2461 lines
188 KiB
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2461 lines
188 KiB
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Entry
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- #614254 - NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT HYPERKINETIC MOVEMENTS AND SEIZURES, AUTOSOMAL DOMINANT; NDHMSD
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- OMIM
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<p>
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<span class="h4">#614254</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/614254"><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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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT HYPERKINETIC MOVEMENTS AND SEIZURES, AUTOSOMAL DOMINANT" 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=18028&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/NBK542807/" 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://www.diseaseinfosearch.org/x/8831" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=614254[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=178469" 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 style="display: table-cell;">Animal Models</div>
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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:0070038" 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/614254" 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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<div><a href="https://wormbase.org/resources/disease/DOID:0070038" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</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>ORPHA:</strong> 178469<br />
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<strong>DO:</strong> 0070038<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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614254
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</span>
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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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NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT HYPERKINETIC MOVEMENTS AND SEIZURES, AUTOSOMAL DOMINANT; NDHMSD
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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="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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MENTAL RETARDATION, AUTOSOMAL DOMINANT 8, FORMERLY; MRD8, FORMERLY
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<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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</th>
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</thead>
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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/9/683?start=-3&limit=10&highlight=683">
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9q34.3
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</a>
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</td>
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<td>
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<span class="mim-font">
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Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/614254"> 614254 </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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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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GRIN1
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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/138249"> 138249 </a>
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</span>
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</td>
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</tr>
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</table>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/614254" 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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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/614254" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/614254" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
|
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> INHERITANCE </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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- 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>
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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">
|
|
<strong> HEAD & NECK </strong>
|
|
</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<em> Head </em>
|
|
</span>
|
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</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Microcephaly (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1148757008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1148757008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q02" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q02</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/742.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">742.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4551563&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4551563</a>, <a href="https://bioportal.bioontology.org/search?q=C0025958&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025958</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000252</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" target="_blank" class="small mim-tip-eom" title="<img src="https://elementsofmorphology.nih.gov/images/terms/Microcephaly-small.jpg"> <br/>Further Information: <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0584d323b99dcd7001cc50e224947aca" 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 />
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</span>
|
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</div>
|
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</div>
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|
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<div>
|
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<div>
|
|
<span class="h5 mim-font">
|
|
<em> Eyes </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Poor visual contact <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3552514&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3552514</a>]</span><br /> -
|
|
Cortical blindness (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413924001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413924001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/68574006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">68574006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H47.61" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H47.61</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/377.75" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">377.75</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0155320&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0155320</a>, <a href="https://bioportal.bioontology.org/search?q=C4048268&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4048268</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100704" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100704</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100704" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100704</a>]</span><br /> -
|
|
Oculogyric crisis <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/5332004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">5332004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085637&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085637</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010553" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010553</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010553" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010553</a>]</span><br />
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|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
|
|
|
|
</div>
|
|
|
|
</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> ABDOMEN </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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|
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Gastrointestinal </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Poor feeding <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/299698007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">299698007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/78164000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">78164000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R63.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R63.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0576456&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0576456</a>, <a href="https://bioportal.bioontology.org/search?q=C0232466&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0232466</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011968" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011968</a>]</span><br /> -
|
|
Constipation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/14760008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">14760008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.0</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/K59.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">K59.00</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/564.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/564.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">564.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0009806&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0009806</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002019</a>]</span><br />
