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Entry
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- #184450 - STUTTERING, FAMILIAL PERSISTENT, 1; STUT1
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- OMIM
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<p>
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<span class="h4">#184450</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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<li role="presentation">
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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/184450"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS184450"> <strong>Phenotypic Series</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="#mapping">Mapping</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 class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</a>
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</h4>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=(STUTTERING, FAMILIAL PERSISTENT) OR (AP4E1)" class="mim-tip-hint" title="Clinical Trials" 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.ncbi.nlm.nih.gov/gtr/all/tests/?term=184450[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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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</a>
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</span>
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</span>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0060243" 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/184450" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>DO:</strong> 0060243<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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184450
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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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STUTTERING, FAMILIAL PERSISTENT, 1; STUT1
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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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STAMMERING
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<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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</tr>
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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/15/210?start=-3&limit=10&highlight=210">
|
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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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Stuttering, familial persistent, 1
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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/184450"> 184450 </a>
|
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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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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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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AP4E1
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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/607244"> 607244 </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 class="btn-group ">
|
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<a href="/clinicalSynopsis/184450" 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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<a href="/phenotypicSeries/PS184450" class="btn btn-info" role="button"> Phenotypic Series </a>
|
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', '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/184450" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/184450" 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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<span class="h5 mim-font">
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<strong> VOICE </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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- Stuttering, persistent <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4231343&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4231343</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MISCELLANEOUS </strong>
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</span>
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</div>
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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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- Onset between ages 2 and 5 years<br /> -
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Exacerbated by stress<br /> -
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Improvement with age<br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> MOLECULAR BASIS </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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- Caused by mutation in the adaptor-related protein complex 4, epsilon-1 subunit gene (AP4E1, <a href="/entry/607244#0004">607244.0004</a>)<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 class="text-right">
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<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
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</div>
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</div>
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</div>
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<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small">
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<div class="row">
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<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
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<h5>
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Stuttering, familial persistent
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- <a href="/phenotypicSeries/PS184450">PS184450</a>
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- 4 Entries
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</h5>
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</div>
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</div>
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<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
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<table class="table table-bordered table-condensed table-hover mim-table-padding">
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<thead>
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<tr>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Location</strong>
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</th>
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<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
