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Entry
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- #617182 - LODDER-MERLA SYNDROME, TYPE 2, WITH DEVELOPMENTAL DELAY AND WITH OR WITHOUT CARDIAC ARRHYTHMIA; LDMLS2
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- OMIM
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<p>
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<span class="h4">#617182</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/617182"><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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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</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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</a>
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=LODDER-MERLA SYNDROME, TYPE 2, WITH DEVELOPMENTAL DELAY AND WITH OR WITHOUT CARDIAC ARRHYTHMIA" 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=28037&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/NBK573218/" 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.ncbi.nlm.nih.gov/gtr/all/tests/?term=617182[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=542306" 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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<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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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 542306<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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617182
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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LODDER-MERLA SYNDROME, TYPE 2, WITH DEVELOPMENTAL DELAY AND WITH OR WITHOUT CARDIAC ARRHYTHMIA; LDMLS2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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LANGUAGE DELAY AND ATTENTION DEFICIT-HYPERACTIVITY DISORDER/COGNITIVE IMPAIRMENT WITH OR WITHOUT CARDIAC ARRHYTHMIA; LADCI
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</span>
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</h4>
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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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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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<tbody>
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<td>
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<span class="mim-font">
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<a href="/geneMap/15/221?start=-3&limit=10&highlight=221">
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15q21.2
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Lodder-Merla syndrome, type 2, with developmental delay and with or without cardiac arrhythmia
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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/617182"> 617182 </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 recessive">AR</abbr>
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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="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</td>
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<td>
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<span class="mim-font">
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GNB5
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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/604447"> 604447 </a>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/617182" 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 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">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/617182" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/617182" 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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<p />
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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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<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 recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</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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<div>
|
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<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
|
</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> Heart </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Sick sinus syndrome (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/36083008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">36083008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I49.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I49.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0037052&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0037052</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011704" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011704</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011704" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011704</a>]</span><br /> -
|
|
Bradycardia (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/48867003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">48867003</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/R00.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R00.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0428977&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0428977</a>, <a href="https://bioportal.bioontology.org/search?q=C3812171&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3812171</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001662" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001662</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001662" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001662</a>]</span><br /> -
|
|
Arrhythmias (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/698247007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">698247007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/I49.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">I49.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/427.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">427.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/427" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">427</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003811&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003811</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011675" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011675</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0011675" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0011675</a>]</span><br />
|
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|
</span>
|
|
</div>
|
|
</div>
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|
|
</div>
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|
|
</div>
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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 (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398151007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398151007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398152000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398152000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0026827&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0026827</a>, <a href="https://bioportal.bioontology.org/search?q=C1858120&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1858120</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001290" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001290</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001252" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001252</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