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|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
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|
|
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|
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|
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|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKELETAL </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Spine </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Scoliosis <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 />
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|
</span>
|
|
</div>
|
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</div>
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</div>
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</div>
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|
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|
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|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MUSCLE, SOFT TISSUES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Hypotonia, severe <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839630&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839630</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006829</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006829" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006829</a>]</span> <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><br />
|
|
|
|
</span>
|
|
</div>
|
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|
|
</div>
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|
|
</div>
|
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|
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> NEUROLOGIC </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
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<div>
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<span class="h5 mim-font">
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<em> Central Nervous System </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Delayed psychomotor development, profound <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278113&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278113</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/224958001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">224958001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F88</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001263" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001263</a>]</span><br /> -
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Intellectual disability, severe <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40700009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40700009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F72" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F72</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/318.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">318.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0036857&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0036857</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010864" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010864</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010864" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010864</a>]</span><br /> -
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Inability to walk independently <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2674510&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2674510</a>]</span><br /> -
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Poor or absent speech <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3278212&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3278212</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000750" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000750</a>]</span><br /> -
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Hyperkinetic movements <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/44548000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">44548000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3887506&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3887506</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002487" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002487</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002487" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002487</a>]</span><br /> -
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Spasticity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/221360009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">221360009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/397790002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">397790002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026838&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026838</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001257" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001257</a>]</span><br /> -
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Hyperreflexia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/86854008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">86854008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151889&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151889</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001347</a>]</span><br /> -
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Dystonia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15802004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15802004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013421&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013421</a>, <a href="https://bioportal.bioontology.org/search?q=C0393593&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0393593</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001332" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001332</a>]</span><br /> -
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Chorea <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/271700006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">271700006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G25.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G25.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0008489&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0008489</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002072" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002072</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002072" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002072</a>]</span><br /> -
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Dyskinesia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/9748009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">9748009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G24" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G24</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0013384&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013384</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100660" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100660</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100660" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100660</a>]</span><br /> -
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Myoclonus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/17450006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">17450006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G25.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G25.3</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/333.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">333.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0027066&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0027066</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001336" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001336</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001336" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001336</a>]</span><br /> -
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Sleep disorder <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/39898005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">39898005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G47" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G47</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G47.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G47.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0851578&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0851578</a>]</span><br /> -