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<strong>Phenotype</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Inheritance</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />mapping key</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Phenotype<br />MIM number</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus</strong>
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</th>
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<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
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<strong>Gene/Locus<br />MIM number</strong>
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/3/536?start=-3&limit=10&highlight=536"> 3q13.2-q13.33 </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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<a href="/entry/614655"> Stuttering, familial persistent, 3 </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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</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="2 - The disorder was placed on the map by statistical methods"> 2 </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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<a href="/entry/614655"> 614655 </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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<a href="/entry/614655"> STUT3 </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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<a href="/entry/614655"> 614655 </a>
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</span>
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</td>
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</tr>
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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/12/777?start=-3&limit=10&highlight=777"> 12q24.1 </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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<a href="/entry/609261"> Stuttering, familial persistent, 2 </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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</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="2 - The disorder was placed on the map by statistical methods"> 2 </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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<a href="/entry/609261"> 609261 </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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<a href="/entry/609261"> STUT2 </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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<a href="/entry/609261"> 609261 </a>
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</span>
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</td>
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</tr>
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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/15/210?start=-3&limit=10&highlight=210"> 15q21.2 </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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<a href="/entry/184450"> Stuttering, familial persistent, 1 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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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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</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/184450"> 184450 </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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<a href="/entry/607244"> AP4E1 </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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<a href="/entry/607244"> 607244 </a>
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</span>
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</td>
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</tr>
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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/16/411?start=-3&limit=10&highlight=411"> 16q12.1-q23.1 </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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<a href="/entry/614668"> Stuttering, familial persistent, 4 </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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</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="2 - The disorder was placed on the map by statistical methods"> 2 </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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<a href="/entry/614668"> 614668 </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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<a href="/entry/614668"> STUT4 </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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<a href="/entry/614668"> 614668 </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 class="text-right small">
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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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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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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</h4>
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<div id="mimTextFold" class="collapse in ">
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that familial persistent stuttering-1 (STUT1) is caused by heterozygous mutation in the AP4E1 gene (<a href="/entry/607244">607244</a>) on chromosome 15q21.</p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
|
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Stuttering is a disorder of the flow of speech characterized by involuntary repetitions or prolongations of sounds or syllables, and by interruptions of speech known as blocks (summary by <a href="#9" class="mim-tip-reference" title="Raza, M. H., Riazuddin, S., Drayna, D. <strong>Identification of an autosomal recessive stuttering locus on chromosome 3q13.2-3q13.33.</strong> Hum. Genet. 128: 461-463, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20706738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20706738</a>] [<a href="https://doi.org/10.1007/s00439-010-0871-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20706738">Raza et al., 2010</a>). Stuttering typically arises in young children, where it affects at least 15% of those in age range 4 to 6 years (<a href="#1" class="mim-tip-reference" title="Bloodstein, O. <strong>A Handbook on Stuttering. (5th ed.)</strong> San Diego, Calif.: Singular Publishing Group (pub.) 1995."None>Bloodstein, 1995</a>). Stuttering usually resolves spontaneously before adolescence, leading to a population prevalence of 1 to 2% among adults. Stuttering beyond childhood is characterized by a significant bias towards males, with males outnumbering females by a ratio of 3:1 to 5:1 (<a href="#11" class="mim-tip-reference" title="Yairi, E., Ambrose, N., Cox, N. <strong>Genetics of stuttering: a critical review.</strong> J. Speech Hear. Res. 39: 771-784, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8844557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8844557</a>] [<a href="https://doi.org/10.1044/jshr.3904.771" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8844557">Yairi et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8844557+20706738" 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>Genetic Heterogeneity of Familial Persistent Stuttering</em></strong></p><p>
