associated with the most severe urogenital abnormalities. However, at other sites, there is no obvious link between genotype and phenotype, and there is considerable variation in the degree of abnormalities seen in individuals with the same mutation. </p><p>Among 22 ATRX patients from 16 families, Badens et al. (2006) found that those with mutations in the PHD-like domain of the ATRX protein had significantly more severe and permanent psychomotor retardation and significantly more severe urogenital anomalies compared to those with mutations in the helicase domain. </p><p>Extreme skewing of X-chromosome inactivation (XCI) is rare in the normal female population but is observed frequently in carriers of some X-linked mutations. Plenge et al. (2002) showed that various forms of X-linked mental retardation (XLMR) have a strong association with skewed XCI in female carriers. The ATRX syndrome is one such disorder; phenotypically normal female carriers virtually all have highly skewed XCI biased against the X chromosome that harbors the mutant allele. Muers et al. (2007) used a mouse model to understand the processes causing skewed XCI. In female mice heterozygous for a null Atrx allele, they found that XCI is balanced early in embryogenesis but becomes skewed over the course of development, because of selection favoring cells expressing the wildtype Atrx allele. Unexpectedly, selection did not appear to be the result of general cellular viability defects in Atrx-deficient cells, since it was restricted to specific stages of development and was not ongoing throughout the life of the animal. Instead, there was evidence that selection results from independent tissue-specific effects. </p>
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<span class="mim-font">
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<strong>Animal Model</strong>
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<span class="mim-text-font">
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<p>Although the ATRX protein is a member of the SWI/SNF family of chromatin remodeling proteins, little is known about the biochemical activity of the ATRX protein or its in vivo function during development. Berube et al. (2002) demonstrated that ATRX is part of a large multiprotein complex similar in size to the SWI/SNF complex. Overexpression of ATRX in transgenic mice was associated with growth retardation, neural tube defects, and a high incidence of embryonic death. Moreover, brains from E10.5 transgenic embryos displayed abnormal growth and organization of the ventricular zone that was highly convoluted in the most severely affected embryos. Transgenic mice that survived to birth exhibited a high incidence of perinatal death as well as seizures, mild craniofacial anomalies, and abnormal behavior. The authors concluded that ATRX dosage is crucial for normal development and organization of the cortex. </p><p>By immunostaining for Atrx in mouse brain, Berube et al. (2005) found that Atrx expression was nuclear in all cells and coincided with regions of intense DAPI staining, consistent with a heterochromatin colocalization. The temporal pattern of Atrx expression followed the process of neuroprogenitor differentiation. To circumvent early lethality in Atrx-null mice, Berube et al. (2005) developed mice with forebrain-targeted conditional loss of Atrx expression. Targeted loss of Atrx caused widespread hypocellularity in the neocortex and hippocampus and a pronounced reduction in forebrain size. Neuronal 'birthdating' confirmed that fewer neurons reached the superficial cortical layers, despite normal progenitor cell proliferation. The loss of cortical mass resulted from a 12-fold increase in neuronal apoptosis during early stages of corticogenesis in the mutant animals. Cultured cortical progenitor cells isolated from Atrx-null mice underwent enhanced apoptosis upon differentiation. Berube et al. (2005) concluded that Atrx is a critical mediator of cell survival during early neuronal differentiation and that neuronal loss may contribute to the mental retardation observed in ATRX syndrome patients. </p><p>Medina et al. (2009) surveyed ATRX syndrome clinical findings and noted that ocular defects were present in 47 (23%) of 202 patients. They showed that Atrx was expressed in the neuroprogenitor pool in embryonic mouse retina and in all cell types of adult mouse retina except rod photoreceptors. Conditional inactivation of Atrx in mouse retina during embryogenesis resulted in loss of only 2 types of neurons, amacrine and horizontal cells. This defect did not arise from a failure to specify these cells, but rather a defect in interneuron differentiation and survival postnatally. The timing of cell loss was concomitant with light-dependent changes in synaptic organization in mouse retina and with a change in Atrx subnuclear localization within these interneurons. The interneuron defects were associated with functional deficits as demonstrated by reduced b-wave amplitudes upon electroretinogram analysis. Medina et al. (2009) proposed a role for Atrx in interneuron survival and differentiation. </p>
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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>26 Selected Examples):</strong>
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</span>
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</h4>
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<h4>
