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<title>
Entry
- #193500 - WAARDENBURG SYNDROME, TYPE 1; WS1
- OMIM
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<span class="h4">#193500</span>
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/193500"><strong>Clinical Synopsis</strong></a>
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<a href="/phenotypicSeries/PS193500"> <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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<li role="presentation" style="margin-left: 1em">
<a href="#otherFeatures">Other Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#diagnosis">Diagnosis</a>
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<a href="#cytogenetics">Cytogenetics</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="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#nomenclature">Nomenclature</a>
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<a href="#history">History</a>
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<a href="#seeAlso"><strong>See Also</strong></a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=WAARDENBURG SYNDROME, TYPE" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=663&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Waardenburg syndrome&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=219&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Waardenburg syndrome type 1&nbsp;</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1531/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
<div><a href="https://www.diseaseinfosearch.org/x/7424" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=193500[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>
<div><a href="#mimOrphanetFold" id="mimOrphanetToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="European reference portal for information on rare diseases and orphan drugs."><span id="mimOrphanetToggleTriangle" class="small" style="margin-left: -0.8em;">&#9658;</span>Orphanet</div>
<div id="mimOrphanetFold" class="collapse">
<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3440" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Waardenburg syndrome</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=894" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Waardenburg syndrome type 1</a></div>
</div>
<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/ded91089-7d95-44fd-845d-acb6aedc74ff/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:0110948" 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>
<div><a href="http://www.informatics.jax.org/disease/193500" 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>
<div><a href="https://omia.org/results?search_type=advanced&omia_id=001059,001688" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<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.">
&nbsp;
</span>
</span>
</div>
<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">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 1010606009<br />
<strong>ORPHA:</strong> 3440, 894<br />
<strong>DO:</strong> 0110948<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
193500
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
WAARDENBURG SYNDROME, TYPE 1; WS1
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
WAARDENBURG SYNDROME WITH DYSTOPIA CANTHORUM
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/1053?start=-3&limit=10&highlight=1053">
2q36.1
</a>
</span>
</td>
<td>
<span class="mim-font">
Waardenburg syndrome, type 1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/193500"> 193500 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
PAX3
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606597"> 606597 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group ">
<a href="/clinicalSynopsis/193500" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<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')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div class="btn-group">
<a href="/phenotypicSeries/PS193500" class="btn btn-info" role="button"> Phenotypic Series </a>
<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')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
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</div>
&nbsp;
<div class="btn-group">
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
PheneGene Graphics <span class="caret"></span>
</button>
<ul class="dropdown-menu" style="width: 17em;">
<li><a href="/graph/linear/193500" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
<li><a href="/graph/radial/193500" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
</ul>
</div>
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Face </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Smooth philtrum <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1142533&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1142533</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000319</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000319" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000319</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=64d497514ce8c2250bd637c9cb83892d" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Philtrum,Smooth-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=64d497514ce8c2250bd637c9cb83892d&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Decreased philtrum length <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1861324&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1861324</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000322</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Ears </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Congenital sensorineural deafness <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/95828007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">95828007</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/700453005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">700453005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H90.5" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H90.5</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1865866&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1865866</a>, <a href="https://bioportal.bioontology.org/search?q=C0339789&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0339789</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008527" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008527</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008527" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008527</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Laterally displaced inner canthi (dystopia canthorum) (95 to 99%)<br /> -
Increased intercanthal distance <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246803005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246803005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423113&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423113</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000506" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000506</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000506" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000506</a>]</span><br /> -
Blepharophimosis <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.52</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/374.46" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">374.46</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0005744&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0005744</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000581" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000581</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000581" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000581</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=0f0375071b81e81be36302aa011b44dc" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Blepharophimosis-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=0f0375071b81e81be36302aa011b44dc&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Hypertelorism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22006008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22006008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q75.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q75.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/376.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">376.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020534&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020534</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000316" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000316</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000316" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000316</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=593a4d488f00bb03351a0ddffaf4ac9a" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Eyes,Widely_Spaced-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=593a4d488f00bb03351a0ddffaf4ac9a&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Heterochromia iridis, complete or partial <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860351&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860351</a>]</span><br /> -
Hypoplastic iris stoma <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860344&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860344</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007990" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007990</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007990" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007990</a>]</span><br /> -
Hypopigmented ocular fundus <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1856885&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1856885</a>]</span><br /> -
Bright blue irides <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2750456&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2750456</a>]</span><br /> -
Synophrys <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/253207002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">253207002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0431447&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0431447</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000664" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000664</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000664" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000664</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=d88a284723f3407bf387ee65da76603e" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Synophrys-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=d88a284723f3407bf387ee65da76603e&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Lower lacrimal dystopia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2749829&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2749829</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Nose </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Broad, high nasal root <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1839324&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1839324</a>]</span><br /> -
Wide nasal bridge <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249321001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249321001</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849367&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849367</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000431" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000431</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000431" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000431</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=3f6587f50506c9d70db0628b3fa5f2c5" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Nasal_Bridge,Wide-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=3f6587f50506c9d70db0628b3fa5f2c5&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br /> -