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Seizures, variable types (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4314178&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4314178</a>]</span> <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">[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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EEG abnormalities <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/274521009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">274521009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R94.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R94.01</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0151611&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0151611</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002353" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002353</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002353" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002353</a>]</span><br /> -
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Cerebral atrophy <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/278849000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">278849000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0235946&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0235946</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002059" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002059</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002059" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002059</a>]</span><br /> -
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Thin corpus callosum <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5441562&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5441562</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033725" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033725</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033725" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033725</a>]</span><br /> -
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Polymicrogyria (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/4945003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">4945003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0266464&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0266464</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002126" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002126</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002126" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002126</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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<span class="h5 mim-font">
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<em> Behavioral Psychiatric Manifestations </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- Autistic features <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1846135&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1846135</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000729" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000729</a>]</span><br /> -
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Stereotypic movements <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853236&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853236</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000733" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000733</a>]</span><br /> -
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Self-injurious behavior <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248062006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248062006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R45.88" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R45.88</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0085271&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0085271</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100716</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100716" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100716</a>]</span><br />
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<strong> MISCELLANEOUS </strong>
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- Onset in infancy <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1848924&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1848924</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003593" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003593</a>]</span><br /> -
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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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<strong> MOLECULAR BASIS </strong>
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- Caused by mutation in the glutamate receptor, ionotropic, N-methyl-D-aspartate, subunit 1 gene (GRIN1, <a href="/entry/138249#0001">138249.0001</a>)<br />
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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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<p>A number sign (#) is used with this entry because of evidence that autosomal dominant neurodevelopmental disorder with or without hyperkinetic movements and seizures (NDHMSD) is caused by heterozygous mutation in the GRIN1 gene (<a href="/entry/138249">138249</a>) on chromosome 9q34.</p><p>Homozygous mutation in the GRIN1 gene can cause autosomal recessive neurodevelopmental disorder with or without hyperkinetic movements and seizures (NDHMSR; <a href="/entry/617820">617820</a>).</p>
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<p>NDHMSD is a severe neurodevelopmental disorder characterized by profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, and a hyperkinetic movement disorder. Additional features may include cortical blindness, generalized cerebral atrophy, and seizures (summary by <a href="#4" class="mim-tip-reference" title="Lemke, J. R., Geider, K., Helbig, K. L., Heyne, H. O., Schutz, H., Hentschel, J., Courage, C., Depienne, C., Nava, C., Heron, D., Moller, R. S., Hjalgrim, H., and 25 others. <strong>Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy.</strong> Neurology 86: 2171-2178, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27164704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27164704</a>] [<a href="https://doi.org/10.1212/WNL.0000000000002740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27164704">Lemke et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27164704" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#3" class="mim-tip-reference" title="Hamdan, F. F., Gauthier, J., Araki, Y., Lin, D.-T., Yoshizawa, Y., Higashi, K., Park, A.-R., Spiegelman, D., Dobrzeniecka, S., Piton, A., Tomitori, H., Daoud, H., and 22 others. <strong>Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.</strong> Am. J. Hum. Genet. 88: 306-316, 2011. Note: Erratum: Am. J. Hum. Genet. 88: 516 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21376300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21376300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21376300[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/10.1016/j.ajhg.2011.02.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21376300">Hamdan et al. (2011)</a> reported 2 unrelated patients with sporadic occurrence of intellectual disability. The first was a 10-year-old girl with moderate mental retardation. There was no evidence of epilepsy, and she had a normal neurologic exam and CT scan. The second patient was a 7.5-year-old male with severe mental retardation, partial complex seizures, hypotonia, and normal brain MRI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21376300" 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="Ohba, C., Shiina, M., Tohyama, J., Haginoya, K., Lerman-Sagie, T., Okamoto, N., Blumkin, L., Lev, D., Mukaida, S., Nozaki, F., Uematsu, M., Onuma, A., and 9 others. <strong>GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders.</strong> Epilepsia 56: 841-848, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25864721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25864721</a>] [<a href="https://doi.org/10.1111/epi.12987" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25864721">Ohba et al. (2015)</a> reported 4 unrelated patients ranging from 5 to 14 years of age with severe developmental delay or even absent development, profound intellectual disability, hyperkinetic movements, and onset of seizures in the first year of life. All were severely affected and bedridden with no head control or purposeful hand movements, very poor or absent eye contact, and no speech. Seizure types included spasm, myoclonic, and partial. EEG studies showed nonspecific focal and diffuse epileptiform abnormality, but no suppression-burst pattern or hypsarrhythmia. Abnormal movements included spastic quadriplegia with hyperreflexia, myoclonus, chorea, dyskinesia, and hand stereotypies; 2 patients had abnormal eye movements resembling oculogyric crises. Additional features included feeding problems with failure to thrive, sleep disorder, bruxism, and inappropriate crying or laughing. Brain imaging showed variable abnormalities, including enlarged ventricles, cerebral atrophy, and thin corpus callosum; 1 patient had cerebellar atrophy. The patients had mild dysmorphic facial features, including deep-set eyes and elongated face. Two patients had progressive microcephaly (-5 SD and -4.3 SD, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25864721" 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="Lemke, J. R., Geider, K., Helbig, K. L., Heyne, H. O., Schutz, H., Hentschel, J., Courage, C., Depienne, C., Nava, C., Heron, D., Moller, R. S., Hjalgrim, H., and 25 others. <strong>Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy.</strong> Neurology 86: 2171-2178, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27164704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27164704</a>] [<a href="https://doi.org/10.1212/WNL.0000000000002740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27164704">Lemke et al. (2016)</a> reported 14 unrelated patients with NDHMSD and reviewed the phenotype of 9 previously reported patients, including the patients reported by <a href="#3" class="mim-tip-reference" title="Hamdan, F. F., Gauthier, J., Araki, Y., Lin, D.-T., Yoshizawa, Y., Higashi, K., Park, A.-R., Spiegelman, D., Dobrzeniecka, S., Piton, A., Tomitori, H., Daoud, H., and 22 others. <strong>Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.</strong> Am. J. Hum. Genet. 88: 306-316, 2011. Note: Erratum: Am. J. Hum. Genet. 88: 516 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21376300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21376300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21376300[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/10.1016/j.ajhg.2011.02.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21376300">Hamdan et al. (2011)</a>. Almost all patients had profound global developmental delay apparent from the neonatal period or early infancy and resulting in severe intellectual disability. Affected individuals usually never acquired the ability to walk and had absent or extremely limited verbal communication skills. A significant number of patients (71%) had severe hypotonia, and about 30% developed corticospinal signs consistent with spastic quadriparesis. The majority of patients (61%) showed choreatic, dystonic, or dyskinetic movement disorders, including oculogyric crises (22%). Nonspecific stereotypic movements were noted in 33% of patients. Most patients (70%) had epilepsy, which varied in age at onset (day 1 to 11 years) and in seizure semiology: patients had infantile spasms, tonic and atonic seizures, hypermotor seizures, focal dyscognitive seizures, febrile seizures, generalized seizures, and status epilepticus. Seizures were associated with abnormal EEG patterns, including hypsarrhythmia, focal, multifocal, and generalized spikes and waves. Some patients had refractory seizures, whereas others showed response to medication. The variability in the epilepsy phenotype was not considered to be consistent with classification as a 'developmental and epileptic encephalopathy' (DEE; see <a href="/entry/308350">308350</a>). Behavioral abnormalities were common, and many patients were diagnosed with autism spectrum disorder. Other behavioral abnormalities included aggression and self-injurious behavior or disturbed pain perception (17%). Less common features included sleep disorder, feeding difficulties, requiring tube feeding in some patients, and microcephaly (26%). Several patients (22%) presented with cortical visual impairment or delayed visual maturation. Brain imaging, available for 19 patients, showed nonspecific volume loss or atrophy in 58% of patients. <a href="#4" class="mim-tip-reference" title="Lemke, J. R., Geider, K., Helbig, K. L., Heyne, H. O., Schutz, H., Hentschel, J., Courage, C., Depienne, C., Nava, C., Heron, D., Moller, R. S., Hjalgrim, H., and 25 others. <strong>Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy.</strong> Neurology 86: 2171-2178, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27164704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27164704</a>] [<a href="https://doi.org/10.1212/WNL.0000000000002740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27164704">Lemke et al. (2016)</a> noted that the least severely affected patient was 1 of the children reported by <a href="#3" class="mim-tip-reference" title="Hamdan, F. F., Gauthier, J., Araki, Y., Lin, D.-T., Yoshizawa, Y., Higashi, K., Park, A.-R., Spiegelman, D., Dobrzeniecka, S., Piton, A., Tomitori, H., Daoud, H., and 22 others. <strong>Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.</strong> Am. J. Hum. Genet. 88: 306-316, 2011. Note: Erratum: Am. J. Hum. Genet. 88: 516 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21376300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21376300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21376300[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/10.1016/j.ajhg.2011.02.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21376300">Hamdan et al. (2011)</a>. This patient was able to walk independently at age 18 months and had speech delay, but did not have seizures, movement disorder, or visual problems. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27164704+21376300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Chen, W., Shieh, C., Swanger, S. A., Tankovic, A., Au, M., McGuire, M., Tagliati, M., Graham, J. M., Madan-Khetarpal, S., Traynelis, S. F., Yuan, H., Pierson, T. M. <strong>Grin1 mutation associated with intellectual disability alters NMDA receptor trafficking and function.</strong> J. Hum. Genet. 62: 589-597, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28228639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28228639</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28228639[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/jhg.2017.19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28228639">Chen et al. (2017)</a> reported 2 unrelated patients with NDHMSD, a 12-year-old boy and a 25-year-old female. Both presented at birth with developmental delay and hypotonia associated with cognitive disability, but no seizures. The boy was able to walk with an ataxic gait at age 5, but had no useful language, and showed abnormal movements of the arms and legs, hyperactivity, and self-injurious behavior. Dysmorphic features included thin elongated face, thick eyebrows, deep-set eyes with hypotelorism, recessed chin, and high-arched palate. The 25-year-old woman had severe intellectual disability, but started walking with difficulty around age 2, acquired over 500 words, and was social with good eye contact. She also had abnormal involuntary movements. She had a thin elongated face with deep-set eyes and a marfanoid body habitus with joint hypermobility and scoliosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28228639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Clinical Variability</em></strong></p><p>
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<a href="#2" class="mim-tip-reference" title="Fry, A. E., Fawcett, K. A., Zelnik, N., Yuan, H., Thompson, B. A. N., Shemer-Meiri, L., Cushion, T. D., Mugalaasi, H., Sims, D., Stoodley, N., Chung, S.-K., Rees, M. I., and 29 others. <strong>De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.</strong> Brain 141: 698-712, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29365063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29365063</a>] [<a href="https://doi.org/10.1093/brain/awx358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29365063">Fry et al. (2018)</a> reported 11 unrelated patients with de novo heterozygous missense variants in the GRIN1 gene. The patients were ascertained from several cohorts of patients diagnosed with polymicrogyria or through clinical research programs who underwent exome sequencing. All mutations were missense mutations that were absent from the ExAC database, and occurred between residues 559 and 828. Most affected the S2 domain or the protein or the adjacent M3 helix. In vitro functional expression studies showed that 3 of the mutations (Y647C, R659W, and R794Q) increased the agonist potential of glutamate and glycine on the NMDA receptor, likely resulting in cytotoxicity and consistent with a gain of function. Another variant studied (N674I) had a different functional effect in expression studies, causing a reduction in glycine potency and a reduction in proton inhibition of the receptor. The patients had severe to profound developmental delay, abnormal movements, spasticity with inability to walk, intractable seizures, and cortical visual impairment. Many had microcephaly (up to -7.1 SD). <a href="#2" class="mim-tip-reference" title="Fry, A. E., Fawcett, K. A., Zelnik, N., Yuan, H., Thompson, B. A. N., Shemer-Meiri, L., Cushion, T. D., Mugalaasi, H., Sims, D., Stoodley, N., Chung, S.-K., Rees, M. I., and 29 others. <strong>De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.</strong> Brain 141: 698-712, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29365063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29365063</a>] [<a href="https://doi.org/10.1093/brain/awx358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29365063">Fry et al. (2018)</a> noted that some previously reported patients with de novo GRIN1 mutations did not have brain imaging, and thus may have had polymicrogyria. The authors also postulated that the location of mutations within the gene may be associated with the development of polymicrogyria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29365063" 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 GRIN1 gene that were identified in patients with NDHMSD by <a href="#4" class="mim-tip-reference" title="Lemke, J. R., Geider, K., Helbig, K. L., Heyne, H. O., Schutz, H., Hentschel, J., Courage, C., Depienne, C., Nava, C., Heron, D., Moller, R. S., Hjalgrim, H., and 25 others. <strong>Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy.</strong> Neurology 86: 2171-2178, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27164704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27164704</a>] [<a href="https://doi.org/10.1212/WNL.0000000000002740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27164704">Lemke et al. (2016)</a> occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27164704" 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 2 unrelated patients with intellectual disability, <a href="#3" class="mim-tip-reference" title="Hamdan, F. F., Gauthier, J., Araki, Y., Lin, D.