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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>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Central Nervous System </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Developmental delay (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248290002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248290002</a>, <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">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/315.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">315.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0557874&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0557874</a>, <a href="https://bioportal.bioontology.org/search?q=C0424605&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424605</a> 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> <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 /> -
|
|
Intellectual disability (in some patients) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/228156007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">228156007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/110359009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">110359009</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/317-319.99" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">317-319.99</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3714756&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3714756</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /> -
|
|
Speech delay <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/229721007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">229721007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241210&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241210</a> 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> <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 /> -
|
|
Impaired fine motor skills (in some patients) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1867864&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867864</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007010" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007010</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007010" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007010</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Behavioral Psychiatric Manifestations </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Attention deficit <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/7461003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">7461003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/406506008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">406506008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/F90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/F90.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">F90.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/314.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">314.01</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/314" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">314</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/314.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">314.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0041671&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0041671</a>, <a href="https://bioportal.bioontology.org/search?q=C1263846&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1263846</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000752" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000752</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0007018" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007018</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007018" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007018</a>]</span><br /> -
|
|
Hyperactivity <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=C0424295&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424295</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000752" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000752</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000752" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000752</a>]</span><br />
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|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
|
</div>
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|
|
</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Onset in early childhood<br /> -
|
|
Three unrelated families have been reported (last curated November 2016)<br />
|
|
|
|
</span>
|
|
</div>
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|
|
</div>
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</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
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|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the guanine nucleotide-binding protein, beta-5 gene (GNB5, <a href="/entry/604447#0006">604447.0006</a>)<br />
|
|
|
|
</span>
|
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</div>
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<p>A number sign (#) is used with this entry because of evidence that Lodder-Merla syndrome type 2 with developmental delay and with or without cardiac arrhythmia (LDMLS2) is caused by homozygous or compound heterozygous mutation in the GNB5 gene (<a href="/entry/604447">604447</a>) on chromosome 15q21.</p><p>Biallelic loss-of-function mutations in the GNB5 gene can cause Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; <a href="/entry/617173">617173</a>), a more severe disorder with overlapping features.</p>
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<p>Lodder-Merla syndrome type 2 with developmental delay and with or without cardiac arrhythmia (LDMLS2) is an autosomal recessive neurodevelopmental disorder characterized by severe expressive and receptive language delay apparent from early childhood. Affected individuals have additional developmental or behavioral abnormalities, including attention deficit, hyperactivity, or mild intellectual disability. Some patients develop cardiac arrhythmias reminiscent of sick sinus syndrome (summary by <a href="#1" class="mim-tip-reference" title="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[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.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al., 2016</a> and <a href="#4" class="mim-tip-reference" title="Shamseldin, H. E., Masuho, I., Alenizi, A., Alyamani, S., Patil, D. N., Ibrahim, N., Martemyanov, K. A., Alkuraya, F. S. <strong>GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition.</strong> Genome Biol. 17: 195, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27677260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27677260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27677260[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13059-016-1061-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27677260">Shamseldin et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27677260+27523599" 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>Genotype-Phenotype Correlation</em></strong></p><p>