Hypoplastic alae nasi <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834055&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834055</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000430" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000430</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000430" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000430</a>]</span><br /> -
Decreased nasal bone length <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2749830&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2749830</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Mouth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Cleft lip/palate <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/66948001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">66948001</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q37" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q37</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q35-Q37" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q35-Q37</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q37.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q37.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/749.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">749.20</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/749" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">749</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/749.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">749.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0158646&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0158646</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000202" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000202</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000202" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000202</a>]</span><br /> -
Mandibular prognathism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/109504005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">109504005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/22810007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">22810007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/M26.213" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">M26.213</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/524.23" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">524.23</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0399526&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0399526</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000303" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000303</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000303" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000303</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CHEST </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Ribs Sternum Clavicles & Scapulae </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Supernumerary ribs <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/205460009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">205460009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q76.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q76.6</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0345397&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0345397</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005815" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005815</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0005815" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0005815</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GENITOURINARY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> External Genitalia (Female) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Absent vagina (rare) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248871003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248871003</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0220763&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0220763</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003250</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003250" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003250</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Internal Genitalia (Female) </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Absent uterine adnexa (rare) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860349&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860349</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Skull </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Aplasia of posterior semicircular canal on CT scan <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860354&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860354</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Spine </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Sprengel anomaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/79120002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">79120002</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q74.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q74.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/755.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">755.52</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0152438&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0152438</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000912" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000912</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000912" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000912</a>]</span><br /> -
Supernumerary vertebrae <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/87294007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">87294007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q76.49" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q76.49</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0265681&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0265681</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002946" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002946</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002946" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002946</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Congenital partial albinism (leukoderma) on face, trunk, or limbs <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/6479008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">6479008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5848166&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5848166</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007443" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007443</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0007443" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0007443</a>]</span><br /> -
Hypopigmented skin lesions <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0748804&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0748804</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Hair </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- White forelock <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/247564004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">247564004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L67.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L67.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0344312&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0344312</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002211" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002211</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002211" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002211</a>]</span><br /> -
White eyelashes and eyebrows <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860346&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860346</a>]</span><br /> -
Bushy eyebrows <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853487&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853487</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000574" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000574</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000574" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000574</a>]</span><br /> -
Premature graying of hair <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/387833009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">387833009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/L67.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">L67.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0263498&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0263498</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002216" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002216</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002216" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002216</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Spina bifida (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/67531005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">67531005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q05.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q05.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q05" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q05</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/741.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">741.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/741.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">741.90</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/741" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">741</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0158534&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0158534</a>, <a href="https://bioportal.bioontology.org/search?q=C0080178&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0080178</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002414" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002414</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002414" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002414</a>]</span><br /> -
Myelomeningocele (less common) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/414667000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">414667000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q05" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q05</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C5781264&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C5781264</a>, <a href="https://bioportal.bioontology.org/search?q=C0025312&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0025312</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002475" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002475</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002475" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002475</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MISCELLANEOUS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Clinical variability seen in Waardenburg syndrome type 1<br /> -
Other variants of Waardenburg syndrome include Waardenburg syndrome type 2 (<a href="/entry/193510">193510</a>), Waardenburg syndrome type 3 (<a href="/entry/148820">148820</a>), and Waardenburg syndrome type 4 (<a href="/entry/277580">277580</a>)<br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Caused by mutation in the paired box 3 gene (PAX3, <a href="/entry/606597#0001">606597.0001</a>)<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small">
<div class="row">
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
<h5>
Waardenburg syndrome
- <a href="/phenotypicSeries/PS193500">PS193500</a>
- 10 Entries
</h5>
</div>
</div>
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
<table class="table table-bordered table-condensed table-hover mim-table-padding">
