2546 lines
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Entry
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- #615879 - TATTON-BROWN-RAHMAN SYNDROME; TBRS
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- OMIM
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<p>
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<span class="h4">#615879</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/615879"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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<div><a href="https://clinicaltrials.gov/search?cond=TATTON-BROWN-RAHMAN SYNDROME" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=22920&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK581652/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/dnmt3a-overgrowth-syndrome" 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=615879[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><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=404443" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/1b9c0c78-c794-4580-bd07-0f7843bced94/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
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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 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/disease/DOID:0112339" 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="http://www.informatics.jax.org/disease/615879" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></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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<a id="title" class="mim-anchor"></a>
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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> 768843007<br />
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<strong>ORPHA:</strong> 404443<br />
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<strong>DO:</strong> 0112339<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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615879
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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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TATTON-BROWN-RAHMAN SYNDROME; TBRS
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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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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/2/97?start=-3&limit=10&highlight=97">
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2p23.3
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Tatton-Brown-Rahman syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<a href="/entry/615879"> 615879 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</td>
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<td>
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<span class="mim-font">
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DNMT3A
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/602769"> 602769 </a>
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</span>
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</td>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/615879" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/615879" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/615879" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<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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<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
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</span>
|
|
</div>
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</div>
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</div>
|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> GROWTH </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Height </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Tall stature (+3 S.D) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014547&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014547</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248328003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248328003</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000098" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000098</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Head </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Large head circumference (+2.5 SD) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014549&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014549</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1145403003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1145403003</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000256" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000256</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Face </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Round face <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0239479&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0239479</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000311" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000311</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000311" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000311</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=2ab9bbad3c428d627c2b454902c17fa0" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Face,Round-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=2ab9bbad3c428d627c2b454902c17fa0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})">Elements of Morphology</a>"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Heavy horizontal eyebrows <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014550&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014550</a>]</span><br /> -
|
|
Narrow palpebral fissures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/370116005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">370116005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2675021&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2675021</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0045025" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0045025</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0045025" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0045025</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Heart </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Atrial septal defect (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253366007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253366007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/405752007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">405752007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/70142008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">70142008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q21.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q21.1</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q21.10" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q21.10</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018817&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018817</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001631" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001631</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001631" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001631</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> External Features </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Umbilical hernia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/396347007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">396347007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K42" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K42</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K42.