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A direct correlation has been noted between the type of GNB5 variant and the severity of the related phenotype. Individuals with missense variants, both in homozygous or compound heterozygous states (LDMLS2), present with a less severe/moderate phenotype characterized mainly by sinus node dysfunction in combination with mild intellectual disabilities, whereas individuals homozygous for null alleles (LDMLS1) have severe ID, global developmental delay including early infantile developmental and epileptic encephalopathy, hypotonia, as well as sinus node dysfunction (<a href="#2" class="mim-tip-reference" title="Malerba, N., Towner, S., Keating, K., Squeo, G. M., Wilson, W., Merla, G. <strong>A NGS-targeted autism/ID panel reveals compound heterozygous GNB5 variants in a novel patient.</strong> Front. Genet. 9: 626, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30631341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30631341</a>] [<a href="https://doi.org/10.3389/fgene.2018.00626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30631341">Malerba et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30631341" 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="#1" class="mim-tip-reference" title="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[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.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al. (2016)</a> reported 3 patients from 2 unrelated families (family E of Moroccan descent and family F of Brazilian descent) with LDMLS2 with cardiac arrhythmia. Two Moroccan sibs, 13 and 8 years of age, presented in early childhood with sinus node dysfunction manifest as sinus bradycardia and sinus arrhythmia without structural heart abnormalities; one child required pacemaker implantation. Both had late speech development associated with mild learning delay or mild mental retardation; one child also had impaired fine motor skills. Neither had seizures or ocular abnormalities; brain imaging and EEG were normal in 1 patient. A 23-year-old man, born of consanguineous Brazilian parents, had borderline to mild intellectual disability, keratoconus, and sinus arrhythmia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27523599" 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="Shamseldin, H. E., Masuho, I., Alenizi, A., Alyamani, S., Patil, D. N., Ibrahim, N., Martemyanov, K. A., Alkuraya, F. S. <strong>GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition.</strong> Genome Biol. 17: 195, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27677260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27677260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27677260[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13059-016-1061-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27677260">Shamseldin et al. (2016)</a> reported a large consanguineous Saudi family in which 5 girls had severe language delay. In 1 sibship, 3 sisters, aged 10, 9, and 3, had expressive and receptive language delay. The oldest also had hyperactivity and was diagnosed with attention deficit-hyperactivity disorder (ADHD), whereas the middle sister had no hyperactivity and was diagnosed with inattentive type ADHD; the youngest was too young to assess for ADHD. All had normal cognition. A 5-year-old first cousin had motor delay, hypotonia, and delayed language with normal cognition. A distant cousin had ADHD, severely delayed language, and mild motor delay. Additional features or involvement of other organ systems, such as cardiac, were not reported in any of the patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27677260" 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="#2" class="mim-tip-reference" title="Malerba, N., Towner, S., Keating, K., Squeo, G. M., Wilson, W., Merla, G. <strong>A NGS-targeted autism/ID panel reveals compound heterozygous GNB5 variants in a novel patient.</strong> Front. Genet. 9: 626, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30631341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30631341</a>] [<a href="https://doi.org/10.3389/fgene.2018.00626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30631341">Malerba et al. (2018)</a> studied a 2.5-year-old girl who had mild to moderate psychomotor delay, with a spoken vocabulary of about 12 words and some use of sign language, and a high activity level with a short attention span. She was hypotonic, with a wide-based gait and poor balance. Cardiac evaluation showed sinus bradycardia and evidence of sinus node dysfunction, with sudden rate drops and pauses lasting longer than 3 seconds. She had experienced frequent falls that improved after pacemaker placement. Neurologic evaluation was negative for epileptic encephalopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30631341" 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 transmission pattern of LDMLS2 in the families reported by <a href="#1" class="mim-tip-reference" title="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[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.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al. (2016)</a> and <a href="#4" class="mim-tip-reference" title="Shamseldin, H. E., Masuho, I., Alenizi, A., Alyamani, S., Patil, D. N., Ibrahim, N., Martemyanov, K. A., Alkuraya, F. S. <strong>GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition.</strong> Genome Biol. 17: 195, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27677260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27677260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27677260[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13059-016-1061-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27677260">Shamseldin et al. (2016)</a> was consistent with autosomal recessive inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27677260+27523599" 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 3 patients from 2 unrelated families (family E of Moroccan ancestry and family F from Brazil) with LDMLS2 with cardiac arrhythmia, <a href="#1" class="mim-tip-reference" title="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[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.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al. (2016)</a> identified a homozygous missense mutation in the GNB5 gene (S81L; <a href="/entry/604447#0006">604447.0006</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variant were not performed. These patients were part of a cohort of 9 patients from 6 families who were found to have GNB5 mutations: those with truncating mutations had a more severe phenotype (IDDCA) than those with the missense mutation, suggesting a genotype/phenotype correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27523599" 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 5 girls from a large consanguineous Saudi family with LDMLS2 without cardiac arrhythmia, <a href="#4" class="mim-tip-reference" title="Shamseldin, H. E., Masuho, I., Alenizi, A., Alyamani, S., Patil, D. N., Ibrahim, N., Martemyanov, K. A., Alkuraya, F. S. <strong>GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition.</strong> Genome Biol. 17: 195, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27677260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27677260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27677260[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13059-016-1061-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27677260">Shamseldin et al. (2016)</a> identified a homozygous S81L substitution in the GNB5 gene. The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. In vitro functional expression assays showed that the S81L mutation resulted in severe but incomplete loss of function, leading to weaker activity of RGS complexes and a decreased ability to deactivate DRD2 (<a href="/entry/126450">126450</a>)-mediated signaling by dopamine. <a href="#4" class="mim-tip-reference" title="Shamseldin, H. E., Masuho, I., Alenizi, A., Alyamani, S., Patil, D. N., Ibrahim, N., Martemyanov, K. A., Alkuraya, F. S. <strong>GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition.</strong> Genome Biol. 17: 195, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27677260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27677260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27677260[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1186/s13059-016-1061-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27677260">Shamseldin et al. (2016)</a> noted that knockdown of the Gnb5 gene in C. elegans results in increased locomotor activity (<a href="#3" class="mim-tip-reference" title="Porter, M. Y., Xie, K., Pozharski, E., Koelle, M. R., Martemyanov, K. A. <strong>A conserved protein interaction interface on the type 5 G protein beta subunit controls proteolytic stability and activity of R7 family regulator of G protein signaling proteins.</strong> J. Biol. Chem. 285: 41100-41112, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20959458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20959458</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20959458[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/10.1074/jbc.M110.163600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20959458">Porter et al., 2010</a>), and that knockdown of the murine ortholog results in hyperactivity and abnormal motor coordination (<a href="#5" class="mim-tip-reference" title="Xie, K., Ge, S., Collins, V. E., Haynes, C. L., Renner, K. J., Meisel, R. L., Lujan, R., Martemyanov, K. A. <strong>G-beta5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.</strong> Psychopharmacology 219: 823-834, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21766168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21766168</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21766168[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/10.1007/s00213-011-2409-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21766168">Xie et al., 2012</a>), making the gene a candidate for ADHD (see ANIMAL MODEL). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27677260+21766168+20959458" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 2.5-year-old girl with moderate psychomotor delay and sinus node dysfunction, <a href="#2" class="mim-tip-reference" title="Malerba, N., Towner, S., Keating, K., Squeo, G. M., Wilson, W., Merla, G. <strong>A NGS-targeted autism/ID panel reveals compound heterozygous GNB5 variants in a novel patient.</strong> Front. Genet. 9: 626, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30631341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30631341</a>] [<a href="https://doi.org/10.3389/fgene.2018.00626" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30631341">Malerba et al. (2018)</a> performed next-generation sequencing using the Autism/ID Xpanded Panel and identified compound heterozygosity for 2 previously reported mutations in exon 2 the GNB5 gene: an S81L substitution (<a href="/entry/604447#0006">604447.0006</a>) and a 5-bp deletion (<a href="/entry/604447#0008">604447.0008</a>). Her unaffected parents were heterozygous for the variants, which were confirmed by Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30631341" 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="#5" class="mim-tip-reference" title="Xie, K., Ge, S., Collins, V. E., Haynes, C. L., Renner, K. J., Meisel, R. L., Lujan, R., Martemyanov, K. A. <strong>G-beta5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.</strong> Psychopharmacology 219: 823-834, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21766168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21766168</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21766168[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/10.1007/s00213-011-2409-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21766168">Xie et al. (2012)</a> found that Gnb5-null mice had hyperactivity and motor learning deficits, as well as a paradoxical adaptation to a novel environment. Gnb5-null mouse brains had lower levels of extracellular dopamine as well as slowed dopamine release and reuptake compared to wildtype. There was also increased sensitivity to inhibitory pre- and postsynaptic G protein-coupled receptor signaling, consistent with the loss of the inhibitory effects of Gnb5/RGS on other receptor signaling pathways. Pharmacologic treatment with monoamine reuptake inhibitors were ineffective in reducing hyperactivity; however, NMDA receptor blockade completely reversed hyperactivity, suggesting that the mutant mice had changes in glutamatergic signaling. The findings indicated that Gnb5-RGS complexes serve as key modulators of signaling pathways that control neuronal excitability and motor activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21766168" 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="Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others. <strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong> Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[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.2016.06.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27523599">Lodder et al. (2016)</a> used CRISPR/Cas9 genome editing to generate complete loss of gnb5 function in zebrafish; mutant zebrafish had impaired swimming activity, remained small, and died 7 to 14 days postfertilization, likely due to an inability to feed. Treatment of mutant larvae with carbachol, a parasympathomimetic compound that activates the GNB5/RGS/GIRK (G protein-coupled inward rectifier potassium) channel pathway, resulted in a strong decrease in heart rate compared to controls. Treatment with a sympathetic agonist resulted in an increased heart rate similar to controls. These findings indicated that loss of gnb5 caused a loss of negative regulation of the cardiac GIRK channel and parasympathetic control, without effects on sympathetic control. Mutant larvae were predominantly unresponsive to repeated tactile stimulation, apparently due to neurologic deficits, not muscle dysfunction, and showed impaired optokinetic responses, also with normal eye muscle function. The findings indicated that Gnb5 is important for neuronal signaling and autonomic function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27523599" 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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Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others.
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<strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong>
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Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27523599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27523599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27523599[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=27523599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Malerba, N., Towner, S., Keating, K., Squeo, G. M., Wilson, W., Merla, G.
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<strong>A NGS-targeted autism/ID panel reveals compound heterozygous GNB5 variants in a novel patient.</strong>
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Front. Genet. 9: 626, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30631341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30631341</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30631341" 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/10.3389/fgene.2018.00626" target="_blank">Full Text</a>]
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Porter, M. Y., Xie, K., Pozharski, E., Koelle, M. R., Martemyanov, K. A.