-T., Yoshizawa, Y., Higashi, K., Park, A.-R., Spiegelman, D., Dobrzeniecka, S., Piton, A., Tomitori, H., Daoud, H., and 22 others. <strong>Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.</strong> Am. J. Hum. Genet. 88: 306-316, 2011. Note: Erratum: Am. J. Hum. Genet. 88: 516 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21376300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21376300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21376300[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/10.1016/j.ajhg.2011.02.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21376300">Hamdan et al. (2011)</a> identified de novo heterozygous mutations in the GRIN1 gene (E662K, <a href="/entry/138249#0001">138249.0001</a> and ser560dup, <a href="/entry/138249#0002">138249.0002</a>). Functional studies in Xenopus oocytes showed that the E662K mutation resulted in a significant increase in NMDAR-induced calcium currents; excessive calcium influx through NMDAR could lead to excitotoxic neuronal cell damage. The ser560dup mutation resulted in loss of activity of the receptor, likely due to a change in the 3-dimensional structure at the receptor's channel pore entrance. The patients were part of a cohort of 95 cases of sporadic intellectual disability in whom 197 candidate genes were sequenced. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21376300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 4 unrelated children with NDHMSD, <a href="#5" class="mim-tip-reference" title="Ohba, C., Shiina, M., Tohyama, J., Haginoya, K., Lerman-Sagie, T., Okamoto, N., Blumkin, L., Lev, D., Mukaida, S., Nozaki, F., Uematsu, M., Onuma, A., and 9 others. <strong>GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders.</strong> Epilepsia 56: 841-848, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25864721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25864721</a>] [<a href="https://doi.org/10.1111/epi.12987" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25864721">Ohba et al. (2015)</a> identified 4 different de novo heterozygous missense mutations at highly conserved residues in the GRIN1 gene (see, e.g., <a href="/entry/138249#0003">138249.0003</a> and <a href="/entry/138249#0005">138249.0005</a>). The mutations were found by exome sequencing of 88 patients with early-onset epileptic encephalopathy and confirmed by Sanger sequencing. One of the patients was somatic mosaic for the mutation, with a mutant allele frequency ranging from 13.4 to 19.7% in various tissue samples. Functional studies of the variant and studies of patient cells were not performed, but structural analysis predicted that the mutations would impair NMDAR channel function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25864721" 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="Lemke, J. R., Geider, K., Helbig, K. L., Heyne, H. O., Schutz, H., Hentschel, J., Courage, C., Depienne, C., Nava, C., Heron, D., Moller, R. S., Hjalgrim, H., and 25 others. <strong>Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy.</strong> Neurology 86: 2171-2178, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27164704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27164704</a>] [<a href="https://doi.org/10.1212/WNL.0000000000002740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27164704">Lemke et al. (2016)</a> reported 14 unrelated patients with NDHMSD who carried heterozygous missense mutations in the GRIN1 gene (see, e.g., <a href="/entry/138249#0006">138249.0006</a> and <a href="/entry/138249#0007">138249.0007</a>) and reevaluated 9 previously reported patients with a similar phenotype and similar missense mutations. Twenty-two of the 23 mutations were demonstrated to have occurred de novo; parental DNA from 1 patient was not available. The patients were ascertained from several diagnostic and research studies, and the mutations were found by next-generation sequencing methods. There were 16 different mutations identified in the 23 novel and published cases. All missense mutations clustered within or in close proximity to the transmembrane domains forming the intrinsic ion channel pore of the receptor, which shows a high level of conservation in different species. Electrophysiologic studies in Xenopus oocytes showed variable detrimental effects of the mutations on channel function when coexpressed with wildtype GRIN2B (<a href="/entry/138252">138252</a>). Some mutants resulted in a complete loss of channel function with no response to glutamate or glycine, whereas others resulted in partial loss of channel function with decreased affinity for glutamate and glycine compared to wildtype. Two mutations (A645S and R844C) showed no significant effects on current or agonist affinity, suggesting that they may alter receptor function through other mechanisms. <a href="#4" class="mim-tip-reference" title="Lemke, J. R., Geider, K., Helbig, K. L., Heyne, H. O., Schutz, H., Hentschel, J., Courage, C., Depienne, C., Nava, C., Heron, D., Moller, R. S., Hjalgrim, H., and 25 others. <strong>Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy.</strong> Neurology 86: 2171-2178, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27164704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27164704</a>] [<a href="https://doi.org/10.1212/WNL.0000000000002740" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27164704">Lemke et al. (2016)</a> concluded that the disease mechanism is loss of NMDAR receptor function with a dominant-negative effect in patients with de novo heterozygous GRIN1 missense mutations, underscoring the importance of receptor subunits in neurodevelopment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27164704" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated patients with NDHMSD, <a href="#1" class="mim-tip-reference" title="Chen, W., Shieh, C., Swanger, S. A., Tankovic, A., Au, M., McGuire, M., Tagliati, M., Graham, J. M., Madan-Khetarpal, S., Traynelis, S. F., Yuan, H., Pierson, T. M. <strong>Grin1 mutation associated with intellectual disability alters NMDA receptor trafficking and function.</strong> J. Hum. Genet. 62: 589-597, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28228639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28228639</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28228639[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/jhg.2017.19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28228639">Chen et al. (2017)</a> identified 2 different de novo heterozygous mutations in the GRIN1 gene, both of which resulted in the same G620R substitution (<a href="/entry/138249#0011">138249.0011</a> and <a href="/entry/138249#0012">138249.0012</a>). In vitro functional expression assays showed that the G620R mutation caused a significant decrease in the potency of glutamate and glycine and a decrease in current amplitude when coexpressed with both GRIN2A (<a href="/entry/138253">138253</a>) and GRIN2B (<a href="/entry/138252">138252</a>). G620R/GRIN2A complexes showed a mild reduction in trafficking of NMDAR to the cell surface, a strong decrease in sensitivity to magnesium inhibition, and enhanced sensitivity to zinc. G620R/GRIN2B complexes showed significantly reduced delivery of NMDAR protein to the cell surface and altered electrophysiology in response to extracellular modulators. <a href="#1" class="mim-tip-reference" title="Chen, W., Shieh, C., Swanger, S. A., Tankovic, A., Au, M., McGuire, M., Tagliati, M., Graham, J. M., Madan-Khetarpal, S., Traynelis, S. F., Yuan, H., Pierson, T. M. <strong>Grin1 mutation associated with intellectual disability alters NMDA receptor trafficking and function.</strong> J. Hum. Genet. 62: 589-597, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28228639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28228639</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28228639[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/jhg.2017.19" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28228639">Chen et al. (2017)</a> concluded that the neurodevelopmental deficits resulted from complex effects on channel function, with a combination of decreased presence of G620R/GRIN2B complexes on the neuronal surface during embryonic brain development and reduced current responses of G620R-containing NMDARs after birth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28228639" 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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Chen, W., Shieh, C., Swanger, S. A., Tankovic, A., Au, M., McGuire, M., Tagliati, M., Graham, J. M., Madan-Khetarpal, S., Traynelis, S. F., Yuan, H., Pierson, T. M.
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<strong>Grin1 mutation associated with intellectual disability alters NMDA receptor trafficking and function.</strong>
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J. Hum. Genet. 62: 589-597, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28228639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28228639</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28228639[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=28228639" 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/jhg.2017.19" target="_blank">Full Text</a>]
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Fry, A. E., Fawcett, K. A., Zelnik, N., Yuan, H., Thompson, B. A. N., Shemer-Meiri, L., Cushion, T. D., Mugalaasi, H., Sims, D., Stoodley, N., Chung, S.-K., Rees, M. I., and 29 others.