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K42.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/553.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">553.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019322&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019322</a>, <a href="https://bioportal.bioontology.org/search?q=C0041636&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0041636</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001537" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001537</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001537" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001537</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKELETAL </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Hypermobile joints <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866237&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866237</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Spine </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Scoliosis (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/298382003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">298382003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/20944008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">20944008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111266001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111266001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M41.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/M41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M41</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q67.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q67.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0559260&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0559260</a>, <a href="https://bioportal.bioontology.org/search?q=C0036439&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036439</a>, <a href="https://bioportal.bioontology.org/search?q=C0700208&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0700208</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002650" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002650</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002650" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002650</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Intellectual disability, mild to moderate <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4014546&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4014546</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/228156007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">228156007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/110359009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">110359009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317-319.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317-319.99</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
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Seizures (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/91175000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">91175000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036572&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036572</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001250</a>]</span><br /> -
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Small optic chiasm <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747764&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747764</a>]</span><br /> -
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Optic nerve hypoplasia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95499004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95499004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.039" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.039</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.03" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.03</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/377.43" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.43</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0338502&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0338502</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000609" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000609</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000609" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000609</a>]</span><br /> -
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Encephalomalacia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/58762006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">58762006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0014068&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0014068</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0040197" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0040197</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0040197" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0040197</a>]</span><br /> -
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Chiari I malformation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253185002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253185002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0750929&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0750929</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007099" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007099</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007099" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007099</a>]</span><br /> -
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Hypotonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br />
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</span>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> NEOPLASIA </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Increased risk of acute myeloid leukemia, particularly associated with R882 mutations <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5232840&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5232840</a>]</span><br /> -
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Increased risk of hematopoietic malignancies <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5678163&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5678163</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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</span>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- De novo mutation <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2985439&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2985439</a>]</span><br />
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</span>
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</div>
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</div>
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </strong>
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</span>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Caused by mutation in the DNA methyltransferase 3A gene (DNMT3A, <a href="/entry/602769#0001">602769.0001</a>)<br />
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</span>
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<div class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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<div>
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<br />