<thead>
<tr>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Location</strong>
</th>
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
<strong>Phenotype</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Inheritance</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />mapping key</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Phenotype<br />MIM number</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus</strong>
</th>
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
<strong>Gene/Locus<br />MIM number</strong>
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/1/817?start=-3&limit=10&highlight=817"> 1p21-p13.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600193"> Waardenburg syndrome, type 2B </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600193"> 600193 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600193"> WS2B </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600193"> 600193 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/1053?start=-3&limit=10&highlight=1053"> 2q36.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/193500"> Waardenburg syndrome, type 1 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/193500"> 193500 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606597"> PAX3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606597"> 606597 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/1053?start=-3&limit=10&highlight=1053"> 2q36.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/148820"> Waardenburg syndrome, type 3 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/148820"> 148820 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606597"> PAX3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606597"> 606597 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/454?start=-3&limit=10&highlight=454"> 3p13 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/193510"> Waardenburg syndrome, type 2A </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/193510"> 193510 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/156845"> MITF </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/156845"> 156845 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/8/5?start=-3&limit=10&highlight=5"> 8p23 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606662"> Waardenburg syndrome, type 2C </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="2 - The disorder was placed on the map by statistical methods"> 2 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606662"> 606662 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606662"> WS2C </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606662"> 606662 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/666?start=-3&limit=10&highlight=666"> 12q21.32 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619947"> Waardenburg syndrome, type 2F </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/619947"> 619947 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/184745"> KITLG </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/184745"> 184745 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/13/236?start=-3&limit=10&highlight=236"> 13q22.3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/277580"> Waardenburg syndrome, type 4A </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/277580"> 277580 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/131244"> EDNRB </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/131244"> 131244 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/20/432?start=-3&limit=10&highlight=432"> 20q13.32 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613265"> Waardenburg syndrome, type 4B </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613265"> 613265 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/131242"> EDN3 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/131242"> 131242 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/22/264?start=-3&limit=10&highlight=264"> 22q13.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613266"> Waardenburg syndrome, type 4C </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/613266"> 613266 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602229"> SOX10 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602229"> 602229 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/22/264?start=-3&limit=10&highlight=264"> 22q13.1 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611584"> Waardenburg syndrome, type 2E, with or without neurologic involvement </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/611584"> 611584 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602229"> SOX10 </a>
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602229"> 602229 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
<div class="text-right small">
<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
</div>
</div>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="text" class="mim-anchor"></a>
<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>TEXT</strong>
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</h4>
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<span class="mim-text-font">
<p>A number sign (#) is used with this entry because of evidence that Waardenburg syndrome type 1 (WS1) is caused by heterozygous mutation in the PAX3 gene (<a href="/entry/606597">606597</a>) on chromosome 2q36.</p><p>Waardenburg syndrome type 3 (WS3; <a href="/entry/148820">148820</a>) is also caused by mutation in the PAX3 gene.</p>
</span>
<div>
<br />
</div>
</div>
<div>
<a id="description" class="mim-anchor"></a>
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<span class="mim-font">
<strong>Description</strong>
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<p>Waardenburg syndrome type 1 (WS1) is an autosomal dominant auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes; congenital sensorineural hearing loss; and 'dystopia canthorum,' the lateral displacement of the ocular inner canthi (reviews by <a href="#50" class="mim-tip-reference" title="Read, A. P., Newton, V. E. &lt;strong&gt;Waardenburg syndrome.&lt;/strong&gt; J. Med. Genet. 34: 656-665, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9279758/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9279758&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.34.8.656&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9279758">Read and Newton, 1997</a>, <a href="#55" class="mim-tip-reference" title="Tamayo, M. L., Gelvez, N., Rodriguez, M., Florez, S., Varon, C., Medina, D., Bernal, J. E. &lt;strong&gt;Screening program for Waardenburg syndrome in Colombia: clinical definition and phenotypic variability.&lt;/strong&gt; Am. J. Med. Genet. 146A: 1026-1031, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18241065/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18241065&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32189&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18241065">Tamayo et al., 2008</a>, and <a href="#47" class="mim-tip-reference" title="Pingault, V., Ente, D., Dastot-Le Moal, F., Goossens, M., Marlin, S., Bondurand, N. &lt;strong&gt;Review and update of mutations causing Waardenburg syndrome.&lt;/strong&gt; Hum. Mutat. 31: 391-406, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20127975/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20127975&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/humu.21211&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20127975">Pingault et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18241065+9279758+20127975" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Clinical Variability of Waardenburg Syndrome Types 1-4</em></strong></p><p>
Waardenburg syndrome is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, including a white forelock and premature graying; pigmentary changes of the iris, such as heterochromia irides and brilliant blue eyes; and congenital sensorineural hearing loss. Waardenburg syndrome has been classified into 4 main phenotypes. WS type 1 is distinguished by the presence of dystopia canthorum. WS type 2 (WS2; see <a href="/entry/193510">193510</a>) is distinguished from type 1 by the absence of dystopia canthorum. WS type 3 (WS3; <a href="/entry/148820">148820</a>) has dystopia canthorum and upper limb abnormalities. WS type 4 (WS4; see <a href="/entry/277580">277580</a>), also known as Waardenburg-Shah syndrome, has the additional feature of Hirschsprung disease (reviews by <a href="#50" class="mim-tip-reference" title="Read, A. P., Newton, V. E. &lt;strong&gt;Waardenburg syndrome.&lt;/strong&gt; J. Med. Genet. 34: 656-665, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9279758/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9279758&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.34.8.656&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9279758">Read and Newton, 1997</a> and <a href="#55" class="mim-tip-reference" title="Tamayo, M. L., Gelvez, N., Rodriguez, M., Florez, S., Varon, C., Medina, D., Bernal, J. E. &lt;strong&gt;Screening program for Waardenburg syndrome in Colombia: clinical definition and phenotypic variability.&lt;/strong&gt; Am. J. Med. Genet. 146A: 1026-1031, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18241065/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18241065&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32189&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18241065">Tamayo et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18241065+9279758" 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 All Types of Waardenburg Syndrome</em></strong></p><p>
Waardenburg syndrome is genetically heterogeneous. WS1 and WS3 are both caused by mutation in the PAX3 gene. See WS2A (<a href="/entry/193510">193510</a>) for a discussion of genetic heterogeneity of WS type 2, and WS4A (<a href="/entry/277580">277580</a>) for a discussion of genetic heterogeneity of WS type 4.</p>
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<p><a href="#58" class="mim-tip-reference" title="Waardenburg, P. &lt;strong&gt;A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness.&lt;/strong&gt; Am. J. Hum. Genet. 3: 195-253, 1951.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14902764/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14902764&lt;/a&gt;]" pmid="14902764">Waardenburg (1951)</a> first delineated the syndrome that bears his name, describing it as a disorder combining anomalies of the eyelids, eyebrows, and nasal root with congenital deafness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14902764" 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="#23" class="mim-tip-reference" title="Feingold, M., Robinson, M. J., Gellis, S. S. &lt;strong&gt;Waardenburg&#x27;s syndrome during the first year of life.&lt;/strong&gt; J. Pediat. 71: 874-876, 1967.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6059431/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6059431&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(67)80015-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6059431">Feingold et al. (1967)</a> noted that the white forelock may be present at birth and later disappear in patients with Waardenburg syndrome. <a href="#3" class="mim-tip-reference" title="Arias, S. &lt;strong&gt;Waardenburg syndrome--two distinct types. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 6: 99-100, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7187610/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7187610&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320060109&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7187610">Arias (1980)</a> suggested that visceral and cranial malformations (such as Hirschsprung megacolon) are associated with Waardenburg syndrome type 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7187610+6059431" 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="#61" class="mim-tip-reference" title="Yoshino, M., Nakao, M., Shiotsuki, Y., Nishiyori, A., Yamashita, F., Karukaya, S., Yoshimura, H., Nishida, H., Shiotani, N., Sugita, A. &lt;strong&gt;Incidences of dystopia canthorum and some other signs in a family with Waardenburg syndrome type I.