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Also see STUT2 (<a href="/entry/609261">609261</a>), mapped to chromosome 12q24; STUT3 (<a href="/entry/614655">614655</a>), mapped to chromosome 3q; and STUT4 (<a href="/entry/614668">614668</a>) mapped to chromosome 16q.</p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="clinicalFeatures" class="mim-anchor"></a>
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<h4 href="#mimClinicalFeaturesFold" id="mimClinicalFeaturesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimClinicalFeaturesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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</span>
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</h4>
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</div>
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<div id="mimClinicalFeaturesFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>Raza et al. (<a href="#7" class="mim-tip-reference" title="Raza, M. H., Gertz, E. M., Mundorff, J., Lukong, J., Kuster, J., Schaffer, A. A., Drayna, D. <strong>Linkage analysis of a large African family segregating stuttering suggests polygenic inheritance.</strong> Hum. Genet. 132: 385-396, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239121</a>] [<a href="https://doi.org/10.1007/s00439-012-1252-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23239121">2013</a>, <a href="#8" class="mim-tip-reference" title="Raza, M. H., Mattera, R., Morell, R., Sainz, E., Rahn, R., Gutierez, J., Paris, E., Root, J., Solomon, B., Brewer, C., Basra M. A. R., Khan, S., Riazuddin, S., Braun, A., Bonifacino, J. S., Drayna, D. <strong>Association between rare variants in AP4E1, a component of intracellular trafficking and persistent stuttering.</strong> Am. J. Hum. Genet. 97: 715-725, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26544806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26544806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26544806[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.2015.10.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26544806">2015</a>) reported a large family from Cameroon in which multiple members had persistent stuttering with onset around ages 2 to 5 years. Most reported that the stuttering was exacerbated under stress and that some improvement in fluency occurred with age. None of the affected individuals had any additional clinical signs or symptoms of other neurologic disease, particularly intellectual disability or spasticity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23239121+26544806" 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 STUT1 in the family reported by <a href="#8" class="mim-tip-reference" title="Raza, M. H., Mattera, R., Morell, R., Sainz, E., Rahn, R., Gutierez, J., Paris, E., Root, J., Solomon, B., Brewer, C., Basra M. A. R., Khan, S., Riazuddin, S., Braun, A., Bonifacino, J. S., Drayna, D. <strong>Association between rare variants in AP4E1, a component of intracellular trafficking and persistent stuttering.</strong> Am. J. Hum. Genet. 97: 715-725, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26544806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26544806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26544806[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.2015.10.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26544806">Raza et al. (2015)</a> was consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26544806" 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>Inherited factors contributing to stuttering were demonstrated in studies by <a href="#6" class="mim-tip-reference" title="Howie, P. M. <strong>Concordance for stuttering in monozygotic and dizygotic twin pairs.</strong> J. Speech Hear. Res. 24: 317-321, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7197739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7197739</a>] [<a href="https://doi.org/10.1044/jshr.2403.317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7197739">Howie (1981)</a>, <a href="#11" class="mim-tip-reference" title="Yairi, E., Ambrose, N., Cox, N. <strong>Genetics of stuttering: a critical review.</strong> J. Speech Hear. Res. 39: 771-784, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8844557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8844557</a>] [<a href="https://doi.org/10.1044/jshr.3904.771" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8844557">Yairi et al. (1996)</a>, and <a href="#5" class="mim-tip-reference" title="Felsenfeld, S., Plomin, R. <strong>Epidemiological and offspring analyses of developmental speech disorders using data from the Colorado Adoption Project.</strong> J. Speech Lang. Hear. Res. 40: 778-791, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9263943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9263943</a>] [<a href="https://doi.org/10.1044/jslhr.4004.778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9263943">Felsenfeld and Plomin (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7197739+9263943+8844557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Chakravartti, R., Roy, A. K., Rao, K. U. M., Chakravartti, M. R. <strong>Hereditary factors in stammering.</strong> J. Genet. Hum. 27: 319-328, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/554863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">554863</a>]" pmid="554863">Chakravartti et al. (1979)</a> studied an Indian kindred with 12 stammerers in 5 generations. Autosomal dominant inheritance was espoused. Stuttering is said to be unusually frequent in Japanese, low in Polynesians, and almost completely absent in American Indians. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=554863" 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="Canhetti-Oliveira, C. M., Richieri-Costa, A. <strong>A study of familial stuttering.</strong> Am. J. Med. Genet. 140A: 2139-2141, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16752384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16752384</a>] [<a href="https://doi.org/10.1002/ajmg.a.31320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16752384">Canhetti-Oliveira and Richieri-Costa (2006)</a> presented 14 stuttering pedigrees. Five of the pedigrees had observed stutterers or recovered stutterers in 3 generations. A predominance of affected males was noted with an M:F ratio of 3.