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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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>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because Tatton-Brown-Rahman syndrome (TBRS) is caused by heterozygous mutation in the DNMT3A gene (<a href="/entry/602769">602769</a>) on chromosome 2p23.</p><p>Heterozygous mutation in the DNMT3A gene can also cause Heyn-Sproul-Jackson syndrome (HESJAS; <a href="/entry/618724">618724</a>), a reciprocal disorder characterized by microcephalic dwarfism and impaired intellectual development.</p>
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<br />
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>Tatton-Brown-Rahman syndrome (TBRS) is characterized by tall stature, a distinctive facial appearance, and impaired intellectual development (<a href="#7" class="mim-tip-reference" title="Tatton-Brown, K., Seal, S., Ruark, E., Harmer, J., Ramsay, E., del Vecchio Duarte, S., Zachariou, A., Hanks, S., O'Brien, E., Aksglaede, L., Baralle, D., Dabir, T., and 12 others. <strong>Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.</strong> Nature Genet. 46: 385-388, 2014. Note: Erratum: Nature Genet. 46: 657 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24614070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24614070</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24614070[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24614070">Tatton-Brown et al., 2014</a>). Some patients may have increased susceptibility to the development of acute myeloid leukemia (AML; <a href="/entry/601626">601626</a>), particularly if they have DNMT3A mutations affecting the R882 residue (<a href="#4" class="mim-tip-reference" title="Hollink, I. H. I. M., van den Ouweland, A. M. W., Beverloo, H. B., Arentsen-Peters, S. T. C. J. M., Zwaan, C. M., Wagner, A. <strong>Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation.</strong> J. Med. Genet. 54: 805-808, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28432085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28432085</a>] [<a href="https://doi.org/10.1136/jmedgenet-2017-104574" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28432085">Hollink et al., 2017</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=24614070+28432085" 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>
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<br />
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<div>
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</h4>
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</div>
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<div id="mimClinicalFeaturesFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#7" class="mim-tip-reference" title="Tatton-Brown, K., Seal, S., Ruark, E., Harmer, J., Ramsay, E., del Vecchio Duarte, S., Zachariou, A., Hanks, S., O'Brien, E., Aksglaede, L., Baralle, D., Dabir, T., and 12 others. <strong>Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.</strong> Nature Genet. 46: 385-388, 2014. Note: Erratum: Nature Genet. 46: 657 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24614070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24614070</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24614070[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24614070">Tatton-Brown et al. (2014)</a> reported 13 unrelated patients with a similar phenotype characterized by tall stature (mean of +3.0 SD), large head circumference (mean of +2.5 SD), and a facial gestalt manifest as round face, heavy horizontal eyebrows, and narrow palpebral fissures. Intellectual disability was described as moderate in 11 patients and mild in 2 patients. Less common and variable features included atrial septal defects, seizures, umbilical hernia, and scoliosis. None of the patients had a hematologic malignancy. <a href="#7" class="mim-tip-reference" title="Tatton-Brown, K., Seal, S., Ruark, E., Harmer, J., Ramsay, E., del Vecchio Duarte, S., Zachariou, A., Hanks, S., O'Brien, E., Aksglaede, L., Baralle, D., Dabir, T., and 12 others. <strong>Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.</strong> Nature Genet. 46: 385-388, 2014. Note: Erratum: Nature Genet. 46: 657 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24614070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24614070</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24614070[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24614070">Tatton-Brown et al. (2014)</a> proposed the term 'DNMT3A overgrowth syndrome' to refer to the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24614070" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Kosaki, R., Terashima, H., Kubota, M., Kosaki, K. <strong>Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation.</strong> Am. J. Med. Genet. 173A: 250-253, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27991732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27991732</a>] [<a href="https://doi.org/10.1002/ajmg.a.37995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27991732">Kosaki et al. (2017)</a> reported a 6-year-old girl, born of healthy nonconsanguineous parents, with Tatton-Brown-Rahman syndrome. Her characteristic features at birth included hypotonia, ventricular septal defect, umbilical hernia, sacral cyst, and Chiari type I anomaly. She had a round face, hypertelorism, narrow palpebral fissures, short upturned nose, deep philtrum, protruding upper lip, and short columella. At age 6 years, she exhibited overgrowth (+3 SD) and intellectual disability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27991732" 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="Shen, W., Heeley, J. M., Carlston, C. M., Acuna-Hidalgo, R., Nillesen, W. M., Dent, K. M., Douglas, G. V., Levine, K. L., Bayrak-Toydemir, P., Marcelis, C. L., Shinawi, M., Carey, J. C. <strong>The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies.</strong> Am. J. Med. Genet. 173A: 3022-3028, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28941052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28941052</a>] [<a href="https://doi.org/10.1002/ajmg.a.38485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28941052">Shen et al. (2017)</a> reported 3 additional patients with Tatton-Brown-Rahman syndrome. Patients 1 and 2 had characteristic features of the disorder, including moderate intellectual disability (IQ, 40 and 50), tall stature, and a long oval-shaped face with heavy eyebrows and narrow palpebral fissures. Patient 3 had atypical features, including severe intellectual disability, short stature, and coarse facies with long palpebral fissures, low-set ears and a prominent chin. The authors suggested that the atypical presentation of patient 3 may have resulted from his complicated prenatal history (maternal diabetes, polyhydramnios, premature rupture of membranes, preterm delivery) and hydrocephaly in early infancy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28941052" 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="Hollink, I. H. I. M., van den Ouweland, A. M. W., Beverloo, H. B., Arentsen-Peters, S. T. C. J. M., Zwaan, C. M., Wagner, A. <strong>Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation.</strong> J. Med. Genet. 