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<span class="mim-font">
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<strong>.0001 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
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</h4>
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ATRX, HIS750ARG
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<br />
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SNP: rs122445093,
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ClinVar: RCV000012487, RCV002285255
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<span class="mim-text-font">
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<p>In a patient with the ATRX syndrome (301040), Gibbons et al. (1995) identified a 2302A-G transition in the XH2 gene, resulting in a his750-to-arg (H750R) substitution. </p>
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<h4>
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<span class="mim-font">
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<strong>.0002 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
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</span>
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<span class="mim-text-font">
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ATRX, CYS755ARG
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<br />
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SNP: rs122445094,
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ClinVar: RCV000012488
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<span class="mim-text-font">
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<p>In a patient with the ATRX syndrome (301040), Gibbons et al. (1995) identified a 2316T-C transition in the XH2 gene, resulting in a cys755-to-arg (C755R) amino acid change. </p>
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</div>
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|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, LYS792ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445095,
|
|
|
|
|
|
|
|
ClinVar: RCV000012489
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with the ATRX syndrome (301040), Gibbons et al. (1995) identified a 2429G-T transversion in the XH2 gene, resulting in a lys792-to-asn (K792N) amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, ASN1002SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs45439799,
|
|
|
|
|
|
gnomAD: rs45439799,
|
|
|
|
|
|
ClinVar: RCV000012490, RCV000078966, RCV000428077, RCV000588578, RCV000590248, RCV002311512, RCV004593961
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with the ATRX syndrome (301040), Gibbons et al. (1995) identified a 3058A-G transition in the XH2 gene, resulting in an asn1002-to-ser (N1002S) amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, ASP1177VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445096,
|
|
|
|
|
|
|
|
ClinVar: RCV000012491
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with the ATRX syndrome (301040), Gibbons et al. (1995) identified a 3583A-T transversion in the XH2 gene, leading to an asp1177-to-val (D1177V) amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, TYR1226HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445097,
|
|
|
|
|
|
|
|
ClinVar: RCV000012492
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with the ATRX syndrome (301040), Gibbons et al. (1995) identified a 3729T-C transition in the XH2 gene, leading to a tyr1226-to-his (Y1226H) amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, TYR1305CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445098,
|
|
|
|
|
|
|
|
ClinVar: RCV000012493
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with the ATRX syndrome (301040), Gibbons et al. (1995) identified a 3967A-G transition in the XH2 gene, leading to a tyr1305-to-cys (Y1305C) amino acid change. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, ARG1528TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445099,
|
|
|
|
|
|
|
|
ClinVar: RCV000012494, RCV000723525, RCV002283442, RCV004532323, RCV005055347
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with the ATRX syndrome (301040), Gibbons et al. (1995) identified a 4635C-T transition in the XH2 gene, leading to premature termination of the polypeptide at codon 1528 (R1528X). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, GLU1530TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445100,
|
|
|
|
|
|
|
|
ClinVar: RCV000012495
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with the ATRX syndrome (301040), Gibbons et al. (1995) identified a 4641G-T transversion in the XH2 gene, resulting in a glu1530-to-ter (E1530X) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, IVSAS, T-A, -10
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs2148261114,
|
|
|
|
|
|
|
|
ClinVar: RCV000012496