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16752384" 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>As part of a linkage study to identify predisposing loci for stuttering, <a href="#4" class="mim-tip-reference" title="Drayna, D., Kilshaw, J., Kelly, J. <strong>The sex ratio in familial persistent stuttering. (Letter)</strong> Am. J. Hum. Genet. 65: 1473-1475, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10521318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10521318</a>] [<a href="https://doi.org/10.1086/302625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10521318">Drayna et al. (1999)</a> assembled more than 100 small- to medium-sized unrelated families with multiple cases of persistent stuttering, chosen to represent the typical presentation of familial stuttering in the adult population. In these families, they observed a male-to-female ratio among the affected individuals that was strikingly different from the generally accepted ratio in the overall adult stuttering population. They found a male-to-female ratio of 1.57 as compared to 7.07 and 4.8 in 2 other studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10521318" 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="#8" class="mim-tip-reference" title="Raza, M. H., Mattera, R., Morell, R., Sainz, E., Rahn, R., Gutierez, J., Paris, E., Root, J., Solomon, B., Brewer, C., Basra M. A. R., Khan, S., Riazuddin, S., Braun, A., Bonifacino, J. S., Drayna, D. <strong>Association between rare variants in AP4E1, a component of intracellular trafficking and persistent stuttering.</strong> Am. J. Hum. Genet. 97: 715-725, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26544806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26544806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26544806[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.2015.10.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26544806">Raza et al. (2015)</a> mapped the STUT1 locus to chromosome 15q21 based on their identification of mutations in the AP4E1 gene (<a href="/entry/607244">607244</a>) in affected members of a family from Cameroon, West Africa, previously reported by <a href="#7" class="mim-tip-reference" title="Raza, M. H., Gertz, E. M., Mundorff, J., Lukong, J., Kuster, J., Schaffer, A. A., Drayna, D. <strong>Linkage analysis of a large African family segregating stuttering suggests polygenic inheritance.</strong> Hum. Genet. 132: 385-396, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239121</a>] [<a href="https://doi.org/10.1007/s00439-012-1252-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23239121">Raza et al. (2013)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23239121+26544806" 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="#7" class="mim-tip-reference" title="Raza, M. H., Gertz, E. M., Mundorff, J., Lukong, J., Kuster, J., Schaffer, A. A., Drayna, D. <strong>Linkage analysis of a large African family segregating stuttering suggests polygenic inheritance.</strong> Hum. Genet. 132: 385-396, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239121</a>] [<a href="https://doi.org/10.1007/s00439-012-1252-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23239121">Raza et al. (2013)</a> reported a large pedigree from the Republic of Cameroon in which at least 33 individuals had persistent stuttering. The large pedigree was divided into 5 subpedigrees, and these were subjected to genomewide linkage analysis individually or in groups. Evidence for linkage was found for several loci, including 2p, 3q, 3p, 14q, and 2 regions on 15q. On 2p, a peak lod score of 3.86 was found using markers <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11127193;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs11127193</a>, D2S405, and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs7560152;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs7560152</a>. On 3q, a peak lod score of 3.47 was found between <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs711995;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs711995</a> and D3S1311. On 3p, a peak lod score of 3.18 was found between markers <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs304838;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs304838</a> and D3S2432. On 14q, a peak lod score of 3.45 was found using <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs975232;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs975232</a>, D14S588, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs8688;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs8688</a>, and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs987579;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs987579</a>. Results for 15q were not as strong, but these loci performed well in 2-locus analysis. A lod score of 3.42 was found by analyzing the data for the 2 loci on chromosome 15q, and lod scores ranging from 4.69 to 6.57 were obtained with a combined 2p/15q analysis. <a href="#7" class="mim-tip-reference" title="Raza, M. H., Gertz, E. M., Mundorff, J., Lukong, J., Kuster, J., Schaffer, A. A., Drayna, D. <strong>Linkage analysis of a large African family segregating stuttering suggests polygenic inheritance.</strong> Hum. Genet. 132: 385-396, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239121</a>] [<a href="https://doi.org/10.1007/s00439-012-1252-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23239121">Raza et al. (2013)</a> concluded that stuttering in this family is likely due to multiple alleles at different loci, which may have resulted from assortative mating. There was no evidence for a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23239121" 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>Heterogeneity</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Shugart, Y. Y., Mundorff, J., Kilshaw, J., Doheny, K., Doan, B., Wanyee, J., Green, E. D., Drayna, D. <strong>Results of a genome-wide linkage scan for stuttering.</strong> Am. J. Med. Genet. 124A: 133-135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14699610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14699610</a>] [<a href="https://doi.org/10.1002/ajmg.a.20347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14699610">Shugart et al. (2004)</a> performed a linkage study of stuttering using 392 markers distributed across the genome in 266 members of 68 families, including 188 affected individuals, in North America and Europe. The single largest pedigree in their sample gave an NPL score of 4.72 at D18S976. Other evidence for linkage was found at D18S78, with an NPL score of 5.143 and Z(lr) score of 2.63 (p = 0.0043). A second region of positive linkage scores was observed on proximal 18q, surrounding marker D18S847 (Z(lr) score, 2.47; p = 0.0068). <a href="#10" class="mim-tip-reference" title="Shugart, Y. Y., Mundorff, J., Kilshaw, J., Doheny, K., Doan, B., Wanyee, J., Green, E. D., Drayna, D. <strong>Results of a genome-wide linkage scan for stuttering.