54: 805-808, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28432085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28432085</a>] [<a href="https://doi.org/10.1136/jmedgenet-2017-104574" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28432085">Hollink et al. (2017)</a> reported a 19-year-old Dutch man with TBRS confirmed by genetic analysis. He had characteristic features of the disorder, including delayed development since infancy, hypotonia, macrocephaly, obesity, scoliosis, minor cardiac septal defect, seizures, and dysmorphic facial features, including heavy eyebrows, narrow palpebral fissures, short neck, and thin upper lip. At age 15 years, he developed AML (FAB type M5), which was successfully treated with chemotherapy. Genetic analysis identified a de novo heterozygous germline R882C mutation in the DNMT3A gene (<a href="/entry/602769#0007">602769.0007</a>). Analysis of leukemic cells showed an aberrant karyotype and a recurrent somatic PTPN11 mutation (T73I; <a href="/entry/176876#0011">176876.0011</a>), but no additional somatic mutations or loss of heterozygosity of the DNMT3A gene. <a href="#4" class="mim-tip-reference" title="Hollink, I. H. I. M., van den Ouweland, A. M. W., Beverloo, H. B., Arentsen-Peters, S. T. C. J. M., Zwaan, C. M., Wagner, A. <strong>Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation.</strong> J. Med. Genet. 54: 805-808, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28432085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28432085</a>] [<a href="https://doi.org/10.1136/jmedgenet-2017-104574" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28432085">Hollink et al. (2017)</a> suggested that mutations at the R882 residue, which are associated with AML in the somatic state, may also predispose germline carriers of the mutation to the development of AML. The authors postulated epigenetic dysregulation as a possible molecular mechanism and suggested that patients with TBRS be followed for hematologic malignancies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28432085" 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 6-year-old girl (patient 5), who was previously reported by <a href="#2" class="mim-tip-reference" title="DeMari, J., Mroske, C., Tang, S., Nimeh, J., Miller, R., Lebel, R. R. <strong>CLTC as a clinically novel gene associated with multiple malformations and developmental delay.</strong> Am. J. Med. Genet. 170A: 958-966, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26822784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26822784</a>] [<a href="https://doi.org/10.1002/ajmg.a.37506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26822784">DeMari et al. (2016)</a> at age 3.5 years with global developmental delay (MRD56; <a href="/entry/617854">617854</a>) and a heterozygous mutation in the CLTC gene (<a href="/entry/118955#0001">118955.0001</a>), <a href="#1" class="mim-tip-reference" title="Balci, T. B., Strong, A., Kalish, J. M., Zackai, E., Maris, J. M., Reilly, A., Surrey, L. F., Werthei, G. B., Marcadier, J. L., Graham, G. E., Carter, M. T. <strong>Tatton-Brown-Rahman syndrome: six individuals with novel features.</strong> Am. J. Med. Genet. 182A: 673-680, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31961069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31961069</a>] [<a href="https://doi.org/10.1002/ajmg.a.61475" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31961069">Balci et al. (2020)</a> identified heterozygosity for the recurrent R882C mutation in the DNMT3A gene. At age 6 years, the child presented with lymphadenopathy, a mediastinal mass, and hypercalcemia, and was diagnosed with T-cell lymphoblastic lymphoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=31961069+26822784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Ferris, M. A., Smith, A. M., Heath, S. E., Duncavage, E. J., Oberley, M., Freyer, D., Wynn, R., Douzgou, S., Maris, J. M., Reilly, A. F., Wu, M. D., Choo, F., Fiets, R. B., Koene, S., Spencer, D. H., Miller, C. A., Shinawi, M., Ley, T. J. <strong>DNMT3A overgrowth syndrome is associated with the development of hematopoietic malignancies in children and young adults. (Letter)</strong> Blood 139: 461-464, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34788385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34788385</a>] [<a href="https://doi.org/10.1182/blood.2021014052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34788385">Ferris et al. (2022)</a> reported 8 patients with TBRS and a history of hematopoietic malignancy and 1 patient with TBRS and chronic multilineage cytopenias. Three of these patients, including patient 3 (patient 5 in <a href="#1" class="mim-tip-reference" title="Balci, T. B., Strong, A., Kalish, J. M., Zackai, E., Maris, J. M., Reilly, A., Surrey, L. F., Werthei, G. B., Marcadier, J. L., Graham, G. E., Carter, M. T. <strong>Tatton-Brown-Rahman syndrome: six individuals with novel features.</strong> Am. J. Med. Genet. 182A: 673-680, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31961069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31961069</a>] [<a href="https://doi.org/10.1002/ajmg.a.61475" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31961069">Balci et al. (2020)</a>), were previously reported. The diagnoses, which were made between the ages of 5 and 34 years, included 4 patients with acute myeloid leukemia, 1 patient with Hodgkin lymphoma, 1 patient with essential thrombocytosis, and 1 patient with B-cell acute lymphoblastic leukemia. One of the previously reported patients (patient 4) had a metastatic ganglioneuroblastoma diagnosed at 1.6 years of age and posttherapy T-cell lymphoblastic leukemia diagnosed at 6 years of age. <a href="#3" class="mim-tip-reference" title="Ferris, M. A., Smith, A. M., Heath, S. E., Duncavage, E. J., Oberley, M., Freyer, D., Wynn, R., Douzgou, S., Maris, J. M., Reilly, A. F., Wu, M. D., Choo, F., Fiets, R. B., Koene, S., Spencer, D. H., Miller, C. A., Shinawi, M., Ley, T. J. <strong>DNMT3A overgrowth syndrome is associated with the development of hematopoietic malignancies in children and young adults. (Letter)</strong> Blood 139: 461-464, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34788385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34788385</a>] [<a href="https://doi.org/10.1182/blood.2021014052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34788385">Ferris et al. (2022)</a> estimated a 4% prevalence of hematopoietic malignancies in known cases of TBRS, which suggests a greater than 250-fold increase in the risk of hematopoietic malignancy. <a href="#3" class="mim-tip-reference" title="Ferris, M. A., Smith, A. M., Heath, S. E., Duncavage, E. J., Oberley, M., Freyer, D., Wynn, R., Douzgou, S., Maris, J. M., Reilly, A. F., Wu, M. D., Choo, F., Fiets, R. B., Koene, S., Spencer, D. H., Miller, C. A., Shinawi, M., Ley, T. J. <strong>DNMT3A overgrowth syndrome is associated with the development of hematopoietic malignancies in children and young adults. (Letter)</strong> Blood 139: 461-464, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34788385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34788385</a>] [<a href="https://doi.org/10.1182/blood.2021014052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34788385">Ferris et al. (2022)</a> recommended annual monitoring of complete blood counts (or more frequently if abnormalities are present) to understand the risk of developing hematopoietic malignancies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=34788385+31961069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The heterozygous mutations in the DNMT3A gene that were identified by <a href="#7" class="mim-tip-reference" title="Tatton-Brown, K., Seal, S., Ruark, E., Harmer, J., Ramsay, E., del Vecchio Duarte, S., Zachariou, A., Hanks, S., O'Brien, E., Aksglaede, L., Baralle, D., Dabir, T., and 12 others. <strong>Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.</strong> Nature Genet. 46: 385-388, 2014. Note: Erratum: Nature Genet. 