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with ATRX syndrome (301040), Villard et al. (1996) identified a T-to-A transversion in the XH2 gene in the consensus splice acceptor site at position -10 on the upstream side of the deleted 176-bp exon, resulting in a premature stop codon and a shortened protein with 638 amino acids. In 2 first cousins presenting the classic ATRX phenotype with alpha-thalassemia and Hb H inclusions, only the abnormal transcript was expressed. In a distant cousin presenting with a similar dysmorphic mental retardation phenotype, but without thalassemia, they found that approximately 30% of the XH2 transcripts were normal. These data suggested that the mode of action of the XH2 gene product on globin expression is distinct from its mode of action in brain development and facial morphogenesis. The mothers of the patients were found to be heterozygotes. It appeared that the mutated splice site could be used with varying efficiency in different individuals. Kiesewetter et al. (1993) reported the same missense mutation in the cystic fibrosis gene, in which it leads to different phenotypes, depending on the genetic background in which the mutation was segregating. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, ARG1272GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445101,
|
|
|
|
|
|
|
|
ClinVar: RCV000012497, RCV000199096, RCV002272014, RCV004528102
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large family with intellectual disability-hypotonic facies syndrome (MRXHF1; 309580), who originally had a diagnosis of Juberg-Marsidi syndrome (Mattei et al., 1983), Villard et al. (1996) identified a mutation in the XH2 gene, resulting in an arg1272-to-gln (R1272Q) substitution in the highly conserved helicase V domain. The helicase V domain was known to be involved in transcriptional control in yeast. Furthermore, the change of amino acid arg1272, which is highly conserved among species from yeast to human, alters the overall charge of the domain. In the family studied, the mutant X chromosome was consistently inactivated in carriers as it is in the ATRX syndrome. This suggested to the authors that the XNP protein either plays a role in a fundamental cellular process, such as X inactivation or cell division, or has a nonspecific deleterious effect with clonal selection of the normal XNP allele. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, PRO852SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445102,
|
|
|
|
|
|
|
|
ClinVar: RCV000012498
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a proband and a maternal uncle with X-linked intellectual disability-hypotonic face syndrome (MRXHF1; 309580), Villard et al. (1996) identified a pro852-to-ser (P852S) substitution in the ATRX gene in a highly-conserved region of helicase domain II. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, 751A-G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1569539477,
|
|
|
|
|
|
|
|
ClinVar: RCV000012499
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic case presenting with a typical ATRX phenotype (301040), Villard et al. (1997) found that the 2 alternatively spliced transcripts of ATRX were smaller than expected. DNA sequencing identified a 751A-G transition in the ATRX gene. This mutation created an effective splicing site with a consensus value (Shapiro and Senapathy, 1987) of 0.9, which is a higher value than that for the usual donor splicing site (0.85) or the nonmutated cryptic site (0.77), probably allowing it to be more efficiently used in vivo than the normal donor site. The event leads to a potential protein missing 21 amino acids. The missing part of the transcript corresponded to the first zinc finger of the gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, PRO73ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445103,
|
|
|
|
|
|
|
|
ClinVar: RCV000012500, RCV000197579
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with ATRX syndrome (301040), Gibbons et al. (1997) identified a 901C-G transversion in the XH2 gene, resulting in a pro73-to-ala (P73A) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0015 MOVED TO 300032.0018</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, ARG1742LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445104,
|
|
|
|
|
|
|
|
ClinVar: RCV000012502
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected patients from a family with ATRX syndrome (301040) reported by Martinez et al. (1998), Lossi et al. (1999) identified a 5459G-A transition in the XH2 gene, resulting in an arg1742-to-lys (R1742K) substitution in the conserved helicase domain III. Affected patients showed hypertonia from birth and spasticity, which are unusual findings in ATRX syndrome. Haplotype analysis identified 2 females who shared the disease-associated haplotype, spanning both the ATRX gene and the X-inactivation center, but lacking the R1742K mutation. Lossi et al. (1999) deduced that the mutation arose de novo in the germline of 1 member of the founding couple. Furthermore, the fact that females in the nonmutated branch of the family did not exhibit a skewed pattern of X inactivation demonstrated that the skewing in carrier females was directly linked to the presence of the mutation in the gene. Lossi et al. (1999) stated that this was the first reported instance in which negative selection against the cells expressing an abnormal gene product in females did not imply a male lethal condition. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, IVS34, A-G, -2
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<br />
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|
SNP: rs1569513021,
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|
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ClinVar: RCV000012503
|
|