&lt;/strong&gt; Jpn. J. Hum. Genet. 31: 373-378, 1986."None>Yoshino et al. (1986)</a> evaluated the incidence of dystopia canthorum in a 3-generation family with Waardenburg syndrome type 1 and concluded that it is the most frequently expressed sign of the condition.</p><p><a href="#17" class="mim-tip-reference" title="da-Silva, E. O. &lt;strong&gt;Waardenburg I syndrome: a clinical and genetic study of two large Brazilian kindreds, and literature review.&lt;/strong&gt; Am. J. Med. Genet. 40: 65-74, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1887852/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1887852&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320400113&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1887852">Da-Silva (1991)</a> reported 2 large multigenerational Brazilian kindreds with WS type 1. The total number of affected individuals was 73. The major manifestations were telecanthus, which was the only constant anomaly, prominent nasal root (78%), round or square tip of nose, hypoplastic alae, smooth philtrum, bushy eyebrows with synophrys (76%), sensorineural deafness (67%), heterochromia or hypoisochromia iridis, hypopigmented ocular fundus, white forelock (29%), premature graying (44%), and hypopigmented skin lesions (55%). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1887852" 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="#60" class="mim-tip-reference" title="Winship, I., Beighton, P. &lt;strong&gt;Phenotypic discriminants in the Waardenburg syndrome.&lt;/strong&gt; Clin. Genet. 41: 181-188, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1576755/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1576755&lt;/a&gt;]" pmid="1576755">Winship and Beighton (1992)</a> reviewed phenotypic variation of Waardenburg syndrome on the basis of an analysis of 68 affected children. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1576755" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a craniofacial anthropometric study of 51 WS type 1 individuals, <a href="#15" class="mim-tip-reference" title="da-Silva, E. O., Batista, J. E. M., Medeiros, M. A. B., Fonteles, S. M. S. &lt;strong&gt;Craniofacial anthropometric studies in Waardenburg syndrome type I.&lt;/strong&gt; Clin. Genet. 44: 20-25, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8403450/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8403450&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1993.tb03836.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8403450">da-Silva et al. (1993)</a> concluded that the most discriminating parameters were, from clinical measurements, increased intercanthal distance and decreased philtrum length, and, from roentgenographic measurements, decreased nasal bone length and increased lower facial height. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8403450" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#50" class="mim-tip-reference" title="Read, A. P., Newton, V. E. &lt;strong&gt;Waardenburg syndrome.&lt;/strong&gt; J. Med. Genet. 34: 656-665, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9279758/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9279758&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.34.8.656&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9279758">Read and Newton (1997)</a> provided a review of the clinical features and molecular basis of Waardenburg syndrome and other auditory pigmentary syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9279758" 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>From a systematic literature search, <a href="#54" class="mim-tip-reference" title="Song, J., Feng, Y., Acke, F. R., Coucke, P., Vleminckx, K., Dhooge, I. J. &lt;strong&gt;Hearing loss in Waardenburg syndrome: a systematic review.&lt;/strong&gt; Clin. Genet. 89: 416-425, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26100139/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26100139&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/cge.12631&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26100139">Song et al. (2016)</a> determined that the prevalence of hearing loss in patients with Waardenburg syndrome differed according to the genotype: the prevalence in those with WS1 due to PAX3 mutations was 52.3%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26100139" 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="#27" class="mim-tip-reference" title="Giacoia, J. P., Klein, S. W. &lt;strong&gt;Waardenburg&#x27;s syndrome with bilateral cleft lip.&lt;/strong&gt; Am. J. Dis. Child. 117: 344-348, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5765156/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5765156&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/archpedi.1969.02100030346020&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5765156">Giacoia and Klein (1969)</a> documented the occurrence of bilateral cleft lip in Waardenburg syndrome. <a href="#2" class="mim-tip-reference" title="Arias, S. &lt;strong&gt;Genetic heterogeneity in the Waardenburg syndrome.&lt;/strong&gt; Birth Defects Orig. Art. Ser. 7(4): 87-101, 1971."None>Arias (1971)</a> observed a black forelock in place of white forelock. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5765156" 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="#29" class="mim-tip-reference" title="Goodman, R. M., Oelsner, G., Berkenstadt, M., Admon, D. &lt;strong&gt;Absence of a vagina and right sided adnexa uteri in the Waardenburg syndrome: a possible clue to the embryological defect.&lt;/strong&gt; J. Med. Genet. 25: 355-357, 1988.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3385746/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3385746&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.25.5.355&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3385746">Goodman et al. (1988)</a> observed absence of vagina and of right-sided uterine adnexa in an 18-year-old woman with WS1. They postulated that these are related to Waardenburg syndrome because of altered invasion of neurons in early embryogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3385746" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Carezani-Gavin, M., Clarren, S. K., Steege, T. &lt;strong&gt;Waardenburg syndrome associated with meningomyelocele. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 42: 135-136, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1308353/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1308353&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320420127&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1308353">Carezani-Gavin et al. (1992)</a> reported a patient with Waardenburg syndrome type 1 who also had a meningomyelocele at the L3-S1 level and Arnold-Chiari malformation. Characteristic features of WS1 were present, including hearing loss, dystopia canthorum, broad nasal root, and narrow nasal tip. There was a family history of the disorder, but none of the other affected individuals had neural tube defects. In the family reported by <a href="#10" class="mim-tip-reference" title="Carezani-Gavin, M., Clarren, S. K., Steege, T. &lt;strong&gt;Waardenburg syndrome associated with meningomyelocele. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 42: 135-136, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1308353/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1308353&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320420127&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1308353">Carezani-Gavin et al. (1992)</a>, <a href="#33" class="mim-tip-reference" title="Hoth, C. F., Milunsky, A., Lipsky, N., Sheffer, R., Clarren, S. K., Baldwin, C. T. &lt;strong&gt;Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I).&lt;/strong&gt; Am. J. Hum. Genet. 52: 455-462, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8447316/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8447316&lt;/a&gt;]" pmid="8447316">Hoth et al. (1993)</a> identified a heterozygous mutation in the PAX3 gene (R56L; <a href="/entry/606597#0014">606597.0014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8447316+1308353" 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="#12" class="mim-tip-reference" title="Chatkupt, S., Chatkupt, S., Johnson, W. G. &lt;strong&gt;Waardenburg syndrome and myelomeningocele in a family.&lt;/strong&gt; J. Med. Genet. 30: 83-84, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8423616/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8423616&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.30.1.83&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8423616">Chatkupt et al. (1993)</a> stated that spina bifida had been noted in at least 4 patients with Waardenburg syndrome. They reported the cases of brothers with both Waardenburg syndrome and lumbosacral myelomeningocele. The mother had features of Waardenburg syndrome. Spina bifida occurs with the 'Splotch' mutation, which molecular studies indicate is the homologous disorder in the mouse (see <a href="/entry/606597">606597</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8423616" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="inheritance" class="mim-anchor"></a>
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<strong>Inheritance</strong>
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<p>Waardenburg syndrome type 1 is an autosomal dominant disorder (<a href="#46" class="mim-tip-reference" title="Pardono, E., van Bever, Y., van den Ende, J., Havrenne, P. C., Iughetti, P., Maestrelli, S. R. P., Costa F, O., Richieri-Costa, A., Frota-Pessoa, O., Otto, P. A. &lt;strong&gt;Waardenburg syndrome: clinical differentiation between types I and II.&lt;/strong&gt; Am. J. Med. Genet. 117A: 223-235, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12599185/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12599185&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.10193&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12599185">Pardono et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12599185" 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="#38" class="mim-tip-reference" title="Jones, K. L., Smith, D. W., Harvey, M. A. S., Hall, B. D., Quan, L. &lt;strong&gt;Older paternal age and fresh gene mutation: data on additional disorders.&lt;/strong&gt; J. Pediat. 86: 84-88, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1110452/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1110452&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(75)80709-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1110452">Jones et al. (1975)</a> found evidence of paternal age effect in new mutations for autosomal dominant Waardenburg syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1110452" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#39" class="mim-tip-reference" title="Kapur, S., Karam, S. &lt;strong&gt;Germ-line mosaicism in Waardenburg syndrome.&lt;/strong&gt; Clin. Genet. 39: 194-198, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2036740/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2036740&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.1991.tb03011.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2036740">Kapur and Karam (1991)</a> described a family in which 3 children with this disorder were born to normal, unrelated parents. Germline mosaicism was postulated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2036740" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="diagnosis" class="mim-anchor"></a>
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<strong>Diagnosis</strong>