46: 657 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24614070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24614070</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24614070[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24614070">Tatton-Brown et al. (2014)</a> in 13 unrelated patients with TBRS occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24614070" 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 13 unrelated patients with tall stature, distinctive facies, and intellectual disability, <a href="#7" class="mim-tip-reference" title="Tatton-Brown, K., Seal, S., Ruark, E., Harmer, J., Ramsay, E., del Vecchio Duarte, S., Zachariou, A., Hanks, S., O'Brien, E., Aksglaede, L., Baralle, D., Dabir, T., and 12 others. <strong>Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.</strong> Nature Genet. 46: 385-388, 2014. Note: Erratum: Nature Genet. 46: 657 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24614070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24614070</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24614070[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24614070">Tatton-Brown et al. (2014)</a> identified 13 different de novo heterozygous mutations in the DNMT3A gene (see, e.g., <a href="/entry/602769#0001">602769.0001</a>-<a href="/entry/602769#0005">602769.0005</a>). The first 2 mutations were found by exome sequencing of 10 patients with an overgrowth disorder, and the subsequent 11 mutations were found by sequencing the DNMT3A gene in 152 patients with an overgrowth disorder. The mutations altered residues in functional domains of the protein, and protein modeling suggested that they may interfere with domain-domain interactions and histone binding, thereby disrupting de novo methylation. However, in vitro functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24614070" 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 6-year-old girl with TBRS, <a href="#5" class="mim-tip-reference" title="Kosaki, R., Terashima, H., Kubota, M., Kosaki, K. <strong>Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation.</strong> Am. J. Med. Genet. 173A: 250-253, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27991732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27991732</a>] [<a href="https://doi.org/10.1002/ajmg.a.37995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27991732">Kosaki et al. (2017)</a> identified a de novo heterozygous missense mutation (R882H; <a href="/entry/602769#0006">602769.0006</a>) in the DNMT3A gene. The authors noted that the arg882 residue is a somatic mutation hotspot for acute myelogeneous leukemia (AML; see <a href="/entry/601626">601626</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27991732" 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 3 unrelated patients with TBRS, <a href="#6" class="mim-tip-reference" title="Shen, W., Heeley, J. M., Carlston, C. M., Acuna-Hidalgo, R., Nillesen, W. M., Dent, K. M., Douglas, G. V., Levine, K. L., Bayrak-Toydemir, P., Marcelis, C. L., Shinawi, M., Carey, J. C. <strong>The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies.</strong> Am. J. Med. Genet. 173A: 3022-3028, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28941052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28941052</a>] [<a href="https://doi.org/10.1002/ajmg.a.38485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28941052">Shen et al. (2017)</a> identified 2 different de novo heterozygous mutations at the arg882 residue in the DNMT3A gene: R882H and R882C (<a href="/entry/602769#0007">602769.0007</a>). <a href="#6" class="mim-tip-reference" title="Shen, W., Heeley, J. M., Carlston, C. M., Acuna-Hidalgo, R., Nillesen, W. M., Dent, K. M., Douglas, G. V., Levine, K. L., Bayrak-Toydemir, P., Marcelis, C. L., Shinawi, M., Carey, J. C. <strong>The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies.</strong> Am. J. Med. Genet. 173A: 3022-3028, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28941052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28941052</a>] [<a href="https://doi.org/10.1002/ajmg.a.38485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28941052">Shen et al. (2017)</a> stated that there were 23 known mutations in the DNMT3A gene in patients with TBRS, including 6 recurrent mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28941052" 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 6-year-old girl (patient 5), who was previously reported by <a href="#2" class="mim-tip-reference" title="DeMari, J., Mroske, C., Tang, S., Nimeh, J., Miller, R., Lebel, R. R. <strong>CLTC as a clinically novel gene associated with multiple malformations and developmental delay.</strong> Am. J. Med. Genet. 170A: 958-966, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26822784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26822784</a>] [<a href="https://doi.org/10.1002/ajmg.a.37506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26822784">DeMari et al. (2016)</a> at age 3.5 years with global developmental delay (MRD56; <a href="/entry/617854">617854</a>) and a heterozygous mutation in the CLTC gene (<a href="/entry/118955#0001">118955.0001</a>), <a href="#1" class="mim-tip-reference" title="Balci, T. B., Strong, A., Kalish, J. M., Zackai, E., Maris, J. M., Reilly, A., Surrey, L. F., Werthei, G. B., Marcadier, J. L., Graham, G. E., Carter, M. T. <strong>Tatton-Brown-Rahman syndrome: six individuals with novel features.</strong> Am. J. Med. Genet. 182A: 673-680, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31961069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31961069</a>] [<a href="https://doi.org/10.1002/ajmg.a.61475" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31961069">Balci et al. (2020)</a> identified heterozygosity for the recurrent R882C mutation in the DNMT3A gene (<a href="/entry/602769#0007">602769.0007</a>). At age 6 years, the child presented with lymphadenopathy, a mediastinal mass, and hypercalcemia, and was diagnosed with T-cell lymphoblastic lymphoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=31961069+26822784" 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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Balci, T. B., Strong, A., Kalish, J. M., Zackai, E., Maris, J. M., Reilly, A., Surrey, L. F., Werthei, G. B., Marcadier, J. L., Graham, G. E., Carter, M. T.
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<strong>Tatton-Brown-Rahman syndrome: six individuals with novel features.</strong>
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Am. J. Med. Genet. 182A: 673-680, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31961069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31961069</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31961069" 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.61475" target="_blank">Full Text</a>]
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<a id="DeMari2016" class="mim-anchor"></a>
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DeMari, J., Mroske, C., Tang, S., Nimeh, J., Miller, R., Lebel, R. R.
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<strong>CLTC as a clinically novel gene associated with multiple malformations and developmental delay.</strong>
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Am. J. Med. Genet. 170A: 958-966, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26822784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26822784</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26822784" 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.37506" target="_blank">Full Text</a>]
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<a id="Ferris2022" class="mim-anchor"></a>
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Ferris, M. A., Smith, A. M., Heath, S. E., Duncavage, E. J., Oberley, M., Freyer, D., Wynn, R., Douzgou, S., Maris, J. M., Reilly, A. F., Wu, M. D., Choo, F., Fiets, R. B., Koene, S., Spencer, D. H., Miller, C. A., Shinawi, M., Ley, T. J.