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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>Villard et al. (2000) demonstrated that 2 brothers reported by Ades et al. (1991) as having the Smith-Fineman-Myers type of mental retardation (MRXHF1; 309580) had a mutation in the ATRX gene: the acceptor splice site of intron 34 was affected, causing a frameshift and the replacement of the 92 amino acids encoded by exon 35 in the wildtype transcript by 46 different amino acids. Three previous mutations had been reported to affect this last exon of the gene. In 2 of the 3, the affected patients presented severe urogenital anomalies which led to female gender assignment. The brothers reported by Ades et al. (1991) and Villard et al. (2000) had bilateral cryptorchidism. </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>.0018 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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ATRX, ARG246CYS
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<br />
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SNP: rs122445105,
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ClinVar: RCV000012501, RCV000078972, RCV000190796, RCV000763634, RCV001249275, RCV001252427
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In 2 presumably unrelated Japanese patients with ATRX syndrome (301040), Wada et al. (2000) identified a mutation in the ATRX gene, resulting in an arg246-to-cys (R246C) substitution. </p><p>Wada et al. (2000) noted that the R246C mutation had previously been reported by Gibbons et al. (1997) in 15 pedigrees. Gibbons et al. (1997) reported the mutation as a 1069C-T transition, resulting in an arg129-to-cys (R129C) substitution. The mutation was de novo in 3 cases. The proportion of cells with Hb H inclusions ranged from 0.006 to 14% in these pedigrees with an identical mutation. The mutation occurred in a CpG dinucleotide. </p><p>Badens et al. (2006) reported a 4-year-old girl with typical features of the ATRX syndrome. Molecular studies showed a totally skewed X-inactivation pattern with the active chromosome carrying a heterozygous R246C mutation, resulting from a 951C-T transition in the zinc finger domain-coding region of the ATRX gene. Neither parent had the mutation in peripheral blood leukocytes, but SNP analysis indicated that the mutation occurred on the maternal chromosome. The child was conceived with assisted reproduction technologies (ART) due to micropolycystic ovaries and endometriosis in the mother. Badens et al. (2006) suggested that some aspect of ART may have disturbed imprinting in this patient. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, THR1621MET
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<br />
|
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|
|
SNP: rs122445106,
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|
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|
|
gnomAD: rs122445106,
|
|
|
|
|
|
ClinVar: RCV000012505, RCV003128081, RCV004734510
|
|
|
|
|
|
</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Yntema et al. (2002) identified a thr1621-to-met (T1621M) missense mutation in the ATRX gene in a patient from a family in which most affected members had only mild mental retardation and no obvious facial dysmorphisms. Linkage analysis showed a maximum lod score of 3.9 at theta = 0.0 for linkage to the ATRX locus. Subsequent analysis of red blood cells revealed hemoglobin H inclusion bodies. Furthermore, X-inactivation studies revealed extreme skewing of X-inactivation in carrier females. In retrospect, facial hypotonia was recognized in pictures taken in childhood, a usual finding in the ATRX syndrome (301040), but this feature was not seen in adulthood. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
|
|
</div>
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|
|
</div>
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<div>
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|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 ALPHA-THALASSEMIA MYELODYSPLASIA SYNDROME, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, IVS1DS, G-A, +1
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776756,
|
|
|
|
|
|
|
|
ClinVar: RCV000012506
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a case of alpha-thalassemia myelodysplasia syndrome (ATMDS; 300448), Gibbons et al. (2003) identified a G-to-A transition in the canonic splice donor site (GT) of intron 1 of the ATRX gene. The mutation was present in granulocytes but absent in DNA from both buccal cells and a lymphoblastoid cell line derived from the patient. Because ATMDS is a clonal disorder affecting myeloid progenitors, DNA isolated from the unfractionated white cells (granulocytes and lymphocytes) in peripheral blood had a mixture of mutant and wildtype sequences. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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|
|
<div>
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|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 ALPHA-THALASSEMIA MYELODYSPLASIA SYNDROME, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, SER79TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445107,
|
|
|
|
|
|
|
|
ClinVar: RCV000012507
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In bone marrow cDNA from a patient with alpha-thalassemia myelodysplasia syndrome (ATMDS; 300448), Gibbons et al. (2003) found a C-to-G transversion in exon 4 of the ATRX gene, resulting in a ser79-to-ter (S79X) substitution. A mixture of mutant and wildtype sequence in DNA from bone marrow and peripheral blood was found. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, ARG37TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445108,