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<p><a href="#41" class="mim-tip-reference" title="Laestadius, N. D., Aase, J. M., Smith, D. W. &lt;strong&gt;Normal inner canthal and outer orbital dimensions.&lt;/strong&gt; J. Pediat. 74: 465-468, 1969.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/5764779/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;5764779&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0022-3476(69)80206-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="5764779">Laestadius et al. (1969)</a> provided normal standards for the measurement of inner canthal and outer canthal distance. Standards were also presented by <a href="#14" class="mim-tip-reference" title="Christian, J. C., Bixler, D., Blythe, S. C., Merritt, A. D. &lt;strong&gt;Familial telecanthus with associated congenital anomalies.&lt;/strong&gt; Birth Defects Orig. Art. Ser. V(2): 82-85, 1969."None>Christian et al. (1969)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5764779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In place of the measurement of inner canthal distance, the Waardenburg Consortium (<a href="#22" class="mim-tip-reference" title="Farrer, L. A., Grundfast, K. M., Amos, J., Arnos, K. S., Asher, J. H., Jr., Beighton, P., Diehl, S. R., Fex, J., Foy, C., Friedman, T. B., Greenberg, J., Hoth, C., Marazita, M., Milunsky, A., Morell, R., Nance, W., Newton, V., Ramesar, R., San Agustin, T. B., Skare, J., Stevens, C. A., Wagner, R. G., Jr., Wilcox, E. R., Winship, I., Read, A. P. &lt;strong&gt;Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS Consortium.&lt;/strong&gt; Am. J. Hum. Genet. 50: 902-913, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1349198/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1349198&lt;/a&gt;]" pmid="1349198">Farrer et al., 1992</a>) recommended the W index: a composite measure including the inner canthal, inner pupillary, and outer canthal distances. Normal and dystopic subjects had W values (mean +/- SD) of 1.76 +/- 0.16 and 2.61 +/- 0.19, respectively (<a href="#44" class="mim-tip-reference" title="Newton, V. E. &lt;strong&gt;Waardenburg&#x27;s syndrome: a comparison of biometric indices used to diagnose lateral displacement of the inner canthi.&lt;/strong&gt; Scand. Audiol. 18: 221-223, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2609099/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2609099&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.3109/01050398909042198&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2609099">Newton, 1989</a>); the Waardenburg Consortium recommended a threshold W value of 2.07. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2609099+1349198" 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="#46" class="mim-tip-reference" title="Pardono, E., van Bever, Y., van den Ende, J., Havrenne, P. C., Iughetti, P., Maestrelli, S. R. P., Costa F, O., Richieri-Costa, A., Frota-Pessoa, O., Otto, P. A. &lt;strong&gt;Waardenburg syndrome: clinical differentiation between types I and II.&lt;/strong&gt; Am. J. Med. Genet. 117A: 223-235, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12599185/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12599185&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.10193&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12599185">Pardono et al. (2003)</a> studied 59 patients with Waardenburg syndrome from 37 families (30 with type 1, 21 with type 2, and 8 isolated individuals without telecanthus). All patients were examined for the presence of 8 cardinal diagnostic signs: telecanthus, synophrys, iris pigmentation disturbances, partial hair albinism, hearing impairment, hypopigmented skin spots, nasal root hyperplasia, and lower lacrimal dystopia. The authors noted that some patients with type 1 may not have dystopia canthorum, but that it is present in 95 to 99% of patients with WS type 1. Using their own data as well as those collected from the literature, the authors estimated the frequencies of these 8 cardinal signs of Waardenburg syndrome based on a sample of 461 affected individuals with type 1 and 121 with type 2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12599185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="cytogenetics" class="mim-anchor"></a>
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<strong>Cytogenetics</strong>
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<p>Ishikiriyama et al. (<a href="#36" class="mim-tip-reference" title="Ishikiriyama, S., Tonoki, H., Shibuya, Y., Chin, S., Harada, N., Abe, K., Niikawa, N. &lt;strong&gt;Waardenburg syndrome type I in a child with de novo inversion (2)(q35q37.3).&lt;/strong&gt; Am. J. Med. Genet. 33: 505-507, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2596512/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2596512&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320330419&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2596512">1989</a>, <a href="#35" class="mim-tip-reference" title="Ishikiriyama, S., Tonoki, H., Shibuya, Y., Chin, S., Harada, N., Abe, K., Niikawa, N. &lt;strong&gt;A sporadic case of Waardenburg syndrome type I associated with de novo inv(2)(q35q37.3). (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 51: 1018, 1989."None>1989</a>) reported a 20-month-old boy with dystopia canthorum, sensorineural deafness, heterochromia iridis, partially albinotic ocular fundi, and partial leukoderma. Cytogenetic studies showed a paracentric inversion (2)(q35q37.3); his parents had normal chromosomes. <a href="#35" class="mim-tip-reference" title="Ishikiriyama, S., Tonoki, H., Shibuya, Y., Chin, S., Harada, N., Abe, K., Niikawa, N. &lt;strong&gt;A sporadic case of Waardenburg syndrome type I associated with de novo inv(2)(q35q37.3). (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 51: 1018, 1989."None>Ishikiriyama et al. (1989)</a> suggest that the gene for Waardenburg syndrome type 1 may be located on chromosome 2q35 or 2q37.3. <a href="#40" class="mim-tip-reference" title="Kirkpatrick, S. J., Kent, C. M., Laxova, R., Sekhon, G. S. &lt;strong&gt;Waardenburg syndrome type I in a child with deletion (2)(q35q36.2). (Letter)&lt;/strong&gt; Am. J. Med. Genet. 44: 699-700, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1481835/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1481835&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320440533&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1481835">Kirkpatrick et al. (1992)</a> described WS type 1 in a child with del(2)(q35q36.2). Because of this report and that of <a href="#42" class="mim-tip-reference" title="Lin, S.-P., Petty, E. M., Gibson, L. H., Inserra, J., Seashore, M. R., Yang-Feng, T. L. &lt;strong&gt;Smallest terminal deletion of the long arm of chromosome 2 in a mildly affected boy.&lt;/strong&gt; Am. J. Med. Genet. 44: 500-502, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1442895/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1442895&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320440424&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1442895">Lin et al. (1992)</a> of deletion of 2q37 without features of WS1, <a href="#37" class="mim-tip-reference" title="Ishikiriyama, S. &lt;strong&gt;Gene for Waardenburg syndrome type I is located at 2q35, not at 2q37.3. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 46: 608, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8322830/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8322830&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320460534&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8322830">Ishikiriyama (1993)</a> concluded that the WS1 gene is located at 2q35. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2596512+1442895+1481835+8322830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="mapping" class="mim-anchor"></a>
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<strong>Mapping</strong>
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<p>On the basis of an analysis of mouse and hamster mutants as models for Waardenburg syndrome(s), <a href="#4" class="mim-tip-reference" title="Asher, J. H., Jr., Friedman, T. B. &lt;strong&gt;Mouse and hamster mutants as models for Waardenburg syndromes in humans.&lt;/strong&gt; J. Med. Genet. 27: 618-626, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2246770/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2246770&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.27.10.618&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2246770">Asher and Friedman (1990)</a> predicted that the gene(s) would be found to be on chromosome 2q near fibronectin-1 (<a href="/entry/135600">135600</a>), on chromosome 3p near the protooncogene RAF1 (<a href="/entry/164760">164760</a>) or 3q near rhodopsin, (RHO; <a href="/entry/180380">180380</a>), or on chromosome 4p near the protooncogene KIT (<a href="/entry/164920">164920</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2246770" 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="#24" class="mim-tip-reference" title="Foy, C., Newton, V., Wellesley, D., Harris, R., Read, A. P. &lt;strong&gt;Assignment of the locus for Waardenburg syndrome type I to human chromosome 2q37 and possible homology to the Splotch mouse.&lt;/strong&gt; Am. J. Hum. Genet. 46: 1017-1023, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2339698/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2339698&lt;/a&gt;]" pmid="2339698">Foy et al. (1990)</a> demonstrated linkage of the Waardenburg syndrome to placental alkaline phosphatase (ALPP; <a href="/entry/171800">171800</a>), which had previously been assigned to 2q37; the peak lod score was 4.76 at a recombination fraction of 0.023. These findings suggest that the distal breakpoint responsible for the paracentric inversion is at the site of the Waardenburg syndrome, namely, 2q37.3. This region of chromosome 2 is homologous to mouse chromosome 1, which contains the 'Splotch' locus (Sp) (PAX3). This patchy pigment mutation is accompanied by a malformation of the inner ear and severe CNS malformation in the homozygote. Whether the heterozygote is deaf is unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2339698" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a family with 11 affected individuals spanning 4 generations, <a href="#5" class="mim-tip-reference" title="Asher, J. H., Jr., Morell, R., Friedman, T. B. &lt;strong&gt;Waardenburg syndrome (WS): the analysis of a single family with a WS1 mutation showing linkage to RFLP markers on human chromosome 2q.&lt;/strong&gt; Am. J. Hum. Genet. 48: 43-52, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1670751/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1670751&lt;/a&gt;]" pmid="1670751">Asher et al. (1991)</a> confirmed the assignment of WS1 to 2q. No recombination was found with ALPP at 2q37 or with FN1 (<a href="/entry/135600">135600</a>) at 2q34-q36. <a href="#30" class="mim-tip-reference" title="Grundfast, K., Farrer, L., Amos, J., Arnos, K. S., Asher, J., Beighton, P., Diehl, S., Fex, J., Foy, C., Friedman, T., Greenberg, J., Hoth, C., Milunsky, A., Morell, R., Nance, W., Newton, V., Ramesar, R., Read, A., Skare, J., SanAgustin, T., Stevens, C., Wagner, R., Jr., Wilcox, E., Winship, I. &lt;strong&gt;Waardenburg syndrome is caused by defects at multiple loci, one of which is tightly linked to ALPP on chromosome 2--first report of the WS consortium. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 49 (suppl.): 17, 1991."None>Grundfast et al. (1991)</a> found no obligatory crossovers between WS1 and ALPP. For a collection of families, they obtained a maximum lod of 12.5 at theta = 0.31 for the WS1/ALPP linkage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1670751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<p><a href="#57" class="mim-tip-reference" title="Tassabehji, M., Read, A. P., Newton, V. E., Harris, R., Balling, R., Gruss, P., Strachan, T. &lt;strong&gt;Waardenburg&#x27;s syndrome patients have mutations in the human homologue of the Pax-3 paired box gene.