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<strong>A conserved protein interaction interface on the type 5 G protein beta subunit controls proteolytic stability and activity of R7 family regulator of G protein signaling proteins.</strong>
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J. Biol. Chem. 285: 41100-41112, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20959458/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20959458</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20959458[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=20959458" 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/10.1074/jbc.M110.163600" target="_blank">Full Text</a>]
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Shamseldin, H. E., Masuho, I., Alenizi, A., Alyamani, S., Patil, D. N., Ibrahim, N., Martemyanov, K. A., Alkuraya, F. S.
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<strong>GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition.</strong>
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Genome Biol. 17: 195, 2016. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27677260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27677260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27677260[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=27677260" 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/10.1186/s13059-016-1061-6" target="_blank">Full Text</a>]
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Xie, K., Ge, S., Collins, V. E., Haynes, C. L., Renner, K. J., Meisel, R. L., Lujan, R., Martemyanov, K. A.
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<strong>G-beta5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.</strong>
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Psychopharmacology 219: 823-834, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21766168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21766168</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21766168[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=21766168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Marla J. F. O'Neill - updated : 08/16/2023
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Cassandra L. Kniffin : 11/03/2016
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joanna : 08/16/2023<br>alopez : 08/16/2023<br>carol : 01/31/2018<br>carol : 11/10/2016<br>carol : 11/09/2016<br>carol : 11/09/2016<br>ckniffin : 11/04/2016
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LODDER-MERLA SYNDROME, TYPE 2, WITH DEVELOPMENTAL DELAY AND WITH OR WITHOUT CARDIAC ARRHYTHMIA; LDMLS2
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LANGUAGE DELAY AND ATTENTION DEFICIT-HYPERACTIVITY DISORDER/COGNITIVE IMPAIRMENT WITH OR WITHOUT CARDIAC ARRHYTHMIA; LADCI
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<strong>ORPHA:</strong> 542306;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus <br /> MIM number
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15q21.2
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Lodder-Merla syndrome, type 2, with developmental delay and with or without cardiac arrhythmia
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<span class="mim-font">
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617182
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Autosomal recessive
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<span class="mim-font">
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3
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GNB5
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604447
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<p>A number sign (#) is used with this entry because of evidence that Lodder-Merla syndrome type 2 with developmental delay and with or without cardiac arrhythmia (LDMLS2) is caused by homozygous or compound heterozygous mutation in the GNB5 gene (604447) on chromosome 15q21.</p><p>Biallelic loss-of-function mutations in the GNB5 gene can cause Lodder-Merla syndrome type 1 with impaired intellectual development and cardiac arrhythmia (LDMLS1; 617173), a more severe disorder with overlapping features.</p>
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<strong>Description</strong>
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<p>Lodder-Merla syndrome type 2 with developmental delay and with or without cardiac arrhythmia (LDMLS2) is an autosomal recessive neurodevelopmental disorder characterized by severe expressive and receptive language delay apparent from early childhood. Affected individuals have additional developmental or behavioral abnormalities, including attention deficit, hyperactivity, or mild intellectual disability. Some patients develop cardiac arrhythmias reminiscent of sick sinus syndrome (summary by Lodder et al., 2016 and Shamseldin et al., 2016). </p><p><strong><em>Genotype-Phenotype Correlation</em></strong></p><p>
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A direct correlation has been noted between the type of GNB5 variant and the severity of the related phenotype. Individuals with missense variants, both in homozygous or compound heterozygous states (LDMLS2), present with a less severe/moderate phenotype characterized mainly by sinus node dysfunction in combination with mild intellectual disabilities, whereas individuals homozygous for null alleles (LDMLS1) have severe ID, global developmental delay including early infantile developmental and epileptic encephalopathy, hypotonia, as well as sinus node dysfunction (Malerba et al., 2018). </p>