</strong> Am. J. Med. Genet. 124A: 133-135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14699610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14699610</a>] [<a href="https://doi.org/10.1002/ajmg.a.20347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14699610">Shugart et al. (2004)</a> suggested that chromosome 18 may harbor a predisposing locus for stuttering, and that additional susceptibility loci for this disorder may exist. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14699610" 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 affected members of a large family of Cameroon descent (CAMST01) with STUT1, originally reported by <a href="#7" class="mim-tip-reference" title="Raza, M. H., Gertz, E. M., Mundorff, J., Lukong, J., Kuster, J., Schaffer, A. A., Drayna, D. <strong>Linkage analysis of a large African family segregating stuttering suggests polygenic inheritance.</strong> Hum. Genet. 132: 385-396, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239121</a>] [<a href="https://doi.org/10.1007/s00439-012-1252-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23239121">Raza et al. (2013)</a>, <a href="#8" class="mim-tip-reference" title="Raza, M. H., Mattera, R., Morell, R., Sainz, E., Rahn, R., Gutierez, J., Paris, E., Root, J., Solomon, B., Brewer, C., Basra M. A. R., Khan, S., Riazuddin, S., Braun, A., Bonifacino, J. S., Drayna, D. <strong>Association between rare variants in AP4E1, a component of intracellular trafficking and persistent stuttering.</strong> Am. J. Hum. Genet. 97: 715-725, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26544806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26544806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26544806[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.2015.10.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26544806">Raza et al. (2015)</a> identified heterozygosity for 2 missense variants in the AP4E1 gene that occurred in cis (V517I and E801K; <a href="/entry/607244#0004">607244.0004</a>). The mutations were found by whole-exome sequencing and segregated with the disorder in the family. The same mutations on the same haplotype were subsequently found in 2 of 96 additional individuals from Cameroon with stuttering. In vitro functional expression studies in HEK293 cells showed that the mutations resulted in slightly decreased assembly of the AP4 complex (about 80% of wildtype). Sequencing of the AP4E1 gene in unrelated affected individuals, including 93 from Cameroon, 132 from Pakistan, and 711 from North America, revealed 23 other rare variants in this gene, including small (1- to 3-bp) deletions, insertions, duplications, frameshifts, and stop codons; no truncating mutations were found in 558 ethnically matched control individuals. Investigation of large population databases, including the 1000 Genomes Project and Exome Sequencing Project, which are not phenotyped for speech fluency, found 3 loss-of-function AP4E1 variants among about 19,000 chromosomes, as well as several rare missense variants; all of these occurred at a significantly lower frequency compared to the variants observed in stuttering individuals. Studies in a yeast 2-hybrid system supported a direct interaction between the AP4 complex and NAGPA (<a href="/entry/607985">607985</a>), variations in which have also been implicated in stuttering (STUT2; <a href="/entry/609261">609261</a>). The findings suggested that defects in intracellular trafficking play a role in persistent stuttering. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23239121+26544806" 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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Drayna, D., Kilshaw, J., Kelly, J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10521318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10521318</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10521318" 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/10.1086/302625" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9263943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9263943</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9263943" 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/10.1044/jslhr.4004.778" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7197739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7197739</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7197739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Raza, M. H., Gertz, E. M., Mundorff, J., Lukong, J., Kuster, J., Schaffer, A. A., Drayna, D.
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<strong>Linkage analysis of a large African family segregating stuttering suggests polygenic inheritance.</strong>
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Hum. Genet. 132: 385-396, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23239121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23239121</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23239121" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Raza, M. H., Mattera, R., Morell, R., Sainz, E., Rahn, R., Gutierez, J., Paris, E., Root, J., Solomon, B., Brewer, C., Basra M. A. R., Khan, S., Riazuddin, S., Braun, A., Bonifacino, J. S., Drayna, D.
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<strong>Association between rare variants in AP4E1, a component of intracellular trafficking and persistent stuttering.</strong>
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Am. J. Hum. Genet. 97: 715-725, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26544806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26544806</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26544806[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=26544806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Identification of an autosomal recessive stuttering locus on chromosome 3q13.2-3q13.33.</strong>
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Hum. Genet. 128: 461-463, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20706738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20706738</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20706738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Shugart, Y. Y., Mundorff, J., Kilshaw, J., Doheny, K., Doan, B., Wanyee, J., Green, E. D., Drayna, D.
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<strong>Results of a genome-wide linkage scan for stuttering.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14699610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14699610</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14699610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Yairi, E., Ambrose, N., Cox, N.