|
|
|
|
|
|
|
|
ClinVar: RCV000012508, RCV000148028, RCV000224314, RCV000680146, RCV002444427, RCV003151722, RCV004795394
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 male cousins with the X-linked intellectual disability-hypotonic facies syndrome (MRXHF1; 309580), Guerrini et al. (2000) identified a 109C-T transition in exon 2 of the ATRX gene, resulting in an arg37-to-ter (R37X) substitution. Two patients had moderate to profound mental retardation and the typical facial features of the syndrome, whereas the other 2 patients presented with mild mental retardation and epilepsy, but without the characteristic facial dysmorphism. </p><p>Howard et al. (2004) found that human embryonic kidney cells carrying the R37X mutation expressed approximately 20% of a slightly shortened ATRX protein compared to controls. Analysis of the 5-prime end of the ATRX gene revealed a downstream AUG start codon at residue 40, suggesting an alternative initiation event. Howard et al. (2004) suggested that 'phenotypic rescue' due to the expression of a truncated ATRX protein using the alternative downstream initiation site underlies the relatively mild phenotype seen in some patients with the R37X mutation. </p><p>Abidi et al. (2005) identified the R37X mutation in 3 affected males originally reported by Chudley et al. (1988) as having Chudley-Lowry syndrome. Western blot and immunocytochemical analyses using a specific monoclonal antibody directed against ATRX showed the protein to be present in lymphoblastoid cells, despite the premature stop codon. Abidi et al. (2005) suggested that the less severe phenotype was due to the presence of some residual ATRX protein. The phenotypic variation between patients with the same mutation suggested that the ATRX gene may influence the expression of several genes in multiple tissues during development. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, LEU409SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445109,
|
|
|
|
|
|
|
|
ClinVar: RCV000012509
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In several members of a family with X-linked intellectual disability-hypotonic facies syndrome (MRXHF1; 309580), Wieland et al. (2005) identified a 1226T-C transition in the ATRX gene, resulting in a leu409-to-ser (L409S) substitution in a conserved residue within the coiled-coil motif of the heterochromatin protein-1 (HP1; 604478)-interacting domain of the ATRX protein. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, ILE2052THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445110,
|
|
|
|
|
|
|
|
ClinVar: RCV000012510, RCV000190781, RCV000717338, RCV003144106
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family with X-linked intellectual disability-hypotonic facies syndrome (MRXHF1; 309580) originally reported by Carpenter et al. (1988, 1999), Abidi et al. (1999) identified a c.6356T-C transition in the ATRX gene, resulting in an ile2052-to-thr (I2052T) substitution in the helicase IV domain. Abidi et al. (1999) referred to the disorder as the Carpenter-Waziri syndrome. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, CYS220TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445111,
|
|
|
|
|
|
|
|
ClinVar: RCV000012511, RCV000624600, RCV001582475
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 obligate carriers from a family with intellectual disability-hypotonic facies syndrome (MRXHF1; 309580) originally reported by Holmes and Gang (1984), Stevenson et al. (2000) identified an 866G-A transition in the XH2 gene, resulting in a cys220-to-tyr (C220Y) substitution in the second zinc finger domain. Carriers in this family, who had no clinical manifestations, showed the typical marked skewing of X inactivation, consistent with a mutation in the XH2 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 INTELLECTUAL DISABILITY-HYPOTONIC FACIES SYNDROME, X-LINKED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ATRX, ARG2271GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs122445112,
|
|
|
|
|
|
gnomAD: rs122445112,
|
|
|
|
|
|
ClinVar: RCV000012512
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-year-old boy with intellectual disability-hypotonic facies syndrome (MRXHF1; 309580), a history of hypotonia followed by hypertonia, and asplenia, Leahy et al. (2005) identified a 6811A-G transition in exon 32 of the ATRX gene, resulting in an arg2271-to-gly (R2271G) substitution. The mother was a carrier of the mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
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|
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|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Abidi, F. E., Cardoso, C., Lossi, A.-M., Lowry, R. B., Depetris, D., Mattei, M.-G., Lubs, H. A., Stevenson, R. E., Fontes, M., Chudley, A. E., Schwartz, C. E.
|
|
<strong>Mutation in the 5-prime alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome.</strong>
|
|
Europ. J. Hum. Genet. 13: 176-183, 2005.
|
|
|
|
|
|
[PubMed: 15508018]
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|
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|
|
[Full Text: https://doi.org/10.1038/sj.ejhg.5201303]
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Abidi, F., Schwartz, C. E., Carpenter, N. J., Villard, L., Fontes, M., Curtis, M.