&lt;/strong&gt; Nature 355: 635-636, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1347148/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1347148&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/355635a0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1347148">Tassabehji et al. (1992)</a> identified variations in the PAX3 gene in 6 of 17 unrelated patients with Waardenburg syndrome type 1 using primers to amplify exons followed by testing for heteroduplex formation on polyacrylamide gels. No variants were seen in any exon in 50 normal controls. In 3 families that were tested, the variant was found to be familial in 2 and apparently de novo in the third. The variant bands showed perfect linkage to WS in the families studied. One family was found to have a heterozygous 18-bp deletion in the central region of exon 2, resulting in loss of amino acids 29 to 34 (<a href="/entry/606597#0001">606597.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1347148" 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>Simultaneously and independently, <a href="#7" class="mim-tip-reference" title="Baldwin, C. T., Hoth, C. F., Amos, J. A., da-Silva, E. O., Milunsky, A. &lt;strong&gt;An exonic mutation in the HuP2 paired domain gene causes Waardenburg&#x27;s syndrome.&lt;/strong&gt; Nature 355: 637-638, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1347149/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1347149&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/355637a0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1347149">Baldwin et al. (1992)</a> identified a heterozygous mutation in the PAX3 gene (P50L; <a href="/entry/606597#0002">606597.0002</a>) in affected members of a large Brazilian family with Waardenburg syndrome type 1 reported by <a href="#17" class="mim-tip-reference" title="da-Silva, E. O. &lt;strong&gt;Waardenburg I syndrome: a clinical and genetic study of two large Brazilian kindreds, and literature review.&lt;/strong&gt; Am. J. Med. Genet. 40: 65-74, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1887852/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1887852&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320400113&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1887852">da-Silva (1991)</a>. There were 49 affected persons in 6 generations, and more than 78% of the affected individuals had hearing loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1347149+1887852" 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="#8" class="mim-tip-reference" title="Baldwin, C. T., Hoth, C. F., Macina, R. A., Milunsky, A. &lt;strong&gt;Mutations in PAX3 that cause Waardenburg syndrome type I: ten new mutations and review of the literature.&lt;/strong&gt; Am. J. Med. Genet. 58: 115-122, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8533800/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8533800&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320580205&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8533800">Baldwin et al. (1995)</a> described 10 additional mutations in the PAX3 gene in families with WS type 1. Eight of these mutations were in a region of PAX3 where only 1 mutation had previously been described. Taken together with previously reported mutations, these mutations covered essentially the entire PAX3 gene. All but 1 of the mutations were 'private;' only 1 mutation had been reported in 2 apparently unrelated families. <a href="#8" class="mim-tip-reference" title="Baldwin, C. T., Hoth, C. F., Macina, R. A., Milunsky, A. &lt;strong&gt;Mutations in PAX3 that cause Waardenburg syndrome type I: ten new mutations and review of the literature.&lt;/strong&gt; Am. J. Med. Genet. 58: 115-122, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8533800/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8533800&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320580205&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8533800">Baldwin et al. (1995)</a> also cataloged 16 previously reported mutations and 5 chromosomal abnormalities affecting the 2q35 region that were associated with WS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8533800" 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>Modifier Genes</em></strong></p><p>
Work in the hamster model for Waardenburg syndrome suggested to <a href="#4" class="mim-tip-reference" title="Asher, J. H., Jr., Friedman, T. B. &lt;strong&gt;Mouse and hamster mutants as models for Waardenburg syndromes in humans.&lt;/strong&gt; J. Med. Genet. 27: 618-626, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2246770/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2246770&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.27.10.618&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2246770">Asher and Friedman (1990)</a> that modifier genes may account for the intrafamilial variation in phenotype in Waardenburg syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2246770" 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="#51" class="mim-tip-reference" title="Reynolds, J. E., Marazita, M. L., Meyer, J. M., Stevens, C. A., Eaves, L. J., Arnos, K. S., Ploughman, L. M., MacLean, C., Nance, W. E., Diehl, S. R. &lt;strong&gt;Major-locus contributions to variability of the craniofacial feature dystopia canthorum in Waardenburg syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 58: 384-392, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8571965/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8571965&lt;/a&gt;]" pmid="8571965">Reynolds et al. (1996)</a> sought to determine whether the W-index is influenced primarily by allelic variation in the PAX3 disease gene or other major loci, by polygenic background effects, or by all of these potential sources of genetic variation. They studied both WS1-affected individuals and their WS1 unaffected relatives. After adjustment of the W-index for WS1 disease status, segregation analyses by the regression approach indicated major-locus control of this variation, although residual parent-offspring and sib-sib correlations were consistent with additional (possibly polygenic) effects. Separate analyses of WS1-affected and WS1-unaffected individuals suggested that epistatic interactions between disease alleles at the PAX3 WS1 locus and a second major locus influenced variation in dystopia canthorum. <a href="#51" class="mim-tip-reference" title="Reynolds, J. E., Marazita, M. L., Meyer, J. M., Stevens, C. A., Eaves, L. J., Arnos, K. S., Ploughman, L. M., MacLean, C., Nance, W. E., Diehl, S. R. &lt;strong&gt;Major-locus contributions to variability of the craniofacial feature dystopia canthorum in Waardenburg syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 58: 384-392, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8571965/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8571965&lt;/a&gt;]" pmid="8571965">Reynolds et al. (1996)</a> suggested that their approach should be applicable for assessing the 'genetic architecture' of variation associated with other genetic diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8571965" 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>While mutations in PAX3 seem to be responsible for most, if not all, WS1 cases, it is not clear what accounts for the reduced penetrance of deafness. Stochastic events during development may be the factors that determine whether a person with a PAX3 mutation will be congenitally deaf or not. Alternatively, genetic background, nonrandom environmental factors, or both may be significant. <a href="#43" class="mim-tip-reference" title="Morell, R., Friedman, T. B., Asher, J. H., Jr., Robbins, L. G. &lt;strong&gt;The incidence of deafness is non-randomly distributed among families segregating for Waardenburg syndrome type 1 (WS1).&lt;/strong&gt; J. Med. Genet. 34: 447-452, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9192262/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9192262&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1136/jmg.34.6.447&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9192262">Morell et al. (1997)</a> compared the likelihood for deafness in affected subjects from 24 families with PAX3 mutations and in 7 of the families originally described by Waardenburg. They found evidence that stochastic variation alone does not explain the differences in penetrance of deafness among WS families. Their analyses suggested that genetic background in combination with certain PAX3 alleles may be important factors in the etiology of deafness in WS1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9192262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="genotypePhenotypeCorrelations" class="mim-anchor"></a>
<h4 href="#mimGenotypePhenotypeCorrelationsFold" id="mimGenotypePhenotypeCorrelationsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Genotype/Phenotype Correlations</strong>
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<p>In a series of patients with Waardenburg syndrome, <a href="#56" class="mim-tip-reference" title="Tassabehji, M., Newton, V. E., Leverton, K., Turnbull, K., Seemanova, E., Kunze, J., Sperling, K., Strachan, T., Read, A. P. &lt;strong&gt;PAX3 gene structure and mutations: close analogies between Waardenburg syndrome and the &#x27;Splotch&#x27; mouse.&lt;/strong&gt; Hum. Molec. Genet. 3: 1069-1074, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7981674/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7981674&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/3.7.1069&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7981674">Tassabehji et al. (1994)</a> found a number of previously unidentified PAX3 mutations. These included a chromosomal deletion, a splice site mutation, and an amino acid substitution that closely corresponded to the molecular changes seen in the 'Splotch-retarded' and 'Splotch-delayed' mouse mutants, respectively. These mutations confirmed that Waardenburg syndrome is produced by gene dosage effects and showed that the phenotypic differences between 'Splotch' mice and humans with Waardenburg syndrome are caused by differences in genetic background rather than different primary effects of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7981674" 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="#11" class="mim-tip-reference" title="Chalepakis, G., Goulding, M., Read, A., Strachan, T., Gruss, P. &lt;strong&gt;Molecular basis of Splotch and Waardenburg Pax-3 mutations.&lt;/strong&gt; Proc. Nat. Acad. Sci. 91: 3685-3689, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7909605/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7909605&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.91.9.3685&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7909605">Chalepakis et al. (1994)</a> studied the functional consequence of the mutations described in <a href="/entry/606597#0001">606597.0001</a> and <a href="/entry/606597#0006">606597.0006</a> on DNA binding and compared the results with those in the 'Splotch' mouse. Combining the phenotypic features of heterozygous mutants and considering that molecular defects ranging from single point mutations to large deletions cause similar phenotypes, they excluded the possibility that the mutated allele in heterozygotes interferes with the function of the wildtype allele. Contrariwise, they considered both WS and 'Splotch' mutants to represent loss-of-function mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7909605" 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="#62" class="mim-tip-reference" title="Zlotogora, J., Lerer, I., Bar-David, S., Ergaz, Z., Abeliovich, D. &lt;strong&gt;Homozygosity for Waardenburg syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 56: 1173-1178, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7726174/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7726174&lt;/a&gt;]" pmid="7726174">Zlotogora et al. (1995)</a> reported a large kindred in which many individuals had Waardenburg syndrome type 1 caused by a heterozygous mutation in the PAX3 gene (S84F; <a href="/entry/606597#0009">606597.0009</a>). However, there was 1 child, born of consanguineous parents, who had a severe phenotype consistent with WS type 3 (<a href="/entry/148820">148820</a>): this patient was found to be homozygous for the S84F mutation. The child presented with dystopia canthorum, partial albinism, and very severe upper limb defects. Since all Pax3 mutations in mice lead to severe neural tube defects and intrauterine or neonatal death, the survival of the homozygote in this case and the absence of neural tube defects were unexpected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7726174" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Ayme, S., Philip, N. &lt;strong&gt;Possible homozygous Waardenburg syndrome in a fetus with exencephaly. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 59: 263-265, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8588597/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8588597&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320590227&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8588597">Ayme and Philip (1995)</a> observed exencephaly in a fetus with possible homozygous Waardenburg syndrome. The fetus was the product of a mating between a gypsy brother and sister, both of whom had Waardenburg syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8588597" 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="#8" class="mim-tip-reference" title="Baldwin, C. T., Hoth, C. F., Macina, R. A., Milunsky, A. &lt;strong&gt;Mutations in PAX3 that cause Waardenburg syndrome type I: ten new mutations and review of the literature.&lt;/strong&gt; Am. J. Med. Genet. 58: 115-122, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8533800/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8533800&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320580205&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8533800">Baldwin et al. (1995)</a> stated that their analysis of a total of 30 PAX3 mutations causing WS type 1 or type 3 demonstrated little correlation between genotype and phenotype. Deletions of the entire PAX3 gene resulted in phenotypes indistinguishable from those associated with single-base substitutions in the paired domain or homeodomain of the gene. Moreover, 2 similar mutations in close proximity could result in significantly different phenotypes, WS type 1 in 1 family and WS type 3 in another. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8533800" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="DeStefano, A. L., Cupples, L. A., Arnos, K. S., Asher, J. H., Jr., Baldwin, C. T., Blanton, S., Carey, M. L., da Silva, E. O., Friedman, T. B., Greenberg, J., Lalwani, A. K., Milunsky, A., Nance, W. E., Pandya, A., Ramesar, R. S., Read, A. P., Tassabejhi, M., Wilcox, E. R., Farrer, L. A. &lt;strong&gt;Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations.&lt;/strong&gt; Hum. Genet. 102: 499-506, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9654197/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9654197&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s004390050732&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9654197">DeStefano et al. (1998)</a> assessed the relationship between phenotype and gene defect in 48 families containing 271 individuals with WS collected by members of the Waardenburg Consortium. They grouped the 42 unique mutations previously identified in the PAX3 gene in these families into 5 mutation categories: amino acid substitution in the paired domain, amino acid substitution in the homeodomain, deletion of the ser-thr-pro-rich region, deletion of the homeodomain and the ser-thr-pro-rich region, and deletion of the entire gene. This classification of mutations was based on the structure of the PAX3 gene and was chosen to group mutations predicted to have similar defects in the gene product. They found that odds for the presence of eye pigment abnormality, white forelock, and skin hypopigmentation were 2, 8, and 5 times greater, respectively, for individuals with deletions of the homeodomain and the pro-ser-thr-rich region compared to individuals with an amino acid substitution in the homeodomain. Odds ratios that differed significantly from 1.0 for these traits may indicate that the gene products resulting from different classes of mutations act differently in the expression of WS. Although a suggestive association was detected for hearing loss with an odds ratio of 2.6 for amino acid substitution in the paired domain compared with amino acid substitution in the homeodomain, this odds ratio did not differ significantly from 1.0. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9654197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="pathogenesis" class="mim-anchor"></a>
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<strong>Pathogenesis</strong>
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<p><a href="#59" class="mim-tip-reference" title="Watanabe, A., Takeda, K., Ploplis, B., Tachibana, M. &lt;strong&gt;Epistatic relationship between Waardenburg syndrome genes MITF and PAX3.&lt;/strong&gt; Nature Genet. 18: 283-286, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9500554/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9500554&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0398-283&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9500554">Watanabe et al. (1998)</a> showed that PAX3 transactivates the MITF (<a href="/entry/156845">156845</a>) promoter. They further showed that PAX3 proteins associated with WS1 in either the paired domain or the homeodomain failed to recognize and transactivate the MITF promoter. These results provided evidence that PAX3 directly regulates MITF, and suggested that the failure of this regulation due to PAX3 mutations causes the auditory-pigmentary symptoms in at least some individuals with WS1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9500554" 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="#9" class="mim-tip-reference" title="Bondurand, N., Pingault, V., Goerich, D. E., Lemort, N., Sock, E., Le Caignec, C., Wegner, M., Goossens, M. &lt;strong&gt;Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.&lt;/strong&gt; Hum. Molec. Genet. 9: 1907-1917, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10942418/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10942418&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/9.13.1907&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10942418">Bondurand et al. (2000)</a> showed that SOX10 (<a href="/entry/602229">602229</a>), in synergy with PAX3, strongly activates MITF expression in transfection assays. Transfection experiments revealed that PAX3 and SOX10 interact directly by binding to a proximal region of the MITF promoter containing binding sites for both factors. Mutant SOX10 or PAX3 proteins failed to transactivate this promoter, providing further evidence that the 2 genes act in concert to directly regulate expression of MITF. In situ hybridization experiments carried out in the dominant megacolon (Dom) mouse confirmed that SOX10 dysfunction impaired Mitf expression as well as melanocytic development and survival. The authors hypothesized that interaction between 3 of the genes that are altered in WS could explain the auditory/pigmentary symptoms of this disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10942418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="populationGenetics" class="mim-anchor"></a>
<h4 href="#mimPopulationGeneticsFold" id="mimPopulationGeneticsToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Population Genetics</strong>
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<p>Waardenburg syndrome has been described in American blacks (<a href="#32" class="mim-tip-reference" title="Hansen, A. C., Ackaouy, G., Crump, E. P. &lt;strong&gt;Waardenburg&#x27;s syndrome: report of a pedigree.&lt;/strong&gt; J. Nat. Med. Assoc. 57: 8-12, 1965.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14269024/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14269024&lt;/a&gt;]" pmid="14269024">Hansen et al., 1965</a>) and in Maoris (<a href="#34" class="mim-tip-reference" title="Houghton, N. I. &lt;strong&gt;Waardenburg&#x27;s syndrome with deafness as the presenting symptom: report of two cases.&lt;/strong&gt; New Zeal. Med. J. 63: 83-89, 1964.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14124244/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14124244&lt;/a&gt;]" pmid="14124244">Houghton, 1964</a>) as well as in Europeans. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14269024+14124244" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the state of South Australia, Waardenburg syndrome is a leading cause of deafness and has a position comparable to porphyria in South Africa, having been introduced by early settlers who had many descendants (<a href="#25" class="mim-tip-reference" title="Fraser, G. R. &lt;strong&gt;Personal Communication.&lt;/strong&gt; Adelaide, Australia 1967."None>Fraser, 1967</a>).</p><p>An affected Chinese family was reported by <a href="#13" class="mim-tip-reference" title="Chew, K. L., Chen, A. J., Tan, K. H. &lt;strong&gt;A Chinese family with Waardenburg&#x27;s syndrome.&lt;/strong&gt; Am. J. Ophthal. 65: 174-182, 1968.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4966266/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4966266&lt;/a&gt;]" pmid="4966266">Chew et al. (1968)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4966266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a report from a consortium, <a href="#30" class="mim-tip-reference" title="Grundfast, K., Farrer, L., Amos, J., Arnos, K. S., Asher, J., Beighton, P., Diehl, S., Fex, J., Foy, C., Friedman, T., Greenberg, J., Hoth, C., Milunsky, A., Morell, R., Nance, W., Newton, V., Ramesar, R., Read, A., Skare, J., SanAgustin, T., Stevens, C., Wagner, R., Jr., Wilcox, E., Winship, I. &lt;strong&gt;Waardenburg syndrome is caused by defects at multiple loci, one of which is tightly linked to ALPP on chromosome 2--first report of the WS consortium. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 49 (suppl.): 17, 1991."None>Grundfast et al. (1991)</a> concluded that about 56% of WS families are linked to 2q markers. <a href="#22" class="mim-tip-reference" title="Farrer, L. A., Grundfast, K. M., Amos, J., Arnos, K. S., Asher, J. H., Jr., Beighton, P., Diehl, S. R., Fex, J., Foy, C., Friedman, T. B., Greenberg, J., Hoth, C., Marazita, M., Milunsky, A., Morell, R., Nance, W., Newton, V., Ramesar, R., San Agustin, T. B., Skare, J., Stevens, C. A., Wagner, R. G., Jr., Wilcox, E. R., Winship, I., Read, A. P. &lt;strong&gt;Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS Consortium.&lt;/strong&gt; Am. J. Hum. Genet. 50: 902-913, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1349198/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1349198&lt;/a&gt;]" pmid="1349198">Farrer et al. (1992)</a> estimated that the WS1 gene on chromosome 2 was responsible for approximately 45% of the 44 families in their sample. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1349198" 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="#2" class="mim-tip-reference" title="Arias, S. &lt;strong&gt;Genetic heterogeneity in the Waardenburg syndrome.&lt;/strong&gt; Birth Defects Orig. Art. Ser. 7(4): 87-101, 1971."None>Arias (1971)</a> proposed the delineation of Waardenburg syndrome type 1 and 2 based on the presence or absence of dystopia canthorum. Thus, descriptions of the disorder before this time refer only to 'Waardenburg syndrome' and not to a specific subtype (<a href="#46" class="mim-tip-reference" title="Pardono, E., van Bever, Y., van den Ende, J., Havrenne, P. C., Iughetti, P., Maestrelli, S. R. P., Costa F, O., Richieri-Costa, A., Frota-Pessoa, O., Otto, P. A. &lt;strong&gt;Waardenburg syndrome: clinical differentiation between types I and II.&lt;/strong&gt; Am. J. Med. Genet. 117A: 223-235, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12599185/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12599185&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.10193&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12599185">Pardono et al., 2003</a>; <a href="#55" class="mim-tip-reference" title="Tamayo, M. L., Gelvez, N., Rodriguez, M., Florez, S., Varon, C., Medina, D., Bernal, J. E. &lt;strong&gt;Screening program for Waardenburg syndrome in Colombia: clinical definition and phenotypic variability.&lt;/strong&gt; Am. J. Med. Genet. 146A: 1026-1031, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18241065/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18241065&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.32189&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18241065">Tamayo et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18241065+12599185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="history" class="mim-anchor"></a>