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<strong>DNMT3A overgrowth syndrome is associated with the development of hematopoietic malignancies in children and young adults. (Letter)</strong>
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Blood 139: 461-464, 2022.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34788385/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34788385</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34788385" 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/10.1182/blood.2021014052" target="_blank">Full Text</a>]
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<a id="Hollink2017" class="mim-anchor"></a>
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Hollink, I. H. I. M., van den Ouweland, A. M. W., Beverloo, H. B., Arentsen-Peters, S. T. C. J. M., Zwaan, C. M., Wagner, A.
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<strong>Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation.</strong>
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J. Med. Genet. 54: 805-808, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28432085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28432085</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28432085" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2017-104574" target="_blank">Full Text</a>]
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<a id="Kosaki2017" class="mim-anchor"></a>
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Kosaki, R., Terashima, H., Kubota, M., Kosaki, K.
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<strong>Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation.</strong>
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Am. J. Med. Genet. 173A: 250-253, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27991732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27991732</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27991732" 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.37995" target="_blank">Full Text</a>]
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Shen, W., Heeley, J. M., Carlston, C. M., Acuna-Hidalgo, R., Nillesen, W. M., Dent, K. M., Douglas, G. V., Levine, K. L., Bayrak-Toydemir, P., Marcelis, C. L., Shinawi, M., Carey, J. C.
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<strong>The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies.</strong>
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Am. J. Med. Genet. 173A: 3022-3028, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28941052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28941052</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28941052" 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.38485" target="_blank">Full Text</a>]
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<a id="Tatton-Brown2014" class="mim-anchor"></a>
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Tatton-Brown, K., Seal, S., Ruark, E., Harmer, J., Ramsay, E., del Vecchio Duarte, S., Zachariou, A., Hanks, S., O'Brien, E., Aksglaede, L., Baralle, D., Dabir, T., and 12 others.
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<strong>Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.</strong>
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Nature Genet. 46: 385-388, 2014. Note: Erratum: Nature Genet. 46: 657 only, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24614070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24614070</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24614070[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=24614070" 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/ng.2917" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 07/27/2022
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Carol A. Bocchini - updated : 03/24/2021<br>Cassandra L. Kniffin - updated : 01/29/2020<br>D. Isum Ward - updated : 03/22/2018
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Cassandra L. Kniffin : 7/9/2014
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carol : 07/28/2022
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carol : 07/27/2022<br>carol : 10/20/2021<br>carol : 03/24/2021<br>alopez : 01/31/2020<br>ckniffin : 01/29/2020<br>carol : 01/02/2020<br>ckniffin : 01/01/2020<br>carol : 03/22/2018<br>carol : 07/10/2014<br>mcolton : 7/10/2014<br>ckniffin : 7/9/2014
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<strong>#</strong> 615879
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TATTON-BROWN-RAHMAN SYNDROME; TBRS
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<strong>SNOMEDCT:</strong> 768843007;
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<strong>ORPHA:</strong> 404443;
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<strong>DO:</strong> 0112339;
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Inheritance
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2p23.3
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<span class="mim-font">
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Tatton-Brown-Rahman syndrome
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615879
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Autosomal dominant
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3
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DNMT3A
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<span class="mim-font">
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602769
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<p>A number sign (#) is used with this entry because Tatton-Brown-Rahman syndrome (TBRS) is caused by heterozygous mutation in the DNMT3A gene (602769) on chromosome 2p23.</p><p>Heterozygous mutation in the DNMT3A gene can also cause Heyn-Sproul-Jackson syndrome (HESJAS; 618724), a reciprocal disorder characterized by microcephalic dwarfism and impaired intellectual development.</p>
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<p>Tatton-Brown-Rahman syndrome (TBRS) is characterized by tall stature, a distinctive facial appearance, and impaired intellectual development (Tatton-Brown et al., 2014). Some patients may have increased susceptibility to the development of acute myeloid leukemia (AML; 601626), particularly if they have DNMT3A mutations affecting the R882 residue (Hollink et al., 2017). </p>
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<strong>Clinical Features</strong>