|
|
<strong>Carpenter-Waziri syndrome results from a mutation in XNP. (Letter)</strong>
|
|
Am. J. Med. Genet. 85: 249-251, 1999.
|
|
|
|
|
|
[PubMed: 10398237]
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|
|
|
|
|
[Full Text: https://doi.org/10.1002/(sici)1096-8628(19990730)85:3<249::aid-ajmg12>3.0.co;2-u]
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ades, L. C., Kerr, B., Turner, G., Wise, G.
|
|
<strong>Smith-Fineman-Myers syndrome in two brothers.</strong>
|
|
Am. J. Med. Genet. 40: 467-470, 1991.
|
|
|
|
|
|
[PubMed: 1684092]
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|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.1320400419]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bachoo, S., Gibbons, R. J.
|
|
<strong>Germline and gonosomal mosaicism in the ATR-X syndrome.</strong>
|
|
Europ. J. Hum. Genet. 7: 933-936, 1999.
|
|
|
|
|
|
[PubMed: 10602370]
|
|
|
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|
|
[Full Text: https://doi.org/10.1038/sj.ejhg.5200387]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Badens, C., Lacoste, C., Philip, N., Martini, N., Courrier, S., Giuliano, F., Verloes, A., Munnich, A., Leheup, B., Burglen, L., Odent, S., Van Esch, H., Levy, N.
|
|
<strong>Mutations in PHD-like domain of the ATRX gene correlate with severe psychomotor impairment and severe urogenital abnormalities in patients with ATRX syndrome.</strong>
|
|
Clin. Genet. 70: 57-62, 2006.
|
|
|
|
|
|
[PubMed: 16813605]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1399-0004.2006.00641.x]
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Badens, C., Martini, N., Courrier, S., DesPortes, V., Touraine, R., Levy, N., Edery, P.
|
|
<strong>ATRX syndrome in a girl with a heterozygous mutation in the ATRX Zn finger domain and a totally skewed X-inactivation pattern.</strong>
|
|
Am. J. Med. Genet. 140A: 2212-2215, 2006.
|
|
|
|
|
|
[PubMed: 16955409]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.31400]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
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Ada Hamosh - updated : 2/1/2016<br>Ada Hamosh - updated : 6/24/2015<br>Ada Hamosh - updated : 3/7/2012<br>Ada Hamosh - updated : 9/2/2011<br>Ada Hamosh - updated : 6/6/2011<br>Patricia A. Hartz - updated : 2/17/2011<br>Cassandra L. Kniffin - updated : 10/13/2010<br>Cassandra L. Kniffin - updated : 1/26/2010<br>George E. Tiller - updated : 8/12/2009<br>Cassandra L. Kniffin - updated : 10/16/2007<br>Victor A. McKusick - updated : 5/23/2007<br>Cassandra L. Kniffin - updated : 4/27/2007<br>Cassandra L. Kniffin - updated : 12/18/2006<br>Cassandra L. Kniffin - updated : 8/24/2006<br>Marla J. F. O'Neill - updated : 11/17/2005<br>Cassandra L. Kniffin - updated : 6/23/2005<br>Cassandra L. Kniffin - updated : 5/12/2005<br>Victor A. McKusick - updated : 4/11/2005<br>Patricia A. Hartz - updated : 2/25/2005<br>Cassandra L. Kniffin - updated : 1/25/2005<br>Victor A. McKusick - updated : 7/30/2003<br>Victor A. McKusick - updated : 6/11/2003<br>George E. Tiller - updated : 9/19/2002<br>Victor A. McKusick - updated : 7/2/2002<br>Victor A. McKusick - updated : 1/3/2001<br>George E. Tiller - updated : 4/14/2000<br>Ada Hamosh - updated : 3/29/2000<br>Victor A. McKusick - updated : 3/1/2000<br>Victor A. McKusick - updated : 2/16/2000<br>Victor A. McKusick - updated : 12/8/1999<br>Michael J. Wright - updated : 11/3/1999<br>Victor A. McKusick - updated : 10/6/1998<br>Victor A. McKusick - updated : 5/8/1998<br>Victor A. McKusick - updated : 4/20/1998<br>Victor A. McKusick - updated : 1/21/1998<br>Moyra Smith - updated : 1/24/1997
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Victor A. McKusick : 2/25/1996
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NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers,
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