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<strong>Clinical Features</strong>
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<p>Lodder et al. (2016) reported 3 patients from 2 unrelated families (family E of Moroccan descent and family F of Brazilian descent) with LDMLS2 with cardiac arrhythmia. Two Moroccan sibs, 13 and 8 years of age, presented in early childhood with sinus node dysfunction manifest as sinus bradycardia and sinus arrhythmia without structural heart abnormalities; one child required pacemaker implantation. Both had late speech development associated with mild learning delay or mild mental retardation; one child also had impaired fine motor skills. Neither had seizures or ocular abnormalities; brain imaging and EEG were normal in 1 patient. A 23-year-old man, born of consanguineous Brazilian parents, had borderline to mild intellectual disability, keratoconus, and sinus arrhythmia. </p><p>Shamseldin et al. (2016) reported a large consanguineous Saudi family in which 5 girls had severe language delay. In 1 sibship, 3 sisters, aged 10, 9, and 3, had expressive and receptive language delay. The oldest also had hyperactivity and was diagnosed with attention deficit-hyperactivity disorder (ADHD), whereas the middle sister had no hyperactivity and was diagnosed with inattentive type ADHD; the youngest was too young to assess for ADHD. All had normal cognition. A 5-year-old first cousin had motor delay, hypotonia, and delayed language with normal cognition. A distant cousin had ADHD, severely delayed language, and mild motor delay. Additional features or involvement of other organ systems, such as cardiac, were not reported in any of the patients. </p><p>Malerba et al. (2018) studied a 2.5-year-old girl who had mild to moderate psychomotor delay, with a spoken vocabulary of about 12 words and some use of sign language, and a high activity level with a short attention span. She was hypotonic, with a wide-based gait and poor balance. Cardiac evaluation showed sinus bradycardia and evidence of sinus node dysfunction, with sudden rate drops and pauses lasting longer than 3 seconds. She had experienced frequent falls that improved after pacemaker placement. Neurologic evaluation was negative for epileptic encephalopathy. </p>
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<span class="mim-font">
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<strong>Inheritance</strong>
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</h4>
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<p>The transmission pattern of LDMLS2 in the families reported by Lodder et al. (2016) and Shamseldin et al. (2016) was consistent with autosomal recessive inheritance. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>In 3 patients from 2 unrelated families (family E of Moroccan ancestry and family F from Brazil) with LDMLS2 with cardiac arrhythmia, Lodder et al. (2016) identified a homozygous missense mutation in the GNB5 gene (S81L; 604447.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variant were not performed. These patients were part of a cohort of 9 patients from 6 families who were found to have GNB5 mutations: those with truncating mutations had a more severe phenotype (IDDCA) than those with the missense mutation, suggesting a genotype/phenotype correlation. </p><p>In 5 girls from a large consanguineous Saudi family with LDMLS2 without cardiac arrhythmia, Shamseldin et al. (2016) identified a homozygous S81L substitution in the GNB5 gene. The mutation, which was found by a combination of linkage analysis and exome sequencing, segregated with the disorder in the family. In vitro functional expression assays showed that the S81L mutation resulted in severe but incomplete loss of function, leading to weaker activity of RGS complexes and a decreased ability to deactivate DRD2 (126450)-mediated signaling by dopamine. Shamseldin et al. (2016) noted that knockdown of the Gnb5 gene in C. elegans results in increased locomotor activity (Porter et al., 2010), and that knockdown of the murine ortholog results in hyperactivity and abnormal motor coordination (Xie et al., 2012), making the gene a candidate for ADHD (see ANIMAL MODEL). </p><p>In a 2.5-year-old girl with moderate psychomotor delay and sinus node dysfunction, Malerba et al. (2018) performed next-generation sequencing using the Autism/ID Xpanded Panel and identified compound heterozygosity for 2 previously reported mutations in exon 2 the GNB5 gene: an S81L substitution (604447.0006) and a 5-bp deletion (604447.0008). Her unaffected parents were heterozygous for the variants, which were confirmed by Sanger sequencing. </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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<span class="mim-text-font">