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<strong>Genetics of stuttering: a critical review.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8844557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8844557</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8844557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Cassandra L. Kniffin - updated : 9/5/2013<br>Victor A. McKusick - updated : 6/18/2007<br>Victor A. McKusick - updated : 3/11/2005<br>Marla J. F. O'Neill - updated : 6/23/2004<br>Victor A. McKusick - updated : 11/15/1999
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<span class="mim-font">
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<strong>#</strong> 184450
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<h3>
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STUTTERING, FAMILIAL PERSISTENT, 1; STUT1
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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STAMMERING
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<span class="mim-text-font">
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<strong>DO:</strong> 0060243;
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<h4>
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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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
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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15q21.2
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<span class="mim-font">
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Stuttering, familial persistent, 1
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<span class="mim-font">
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184450
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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AP4E1
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<span class="mim-font">
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607244
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<strong>TEXT</strong>
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<span class="mim-text-font">
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<p>A number sign (#) is used with this entry because of evidence that familial persistent stuttering-1 (STUT1) is caused by heterozygous mutation in the AP4E1 gene (607244) on chromosome 15q21.</p>
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<strong>Description</strong>
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</div>
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<span class="mim-text-font">
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<p>Stuttering is a disorder of the flow of speech characterized by involuntary repetitions or prolongations of sounds or syllables, and by interruptions of speech known as blocks (summary by Raza et al., 2010). Stuttering typically arises in young children, where it affects at least 15% of those in age range 4 to 6 years (Bloodstein, 1995). Stuttering usually resolves spontaneously before adolescence, leading to a population prevalence of 1 to 2% among adults. Stuttering beyond childhood is characterized by a significant bias towards males, with males outnumbering females by a ratio of 3:1 to 5:1 (Yairi et al., 1996). </p><p><strong><em>Genetic Heterogeneity of Familial Persistent Stuttering</em></strong></p><p>
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Also see STUT2 (609261), mapped to chromosome 12q24; STUT3 (614655), mapped to chromosome 3q; and STUT4 (614668) mapped to chromosome 16q.</p>
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<h4>
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<span class="mim-font">
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<strong>Clinical Features</strong>
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<span class="mim-text-font">
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<p>Raza et al. (2013, 2015) reported a large family from Cameroon in which multiple members had persistent stuttering with onset around ages 2 to 5 years. Most reported that the stuttering was exacerbated under stress and that some improvement in fluency occurred with age. None of the affected individuals had any additional clinical signs or symptoms of other neurologic disease, particularly intellectual disability or spasticity. </p>
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<h4>
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<span class="mim-font">
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<strong>Inheritance</strong>
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<p>The transmission pattern of STUT1 in the family reported by Raza et al. (2015) was consistent with autosomal dominant inheritance. </p><p>Inherited factors contributing to stuttering were demonstrated in studies by Howie (1981), Yairi et al. (1996), and Felsenfeld and Plomin (1997). </p><p>Chakravartti et al. (1979) studied an Indian kindred with 12 stammerers in 5 generations. Autosomal dominant inheritance was espoused. Stuttering is said to be unusually frequent in Japanese, low in Polynesians, and almost completely absent in American Indians. </p><p>Canhetti-Oliveira and Richieri-Costa (2006) presented 14 stuttering pedigrees. Five of the pedigrees had observed stutterers or recovered stutterers in 3 generations. A predominance of affected males was noted with an M:F ratio of 3.2. </p><p>As part of a linkage study to identify predisposing loci for stuttering, Drayna et al. (1999) assembled more than 100 small- to medium-sized unrelated families with multiple cases of persistent stuttering, chosen to represent the typical presentation of familial stuttering in the adult population. In these families, they observed a male-to-female ratio among the affected individuals that was strikingly different from the generally accepted ratio in the overall adult stuttering population. They found a male-to-female ratio of 1.57 as compared to 7.07 and 4.8 in 2 other studies. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Raza et al. (2015) mapped the STUT1 locus to chromosome 15q21 based on their identification of mutations in the AP4E1 gene (607244) in affected members of a family from Cameroon, West Africa, previously reported by Raza et al. (2013). </p><p>Raza et al. (2013) reported a large pedigree from the Republic of Cameroon in which at least 33 individuals had persistent stuttering. The large pedigree was divided into 5 subpedigrees, and these were subjected to genomewide linkage analysis individually or in groups. Evidence for linkage was found for several loci, including 2p, 3q, 3p, 14q, and 2 regions on 15q. On 2p, a peak lod score of 3.86 was found using markers rs11127193, D2S405, and rs7560152. On 3q, a peak lod score of 3.47 was found between rs711995 and D3S1311. On 3p, a peak lod score of 3.18 was found between markers rs304838 and D3S2432. On 14q, a peak lod score of 3.45 was found using rs975232, D14S588, rs8688, and rs987579. Results for 15q were not as strong, but these loci performed well in 2-locus analysis. A lod score of 3.42 was found by analyzing the data for the 2 loci on chromosome 15q, and lod scores ranging from 4.69 to 6.57 were obtained with a combined 2p/15q analysis. Raza et al. (2013) concluded that stuttering in this family is likely due to multiple alleles at different loci, which may have resulted from assortative mating. There was no evidence for a founder effect. </p><p><strong><em>Heterogeneity</em></strong></p><p>
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Shugart et al. (2004) performed a linkage study of stuttering using 392 markers distributed across the genome in 266 members of 68 families, including 188 affected individuals, in North America and Europe. The single largest pedigree in their sample gave an NPL score of 4.72 at D18S976. Other evidence for linkage was found at D18S78, with an NPL score of 5.143 and Z(lr) score of 2.63 (p = 0.0043). A second region of positive linkage scores was observed on proximal 18q, surrounding marker D18S847 (Z(lr) score, 2.47; p = 0.0068). Shugart et al. (2004) suggested that chromosome 18 may harbor a predisposing locus for stuttering, and that additional susceptibility loci for this disorder may exist. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In affected members of a large family of Cameroon descent (CAMST01) with STUT1, originally reported by Raza et al. (2013), Raza et al. (2015) identified heterozygosity for 2 missense variants in the AP4E1 gene that occurred in cis (V517I and E801K; 607244.0004). The mutations were found by whole-exome sequencing and segregated with the disorder in the family. The same mutations on the same haplotype were subsequently found in 2 of 96 additional individuals from Cameroon with stuttering. In vitro functional expression studies in HEK293 cells showed that the mutations resulted in slightly decreased assembly of the AP4 complex (about 80% of wildtype). Sequencing of the AP4E1 gene in unrelated affected individuals, including 93 from Cameroon, 132 from Pakistan, and 711 from North America, revealed 23 other rare variants in this gene, including small (1- to 3-bp) deletions, insertions, duplications, frameshifts, and stop codons; no truncating mutations were found in 558 ethnically matched control individuals. Investigation of large population databases, including the 1000 Genomes Project and Exome Sequencing Project, which are not phenotyped for speech fluency, found 3 loss-of-function AP4E1 variants among about 19,000 chromosomes, as well as several rare missense variants; all of these occurred at a significantly lower frequency compared to the variants observed in stuttering individuals. Studies in a yeast 2-hybrid system supported a direct interaction between the AP4 complex and NAGPA (607985), variations in which have also been implicated in stuttering (STUT2; 609261). The findings suggested that defects in intracellular trafficking play a role in persistent stuttering. </p>
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</span>
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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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Bloodstein, O.
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<strong>A Handbook on Stuttering. (5th ed.)</strong>
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San Diego, Calif.: Singular Publishing Group (pub.) 1995.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Canhetti-Oliveira, C. M., Richieri-Costa, A.
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<strong>A study of familial stuttering.</strong>
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Am. J. Med. Genet. 140A: 2139-2141, 2006.
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[PubMed: 16752384]
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[Full Text: https://doi.org/10.1002/ajmg.a.31320]
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<p class="mim-text-font">
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Chakravartti, R., Roy, A. K., Rao, K. U. M., Chakravartti, M. R.
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<strong>Hereditary factors in stammering.</strong>
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J. Genet. Hum. 27: 319-328, 1979.
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[PubMed: 554863]
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<li>
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<p class="mim-text-font">
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Drayna, D., Kilshaw, J., Kelly, J.
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<strong>The sex ratio in familial persistent stuttering. (Letter)</strong>
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Am. J. Hum. Genet. 65: 1473-1475, 1999.
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[PubMed: 10521318]
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[Full Text: https://doi.org/10.1086/302625]
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</p>
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<li>
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<p class="mim-text-font">
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Felsenfeld, S., Plomin, R.