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<p>Tatton-Brown et al. (2014) reported 13 unrelated patients with a similar phenotype characterized by tall stature (mean of +3.0 SD), large head circumference (mean of +2.5 SD), and a facial gestalt manifest as round face, heavy horizontal eyebrows, and narrow palpebral fissures. Intellectual disability was described as moderate in 11 patients and mild in 2 patients. Less common and variable features included atrial septal defects, seizures, umbilical hernia, and scoliosis. None of the patients had a hematologic malignancy. Tatton-Brown et al. (2014) proposed the term 'DNMT3A overgrowth syndrome' to refer to the disorder. </p><p>Kosaki et al. (2017) reported a 6-year-old girl, born of healthy nonconsanguineous parents, with Tatton-Brown-Rahman syndrome. Her characteristic features at birth included hypotonia, ventricular septal defect, umbilical hernia, sacral cyst, and Chiari type I anomaly. She had a round face, hypertelorism, narrow palpebral fissures, short upturned nose, deep philtrum, protruding upper lip, and short columella. At age 6 years, she exhibited overgrowth (+3 SD) and intellectual disability. </p><p>Shen et al. (2017) reported 3 additional patients with Tatton-Brown-Rahman syndrome. Patients 1 and 2 had characteristic features of the disorder, including moderate intellectual disability (IQ, 40 and 50), tall stature, and a long oval-shaped face with heavy eyebrows and narrow palpebral fissures. Patient 3 had atypical features, including severe intellectual disability, short stature, and coarse facies with long palpebral fissures, low-set ears and a prominent chin. The authors suggested that the atypical presentation of patient 3 may have resulted from his complicated prenatal history (maternal diabetes, polyhydramnios, premature rupture of membranes, preterm delivery) and hydrocephaly in early infancy. </p><p>Hollink et al. (2017) reported a 19-year-old Dutch man with TBRS confirmed by genetic analysis. He had characteristic features of the disorder, including delayed development since infancy, hypotonia, macrocephaly, obesity, scoliosis, minor cardiac septal defect, seizures, and dysmorphic facial features, including heavy eyebrows, narrow palpebral fissures, short neck, and thin upper lip. At age 15 years, he developed AML (FAB type M5), which was successfully treated with chemotherapy. Genetic analysis identified a de novo heterozygous germline R882C mutation in the DNMT3A gene (602769.0007). Analysis of leukemic cells showed an aberrant karyotype and a recurrent somatic PTPN11 mutation (T73I; 176876.0011), but no additional somatic mutations or loss of heterozygosity of the DNMT3A gene. Hollink et al. (2017) suggested that mutations at the R882 residue, which are associated with AML in the somatic state, may also predispose germline carriers of the mutation to the development of AML. The authors postulated epigenetic dysregulation as a possible molecular mechanism and suggested that patients with TBRS be followed for hematologic malignancies. </p><p>In a 6-year-old girl (patient 5), who was previously reported by DeMari et al. (2016) at age 3.5 years with global developmental delay (MRD56; 617854) and a heterozygous mutation in the CLTC gene (118955.0001), Balci et al. (2020) identified heterozygosity for the recurrent R882C mutation in the DNMT3A gene. At age 6 years, the child presented with lymphadenopathy, a mediastinal mass, and hypercalcemia, and was diagnosed with T-cell lymphoblastic lymphoma. </p><p>Ferris et al. (2022) reported 8 patients with TBRS and a history of hematopoietic malignancy and 1 patient with TBRS and chronic multilineage cytopenias. Three of these patients, including patient 3 (patient 5 in Balci et al. (2020)), were previously reported. The diagnoses, which were made between the ages of 5 and 34 years, included 4 patients with acute myeloid leukemia, 1 patient with Hodgkin lymphoma, 1 patient with essential thrombocytosis, and 1 patient with B-cell acute lymphoblastic leukemia. One of the previously reported patients (patient 4) had a metastatic ganglioneuroblastoma diagnosed at 1.6 years of age and posttherapy T-cell lymphoblastic leukemia diagnosed at 6 years of age. Ferris et al. (2022) estimated a 4% prevalence of hematopoietic malignancies in known cases of TBRS, which suggests a greater than 250-fold increase in the risk of hematopoietic malignancy. Ferris et al. (2022) recommended annual monitoring of complete blood counts (or more frequently if abnormalities are present) to understand the risk of developing hematopoietic malignancies. </p>
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<strong>Inheritance</strong>
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<p>The heterozygous mutations in the DNMT3A gene that were identified by Tatton-Brown et al. (2014) in 13 unrelated patients with TBRS occurred de novo. </p>
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<strong>Molecular Genetics</strong>
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<p>In 13 unrelated patients with tall stature, distinctive facies, and intellectual disability, Tatton-Brown et al. (2014) identified 13 different de novo heterozygous mutations in the DNMT3A gene (see, e.g., 602769.0001-602769.0005). The first 2 mutations were found by exome sequencing of 10 patients with an overgrowth disorder, and the subsequent 11 mutations were found by sequencing the DNMT3A gene in 152 patients with an overgrowth disorder. The mutations altered residues in functional domains of the protein, and protein modeling suggested that they may interfere with domain-domain interactions and histone binding, thereby disrupting de novo methylation. However, in vitro functional studies were not performed. </p><p>In a 6-year-old girl with TBRS, Kosaki et al. (2017) identified a de novo heterozygous missense mutation (R882H; 602769.0006) in the DNMT3A gene. The authors noted that the arg882 residue is a somatic mutation hotspot for acute myelogeneous leukemia (AML; see 601626). </p><p>In 3 unrelated patients with TBRS, Shen et al. (2017) identified 2 different de novo heterozygous mutations at the arg882 residue in the DNMT3A gene: R882H and R882C (602769.0007). Shen et al. (2017) stated that there were 23 known mutations in the DNMT3A gene in patients with TBRS, including 6 recurrent mutations. </p><p>In a 6-year-old girl (patient 5), who was previously reported by DeMari et al. (2016) at age 3.5 years with global developmental delay (MRD56; 617854) and a heterozygous mutation in the CLTC gene (118955.0001), Balci et al. (2020) identified heterozygosity for the recurrent R882C mutation in the DNMT3A gene (602769.0007). At age 6 years, the child presented with lymphadenopathy, a mediastinal mass, and hypercalcemia, and was diagnosed with T-cell lymphoblastic lymphoma. </p>
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<strong>REFERENCES</strong>
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Balci, T. B., Strong, A., Kalish, J. M., Zackai, E., Maris, J. M., Reilly, A., Surrey, L. F., Werthei, G. B., Marcadier, J. L., Graham, G. E., Carter, M. T.