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<strong>De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.</strong>
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Brain 141: 698-712, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29365063/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29365063</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29365063" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awx358" target="_blank">Full Text</a>]
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Hamdan, F. F., Gauthier, J., Araki, Y., Lin, D.-T., Yoshizawa, Y., Higashi, K., Park, A.-R., Spiegelman, D., Dobrzeniecka, S., Piton, A., Tomitori, H., Daoud, H., and 22 others.
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<strong>Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.</strong>
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Am. J. Hum. Genet. 88: 306-316, 2011. Note: Erratum: Am. J. Hum. Genet. 88: 516 only, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21376300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21376300</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21376300[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=21376300" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Lemke, J. R., Geider, K., Helbig, K. L., Heyne, H. O., Schutz, H., Hentschel, J., Courage, C., Depienne, C., Nava, C., Heron, D., Moller, R. S., Hjalgrim, H., and 25 others.
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<strong>Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy.</strong>
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Neurology 86: 2171-2178, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27164704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27164704</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27164704" 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/10.1212/WNL.0000000000002740" target="_blank">Full Text</a>]
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Ohba, C., Shiina, M., Tohyama, J., Haginoya, K., Lerman-Sagie, T., Okamoto, N., Blumkin, L., Lev, D., Mukaida, S., Nozaki, F., Uematsu, M., Onuma, A., and 9 others.
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<strong>GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders.</strong>
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Epilepsia 56: 841-848, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25864721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25864721</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25864721" 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/10.1111/epi.12987" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 10/11/2018
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Cassandra L. Kniffin - updated : 12/28/2017
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Ada Hamosh : 9/28/2011
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alopez : 09/29/2023
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carol : 12/04/2020<br>carol : 01/30/2019<br>ckniffin : 10/11/2018<br>carol : 01/10/2018<br>alopez : 01/09/2018<br>ckniffin : 12/28/2017<br>carol : 12/20/2017<br>terry : 07/06/2012<br>alopez : 11/2/2011<br>alopez : 9/28/2011
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<strong>#</strong> 614254
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NEURODEVELOPMENTAL DISORDER WITH OR WITHOUT HYPERKINETIC MOVEMENTS AND SEIZURES, AUTOSOMAL DOMINANT; NDHMSD
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MENTAL RETARDATION, AUTOSOMAL DOMINANT 8, FORMERLY; MRD8, FORMERLY
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<strong>ORPHA:</strong> 178469;
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<strong>DO:</strong> 0070038;
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<strong>Phenotype-Gene Relationships</strong>
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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9q34.3
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Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant
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614254
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Autosomal dominant
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GRIN1
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138249
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<p>A number sign (#) is used with this entry because of evidence that autosomal dominant neurodevelopmental disorder with or without hyperkinetic movements and seizures (NDHMSD) is caused by heterozygous mutation in the GRIN1 gene (138249) on chromosome 9q34.</p><p>Homozygous mutation in the GRIN1 gene can cause autosomal recessive neurodevelopmental disorder with or without hyperkinetic movements and seizures (NDHMSR; 617820).</p>
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<p>NDHMSD is a severe neurodevelopmental disorder characterized by profound developmental delay, severe intellectual disability with absent speech, muscular hypotonia, and a hyperkinetic movement disorder. Additional features may include cortical blindness, generalized cerebral atrophy, and seizures (summary by Lemke et al., 2016). </p>
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<p>Hamdan et al. (2011) reported 2 unrelated patients with sporadic occurrence of intellectual disability. The first was a 10-year-old girl with moderate mental retardation. There was no evidence of epilepsy, and she had a normal neurologic exam and CT scan. The second patient was a 7.5-year-old male with severe mental retardation, partial complex seizures, hypotonia, and normal brain MRI. </p><p>Ohba et al. (2015) reported 4 unrelated patients ranging from 5 to 14 years of age with severe developmental delay or even absent development, profound intellectual disability, hyperkinetic movements, and onset of seizures in the first year of life. All were severely affected and bedridden with no head control or purposeful hand movements, very poor or absent eye contact, and no speech. Seizure types included spasm, myoclonic, and partial. EEG studies showed nonspecific focal and diffuse epileptiform abnormality, but no suppression-burst pattern or hypsarrhythmia. Abnormal movements included spastic quadriplegia with hyperreflexia, myoclonus, chorea, dyskinesia, and hand stereotypies; 2 patients had abnormal eye movements resembling oculogyric crises. Additional features included feeding problems with failure to thrive, sleep disorder, bruxism, and inappropriate crying or laughing. Brain imaging showed variable abnormalities, including enlarged ventricles, cerebral atrophy, and thin corpus