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<strong>Epidemiological and offspring analyses of developmental speech disorders using data from the Colorado Adoption Project.</strong>
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J. Speech Lang. Hear. Res. 40: 778-791, 1997.
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[PubMed: 9263943]
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[Full Text: https://doi.org/10.1044/jslhr.4004.778]
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</p>
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<li>
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<p class="mim-text-font">
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Howie, P. M.
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<strong>Concordance for stuttering in monozygotic and dizygotic twin pairs.</strong>
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J. Speech Hear. Res. 24: 317-321, 1981.
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[PubMed: 7197739]
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[Full Text: https://doi.org/10.1044/jshr.2403.317]
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<li>
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<p class="mim-text-font">
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Raza, M. H., Gertz, E. M., Mundorff, J., Lukong, J., Kuster, J., Schaffer, A. A., Drayna, D.
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<strong>Linkage analysis of a large African family segregating stuttering suggests polygenic inheritance.</strong>
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Hum. Genet. 132: 385-396, 2013.
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[PubMed: 23239121]
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[Full Text: https://doi.org/10.1007/s00439-012-1252-5]
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<p class="mim-text-font">
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Raza, M. H., Mattera, R., Morell, R., Sainz, E., Rahn, R., Gutierez, J., Paris, E., Root, J., Solomon, B., Brewer, C., Basra M. A. R., Khan, S., Riazuddin, S., Braun, A., Bonifacino, J. S., Drayna, D.
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<strong>Association between rare variants in AP4E1, a component of intracellular trafficking and persistent stuttering.</strong>
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Am. J. Hum. Genet. 97: 715-725, 2015.
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[PubMed: 26544806]
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[Full Text: https://doi.org/10.1016/j.ajhg.2015.10.007]
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<li>
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<p class="mim-text-font">
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Raza, M. H., Riazuddin, S., Drayna, D.
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<strong>Identification of an autosomal recessive stuttering locus on chromosome 3q13.2-3q13.33.</strong>
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Hum. Genet. 128: 461-463, 2010.
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[PubMed: 20706738]
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[Full Text: https://doi.org/10.1007/s00439-010-0871-y]
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<li>
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<p class="mim-text-font">
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Shugart, Y. Y., Mundorff, J., Kilshaw, J., Doheny, K., Doan, B., Wanyee, J., Green, E. D., Drayna, D.
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<strong>Results of a genome-wide linkage scan for stuttering.</strong>
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Am. J. Med. Genet. 124A: 133-135, 2004.
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[PubMed: 14699610]
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[Full Text: https://doi.org/10.1002/ajmg.a.20347]
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<li>
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<p class="mim-text-font">
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Yairi, E., Ambrose, N., Cox, N.
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<strong>Genetics of stuttering: a critical review.</strong>
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J. Speech Hear. Res. 39: 771-784, 1996.
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[PubMed: 8844557]
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[Full Text: https://doi.org/10.1044/jshr.3904.771]
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</ol>
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<div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 3/15/2016<br>Cassandra L. Kniffin - updated : 9/5/2013<br>Victor A. McKusick - updated : 6/18/2007<br>Victor A. McKusick - updated : 3/11/2005<br>Marla J. F. O'Neill - updated : 6/23/2004<br>Victor A. McKusick - updated : 11/15/1999
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</span>
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</div>
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</div>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/2/1986
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</span>
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</div>
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carol : 07/07/2016<br>carol : 3/16/2016<br>ckniffin : 3/15/2016<br>carol : 5/1/2014<br>tpirozzi : 9/12/2013<br>ckniffin : 9/5/2013<br>carol : 6/5/2012<br>alopez : 6/4/2012<br>ckniffin : 6/4/2012<br>alopez : 6/19/2007<br>terry : 6/18/2007<br>wwang : 3/18/2005<br>wwang : 3/14/2005<br>terry : 3/11/2005<br>carol : 6/29/2004<br>terry : 6/23/2004<br>carol : 3/14/2000<br>mgross : 12/1/1999<br>mgross : 11/30/1999<br>terry : 11/15/1999<br>mimadm : 5/10/1995<br>supermim : 3/16/1992<br>supermim : 3/20/1990<br>ddp : 10/27/1989<br>marie : 3/25/1988<br>reenie : 6/2/1986
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