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<p>Xie et al. (2012) found that Gnb5-null mice had hyperactivity and motor learning deficits, as well as a paradoxical adaptation to a novel environment. Gnb5-null mouse brains had lower levels of extracellular dopamine as well as slowed dopamine release and reuptake compared to wildtype. There was also increased sensitivity to inhibitory pre- and postsynaptic G protein-coupled receptor signaling, consistent with the loss of the inhibitory effects of Gnb5/RGS on other receptor signaling pathways. Pharmacologic treatment with monoamine reuptake inhibitors were ineffective in reducing hyperactivity; however, NMDA receptor blockade completely reversed hyperactivity, suggesting that the mutant mice had changes in glutamatergic signaling. The findings indicated that Gnb5-RGS complexes serve as key modulators of signaling pathways that control neuronal excitability and motor activity. </p><p>Lodder et al. (2016) used CRISPR/Cas9 genome editing to generate complete loss of gnb5 function in zebrafish; mutant zebrafish had impaired swimming activity, remained small, and died 7 to 14 days postfertilization, likely due to an inability to feed. Treatment of mutant larvae with carbachol, a parasympathomimetic compound that activates the GNB5/RGS/GIRK (G protein-coupled inward rectifier potassium) channel pathway, resulted in a strong decrease in heart rate compared to controls. Treatment with a sympathetic agonist resulted in an increased heart rate similar to controls. These findings indicated that loss of gnb5 caused a loss of negative regulation of the cardiac GIRK channel and parasympathetic control, without effects on sympathetic control. Mutant larvae were predominantly unresponsive to repeated tactile stimulation, apparently due to neurologic deficits, not muscle dysfunction, and showed impaired optokinetic responses, also with normal eye muscle function. The findings indicated that Gnb5 is important for neuronal signaling and autonomic function. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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<ol>
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<p class="mim-text-font">
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Lodder, E. M., De Nittis, P., Koopman, C. D., Wiszniewski, W., Moura de Souza, C. F., Lahrouchi, N., Guex, N., Napolioni, V., Tessadori, F., Beekman, L., Nannenberg, E. A., Boualla, L., and 21 others.
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<strong>GNB5 mutations cause an autosomal-recessive multisystem syndrome with sinus bradycardia and cognitive disability.</strong>
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Am. J. Hum. Genet. 99: 704-710, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 786 only, 2016.
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[PubMed: 27523599]
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[Full Text: https://doi.org/10.1016/j.ajhg.2016.06.025]
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Malerba, N., Towner, S., Keating, K., Squeo, G. M., Wilson, W., Merla, G.
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<strong>A NGS-targeted autism/ID panel reveals compound heterozygous GNB5 variants in a novel patient.</strong>
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Front. Genet. 9: 626, 2018.
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[PubMed: 30631341]
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[Full Text: https://doi.org/10.3389/fgene.2018.00626]
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Porter, M. Y., Xie, K., Pozharski, E., Koelle, M. R., Martemyanov, K. A.
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<strong>A conserved protein interaction interface on the type 5 G protein beta subunit controls proteolytic stability and activity of R7 family regulator of G protein signaling proteins.</strong>
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J. Biol. Chem. 285: 41100-41112, 2010.
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[PubMed: 20959458]
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[Full Text: https://doi.org/10.1074/jbc.M110.163600]
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<li>
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<p class="mim-text-font">
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Shamseldin, H. E., Masuho, I., Alenizi, A., Alyamani, S., Patil, D. N., Ibrahim, N., Martemyanov, K. A., Alkuraya, F. S.
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<strong>GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition.</strong>
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Genome Biol. 17: 195, 2016. Note: Electronic Article.
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[PubMed: 27677260]
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[Full Text: https://doi.org/10.1186/s13059-016-1061-6]
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<p class="mim-text-font">
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Xie, K., Ge, S., Collins, V. E., Haynes, C. L., Renner, K. J., Meisel, R. L., Lujan, R., Martemyanov, K. A.
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<strong>G-beta5-RGS complexes are gatekeepers of hyperactivity involved in control of multiple neurotransmitter systems.</strong>
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Psychopharmacology 219: 823-834, 2012.
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[PubMed: 21766168]
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[Full Text: https://doi.org/10.1007/s00213-011-2409-y]
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 08/16/2023
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Creation Date:
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Cassandra L. Kniffin : 11/03/2016
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carol : 08/17/2023<br>joanna : 08/16/2023<br>alopez : 08/16/2023<br>carol : 01/31/2018<br>carol : 11/10/2016<br>carol : 11/09/2016<br>carol : 11/09/2016<br>ckniffin : 11/04/2016
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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