callosum; 1 patient had cerebellar atrophy. The patients had mild dysmorphic facial features, including deep-set eyes and elongated face. Two patients had progressive microcephaly (-5 SD and -4.3 SD, respectively). </p><p>Lemke et al. (2016) reported 14 unrelated patients with NDHMSD and reviewed the phenotype of 9 previously reported patients, including the patients reported by Hamdan et al. (2011). Almost all patients had profound global developmental delay apparent from the neonatal period or early infancy and resulting in severe intellectual disability. Affected individuals usually never acquired the ability to walk and had absent or extremely limited verbal communication skills. A significant number of patients (71%) had severe hypotonia, and about 30% developed corticospinal signs consistent with spastic quadriparesis. The majority of patients (61%) showed choreatic, dystonic, or dyskinetic movement disorders, including oculogyric crises (22%). Nonspecific stereotypic movements were noted in 33% of patients. Most patients (70%) had epilepsy, which varied in age at onset (day 1 to 11 years) and in seizure semiology: patients had infantile spasms, tonic and atonic seizures, hypermotor seizures, focal dyscognitive seizures, febrile seizures, generalized seizures, and status epilepticus. Seizures were associated with abnormal EEG patterns, including hypsarrhythmia, focal, multifocal, and generalized spikes and waves. Some patients had refractory seizures, whereas others showed response to medication. The variability in the epilepsy phenotype was not considered to be consistent with classification as a 'developmental and epileptic encephalopathy' (DEE; see 308350). Behavioral abnormalities were common, and many patients were diagnosed with autism spectrum disorder. Other behavioral abnormalities included aggression and self-injurious behavior or disturbed pain perception (17%). Less common features included sleep disorder, feeding difficulties, requiring tube feeding in some patients, and microcephaly (26%). Several patients (22%) presented with cortical visual impairment or delayed visual maturation. Brain imaging, available for 19 patients, showed nonspecific volume loss or atrophy in 58% of patients. Lemke et al. (2016) noted that the least severely affected patient was 1 of the children reported by Hamdan et al. (2011). This patient was able to walk independently at age 18 months and had speech delay, but did not have seizures, movement disorder, or visual problems. </p><p>Chen et al. (2017) reported 2 unrelated patients with NDHMSD, a 12-year-old boy and a 25-year-old female. Both presented at birth with developmental delay and hypotonia associated with cognitive disability, but no seizures. The boy was able to walk with an ataxic gait at age 5, but had no useful language, and showed abnormal movements of the arms and legs, hyperactivity, and self-injurious behavior. Dysmorphic features included thin elongated face, thick eyebrows, deep-set eyes with hypotelorism, recessed chin, and high-arched palate. The 25-year-old woman had severe intellectual disability, but started walking with difficulty around age 2, acquired over 500 words, and was social with good eye contact. She also had abnormal involuntary movements. She had a thin elongated face with deep-set eyes and a marfanoid body habitus with joint hypermobility and scoliosis. </p><p><strong><em>Clinical Variability</em></strong></p><p>
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Fry et al. (2018) reported 11 unrelated patients with de novo heterozygous missense variants in the GRIN1 gene. The patients were ascertained from several cohorts of patients diagnosed with polymicrogyria or through clinical research programs who underwent exome sequencing. All mutations were missense mutations that were absent from the ExAC database, and occurred between residues 559 and 828. Most affected the S2 domain or the protein or the adjacent M3 helix. In vitro functional expression studies showed that 3 of the mutations (Y647C, R659W, and R794Q) increased the agonist potential of glutamate and glycine on the NMDA receptor, likely resulting in cytotoxicity and consistent with a gain of function. Another variant studied (N674I) had a different functional effect in expression studies, causing a reduction in glycine potency and a reduction in proton inhibition of the receptor. The patients had severe to profound developmental delay, abnormal movements, spasticity with inability to walk, intractable seizures, and cortical visual impairment. Many had microcephaly (up to -7.1 SD). Fry et al. (2018) noted that some previously reported patients with de novo GRIN1 mutations did not have brain imaging, and thus may have had polymicrogyria. The authors also postulated that the location of mutations within the gene may be associated with the development of polymicrogyria. </p>
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<strong>Inheritance</strong>
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<p>The heterozygous mutations in the GRIN1 gene that were identified in patients with NDHMSD by Lemke et al. (2016) occurred de novo. </p>
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<strong>Molecular Genetics</strong>
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<p>In 2 unrelated patients with intellectual disability, Hamdan et al. (2011) identified de novo heterozygous mutations in the GRIN1 gene (E662K, 138249.0001 and ser560dup, 138249.0002). Functional studies in Xenopus oocytes showed that the E662K mutation resulted in a significant increase in NMDAR-induced calcium currents; excessive calcium influx through NMDAR could lead to excitotoxic neuronal cell damage. The ser560dup mutation resulted in loss of activity of the receptor, likely due to a change in the 3-dimensional structure at the receptor's channel pore entrance. The patients were part of a cohort of 95 cases of sporadic intellectual disability in whom 197 candidate genes were sequenced. </p><p>In 4 unrelated children with NDHMSD, Ohba et al. (2015) identified 4 different de novo heterozygous missense mutations at highly conserved residues in the GRIN1 gene (see, e.g., 138249.0003 and 138249.0005). The mutations were found by exome sequencing of 88 patients with early-onset epileptic encephalopathy and confirmed by Sanger sequencing. One of the patients was somatic mosaic for the mutation, with a mutant allele frequency ranging from 13.4 to 19.7% in various tissue samples. Functional studies of the variant and studies of patient cells were not performed, but structural analysis predicted that the mutations