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<strong>Tatton-Brown-Rahman syndrome: six individuals with novel features.</strong>
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Am. J. Med. Genet. 182A: 673-680, 2020.
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[PubMed: 31961069]
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[Full Text: https://doi.org/10.1002/ajmg.a.61475]
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DeMari, J., Mroske, C., Tang, S., Nimeh, J., Miller, R., Lebel, R. R.
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<strong>CLTC as a clinically novel gene associated with multiple malformations and developmental delay.</strong>
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Am. J. Med. Genet. 170A: 958-966, 2016.
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[PubMed: 26822784]
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[Full Text: https://doi.org/10.1002/ajmg.a.37506]
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Ferris, M. A., Smith, A. M., Heath, S. E., Duncavage, E. J., Oberley, M., Freyer, D., Wynn, R., Douzgou, S., Maris, J. M., Reilly, A. F., Wu, M. D., Choo, F., Fiets, R. B., Koene, S., Spencer, D. H., Miller, C. A., Shinawi, M., Ley, T. J.
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<strong>DNMT3A overgrowth syndrome is associated with the development of hematopoietic malignancies in children and young adults. (Letter)</strong>
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Blood 139: 461-464, 2022.
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[PubMed: 34788385]
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[Full Text: https://doi.org/10.1182/blood.2021014052]
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Hollink, I. H. I. M., van den Ouweland, A. M. W., Beverloo, H. B., Arentsen-Peters, S. T. C. J. M., Zwaan, C. M., Wagner, A.
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<strong>Acute myeloid leukaemia in a case with Tatton-Brown-Rahman syndrome: the peculiar DNMT3A R882 mutation.</strong>
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J. Med. Genet. 54: 805-808, 2017.
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[PubMed: 28432085]
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[Full Text: https://doi.org/10.1136/jmedgenet-2017-104574]
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Kosaki, R., Terashima, H., Kubota, M., Kosaki, K.
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<strong>Acute myeloid leukemia-associated DNMT3A p.Arg882His mutation in a patient with Tatton-Brown-Rahman overgrowth syndrome as a constitutional mutation.</strong>
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Am. J. Med. Genet. 173A: 250-253, 2017.
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[PubMed: 27991732]
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[Full Text: https://doi.org/10.1002/ajmg.a.37995]
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Shen, W., Heeley, J. M., Carlston, C. M., Acuna-Hidalgo, R., Nillesen, W. M., Dent, K. M., Douglas, G. V., Levine, K. L., Bayrak-Toydemir, P., Marcelis, C. L., Shinawi, M., Carey, J. C.
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<strong>The spectrum of DNMT3A variants in Tatton-Brown-Rahman syndrome overlaps with that in hematologic malignancies.</strong>
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Am. J. Med. Genet. 173A: 3022-3028, 2017.
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[PubMed: 28941052]
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[Full Text: https://doi.org/10.1002/ajmg.a.38485]
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Tatton-Brown, K., Seal, S., Ruark, E., Harmer, J., Ramsay, E., del Vecchio Duarte, S., Zachariou, A., Hanks, S., O'Brien, E., Aksglaede, L., Baralle, D., Dabir, T., and 12 others.
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<strong>Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.</strong>
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Nature Genet. 46: 385-388, 2014. Note: Erratum: Nature Genet. 46: 657 only, 2014.
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[PubMed: 24614070]
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[Full Text: https://doi.org/10.1038/ng.2917]
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Hilary J. Vernon - updated : 07/27/2022<br>Carol A. Bocchini - updated : 03/24/2021<br>Cassandra L. Kniffin - updated : 01/29/2020<br>D. Isum Ward - updated : 03/22/2018
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