would impair NMDAR channel function. </p><p>Lemke et al. (2016) reported 14 unrelated patients with NDHMSD who carried heterozygous missense mutations in the GRIN1 gene (see, e.g., 138249.0006 and 138249.0007) and reevaluated 9 previously reported patients with a similar phenotype and similar missense mutations. Twenty-two of the 23 mutations were demonstrated to have occurred de novo; parental DNA from 1 patient was not available. The patients were ascertained from several diagnostic and research studies, and the mutations were found by next-generation sequencing methods. There were 16 different mutations identified in the 23 novel and published cases. All missense mutations clustered within or in close proximity to the transmembrane domains forming the intrinsic ion channel pore of the receptor, which shows a high level of conservation in different species. Electrophysiologic studies in Xenopus oocytes showed variable detrimental effects of the mutations on channel function when coexpressed with wildtype GRIN2B (138252). Some mutants resulted in a complete loss of channel function with no response to glutamate or glycine, whereas others resulted in partial loss of channel function with decreased affinity for glutamate and glycine compared to wildtype. Two mutations (A645S and R844C) showed no significant effects on current or agonist affinity, suggesting that they may alter receptor function through other mechanisms. Lemke et al. (2016) concluded that the disease mechanism is loss of NMDAR receptor function with a dominant-negative effect in patients with de novo heterozygous GRIN1 missense mutations, underscoring the importance of receptor subunits in neurodevelopment. </p><p>In 2 unrelated patients with NDHMSD, Chen et al. (2017) identified 2 different de novo heterozygous mutations in the GRIN1 gene, both of which resulted in the same G620R substitution (138249.0011 and 138249.0012). In vitro functional expression assays showed that the G620R mutation caused a significant decrease in the potency of glutamate and glycine and a decrease in current amplitude when coexpressed with both GRIN2A (138253) and GRIN2B (138252). G620R/GRIN2A complexes showed a mild reduction in trafficking of NMDAR to the cell surface, a strong decrease in sensitivity to magnesium inhibition, and enhanced sensitivity to zinc. G620R/GRIN2B complexes showed significantly reduced delivery of NMDAR protein to the cell surface and altered electrophysiology in response to extracellular modulators. Chen et al. (2017) concluded that the neurodevelopmental deficits resulted from complex effects on channel function, with a combination of decreased presence of G620R/GRIN2B complexes on the neuronal surface during embryonic brain development and reduced current responses of G620R-containing NMDARs after birth. </p>
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<strong>REFERENCES</strong>
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Chen, W., Shieh, C., Swanger, S. A., Tankovic, A., Au, M., McGuire, M., Tagliati, M., Graham, J. M., Madan-Khetarpal, S., Traynelis, S. F., Yuan, H., Pierson, T. M.
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<strong>Grin1 mutation associated with intellectual disability alters NMDA receptor trafficking and function.</strong>
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J. Hum. Genet. 62: 589-597, 2017.
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[PubMed: 28228639]
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[Full Text: https://doi.org/10.1038/jhg.2017.19]
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Fry, A. E., Fawcett, K. A., Zelnik, N., Yuan, H., Thompson, B. A. N., Shemer-Meiri, L., Cushion, T. D., Mugalaasi, H., Sims, D., Stoodley, N., Chung, S.-K., Rees, M. I., and 29 others.
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<strong>De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.</strong>
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Brain 141: 698-712, 2018.
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[PubMed: 29365063]
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[Full Text: https://doi.org/10.1093/brain/awx358]
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Hamdan, F. F., Gauthier, J., Araki, Y., Lin, D.-T., Yoshizawa, Y., Higashi, K., Park, A.-R., Spiegelman, D., Dobrzeniecka, S., Piton, A., Tomitori, H., Daoud, H., and 22 others.
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<strong>Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.</strong>
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Am. J. Hum. Genet. 88: 306-316, 2011. Note: Erratum: Am. J. Hum. Genet. 88: 516 only, 2011.
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[PubMed: 21376300]
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[Full Text: https://doi.org/10.1016/j.ajhg.2011.02.001]
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Lemke, J. R., Geider, K., Helbig, K. L., Heyne, H. O., Schutz, H., Hentschel, J., Courage, C., Depienne, C., Nava, C., Heron, D., Moller, R. S., Hjalgrim, H., and 25 others.
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<strong>Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy.</strong>
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Neurology 86: 2171-2178, 2016.
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[PubMed: 27164704]
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[Full Text: https://doi.org/10.1212/WNL.0000000000002740]
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Ohba, C., Shiina, M., Tohyama, J., Haginoya, K., Lerman-Sagie, T., Okamoto, N., Blumkin, L., Lev, D., Mukaida, S., Nozaki, F., Uematsu, M., Onuma, A., and 9 others.
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<strong>GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders.</strong>
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Epilepsia 56: 841-848, 2015.
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[PubMed: 25864721]
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[Full Text: https://doi.org/10.1111/epi.12987]
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Cassandra L. Kniffin - updated : 10/11/2018<br>Cassandra L. Kniffin - updated : 12/28/2017
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Ada Hamosh : 9/28/2011
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alopez : 09/29/2023<br>carol : 12/04/2020<br>carol : 01/30/2019<br>ckniffin : 10/11/2018<br>carol : 01/10/2018<br>alopez : 01/09/2018<br>ckniffin : 12/28/2017<br>carol : 12/20/2017<br>terry : 07/06/2012<br>alopez : 11/2/2011<br>alopez : 9/28/2011
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