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<strong>History</strong>
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<p><a href="#53" class="mim-tip-reference" title="Simpson, J. L., Falk, C. T., Morillo-Cucci, G., Allen, F. H., Jr., German, J. &lt;strong&gt;Analysis for possible linkage between the loci for the Waardenburg syndrome and various blood groups and serological traits.&lt;/strong&gt; Humangenetik 23: 45-50, 1974.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/4211154/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;4211154&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00295681&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="4211154">Simpson et al. (1974)</a> and <a href="#1" class="mim-tip-reference" title="Arias, S., Mota, M., de Yanez, A., Bolivar, M. &lt;strong&gt;Probable loose linkage between the ABO locus and Waardenburg syndrome type I.&lt;/strong&gt; Humangenetik 27: 145-149, 1975.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1150237/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1150237&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00273330&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1150237">Arias et al. (1975)</a> found a weak suggestion of linkage between Waardenburg syndrome and the ABO locus (<a href="/entry/110300">110300</a>), known to be located in 9q34. However, <a href="#49" class="mim-tip-reference" title="Read, A. P., Foy, C., Newton, V. &lt;strong&gt;Exclusion mapping in Waardenburg syndrome. (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 51: 1064, 1989."None>Read et al. (1989)</a> excluded linkage to ABO. In a study of 2 large kindreds in northeastern Brazil, <a href="#16" class="mim-tip-reference" title="da-Silva, E. O., Salzano, F. M., Weimer, T. A. &lt;strong&gt;Is the Waardenburg I syndrome gene located on chromosome 9?&lt;/strong&gt; Rev. Brasil. Genet. 13: 551-556, 1990."None>da-Silva et al. (1990)</a> could not confirm linkage to ABO. Since a plausible mouse model is 'Steel' (Sl), a dominant mutation on mouse chromosome 10 closely linked to Pep-2, <a href="#49" class="mim-tip-reference" title="Read, A. P., Foy, C., Newton, V. &lt;strong&gt;Exclusion mapping in Waardenburg syndrome. (Abstract)&lt;/strong&gt; Cytogenet. Cell Genet. 51: 1064, 1989."None>Read et al. (1989)</a> studied polymorphic probes for loci on human chromosome 12 close to PEPB (<a href="/entry/169900">169900</a>), the human homolog, in 7 families. They excluded a sizable region of 12q as the site of this gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1150237+4211154" 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>Quoting William Harvey's famous observation that 'Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path,' <a href="#21" class="mim-tip-reference" title="Duyk, G., Gastier, J. M., Mueller, R. F. &lt;strong&gt;Traces of her workings.&lt;/strong&gt; Nature Genet. 2: 5-8, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1303249/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1303249&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng0992-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1303249">Duyk et al. (1992)</a> reviewed the forms of deafness, syndromal and nonsyndromal, for which linkage has been established. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1303249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="seeAlso" class="mim-anchor"></a>
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<strong>See Also:</strong>
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<a href="#David1972" class="mim-tip-reference" title="David, T. J., Warin, R. P. &lt;strong&gt;Waardenburg&#x27;s syndrome in two siblings, both parents and their maternal grandmother.&lt;/strong&gt; Proc. Roy. Soc. Med. 65: 601-602, 1972.">David and Warin (1972)</a>; <a href="#Delleman1978" class="mim-tip-reference" title="Delleman, J. W., Hageman, M. J. &lt;strong&gt;Ophthalmological findings in 34 patients with Waardenburg syndrome.&lt;/strong&gt; J. Pediat. Ophthal. Strabismus 15: 341-345, 1978.">Delleman and Hageman (1978)</a>; <a href="#Fraser1976" class="mim-tip-reference" title="Fraser, G. R. &lt;strong&gt;The Causes of Profound Deafness in Childhood.&lt;/strong&gt; Baltimore: Johns Hopkins Univ. Press (pub.) 1976. P. 106.">Fraser (1976)</a>; <a href="#Goldberg1966" class="mim-tip-reference" title="Goldberg, M. F. &lt;strong&gt;Waardenburg&#x27;s syndrome with fundus and other anomalies.&lt;/strong&gt; Arch. Ophthal. 76: 797-810, 1966.">Goldberg (1966)</a>; <a href="#Hageman1978" class="mim-tip-reference" title="Hageman, M. J. &lt;strong&gt;Waardenburg&#x27;s syndrome in Kenyan Africans.&lt;/strong&gt; Trop. Geogr. Med. 30: 45-55, 1978.">Hageman (1978)</a>; <a href="#Opitz1980" class="mim-tip-reference" title="Opitz, J. M. &lt;strong&gt;In memoriam: Petrus Johannes Waardenburg, 1886-1979.&lt;/strong&gt; Am. J. Med. Genet. 7: 35-39, 1980.">Opitz (1980)</a>; <a href="#Preus1983" class="mim-tip-reference" title="Preus, M., Linstrom, C., Polomeno, R. C., Milot, J. &lt;strong&gt;Waardenburg syndrome--penetrance of major signs.&lt;/strong&gt; Am. J. Med. Genet. 15: 383-388, 1983.">Preus et al. (1983)</a>; <a href="#Settelmayer1961" class="mim-tip-reference" title="Settelmayer, J. R., Hogan, M. &lt;strong&gt;Waardenburg&#x27;s syndrome--report of a case in a non-Dutch family.&lt;/strong&gt; New Eng. J. Med. 264: 500-501, 1961.">Settelmayer and Hogan (1961)</a>
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<a id="references"class="mim-anchor"></a>
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<span class="mim-font">
<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Arias1975" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Arias, S., Mota, M., de Yanez, A., Bolivar, M.
<strong>Probable loose linkage between the ABO locus and Waardenburg syndrome type I.</strong>
Humangenetik 27: 145-149, 1975.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1150237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1150237</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1150237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/BF00273330" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
<a id="Arias1971" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Arias, S.
<strong>Genetic heterogeneity in the Waardenburg syndrome.</strong>
Birth Defects Orig. Art. Ser. 7(4): 87-101, 1971.
</p>
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<a id="3" class="mim-anchor"></a>
<a id="Arias1980" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Arias, S.
<strong>Waardenburg syndrome--two distinct types. (Letter)</strong>
Am. J. Med. Genet. 6: 99-100, 1980.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7187610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7187610</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7187610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320060109" target="_blank">Full Text</a>]
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<a id="Asher1990" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Asher, J. H., Jr., Friedman, T. B.
<strong>Mouse and hamster mutants as models for Waardenburg syndromes in humans.</strong>
J. Med. Genet. 27: 618-626, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2246770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2246770</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2246770" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1136/jmg.27.10.618" target="_blank">Full Text</a>]
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<a id="Asher1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Asher, J. H., Jr., Morell, R., Friedman, T. B.
<strong>Waardenburg syndrome (WS): the analysis of a single family with a WS1 mutation showing linkage to RFLP markers on human chromosome 2q.</strong>
Am. J. Hum. Genet. 48: 43-52, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1670751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1670751</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1670751" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
</p>
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<a id="6" class="mim-anchor"></a>
<a id="Ayme1995" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ayme, S., Philip, N.
<strong>Possible homozygous Waardenburg syndrome in a fetus with exencephaly. (Letter)</strong>
Am. J. Med. Genet. 59: 263-265, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8588597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8588597</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8588597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320590227" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
<a id="Baldwin1992" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Baldwin, C. T., Hoth, C. F., Amos, J. A., da-Silva, E. O., Milunsky, A.
<strong>An exonic mutation in the HuP2 paired domain gene causes Waardenburg's syndrome.</strong>
Nature 355: 637-638, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1347149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1347149</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1347149" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/355637a0" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
<a id="Baldwin1995" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Baldwin, C. T., Hoth, C. F., Macina, R. A., Milunsky, A.
<strong>Mutations in PAX3 that cause Waardenburg syndrome type I: ten new mutations and review of the literature.</strong>
Am. J. Med. Genet. 58: 115-122, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8533800/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8533800</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8533800" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320580205" target="_blank">Full Text</a>]
</p>
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<a id="Bondurand2000" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Bondurand, N., Pingault, V., Goerich, D. E., Lemort, N., Sock, E., Le Caignec, C., Wegner, M., Goossens, M.
<strong>Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.</strong>
Hum. Molec. Genet. 9: 1907-1917, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10942418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10942418</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10942418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/9.13.1907" target="_blank">Full Text</a>]
</p>
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<a id="10" class="mim-anchor"></a>
<a id="Carezani-Gavin1992" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Carezani-Gavin, M., Clarren, S. K., Steege, T.
<strong>Waardenburg syndrome associated with meningomyelocele. (Letter)</strong>
Am. J. Med. Genet. 42: 135-136, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1308353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1308353</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1308353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.1320420127" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.91.9.3685" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.30.1.83" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1993.tb03836.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320400113" target="_blank">Full Text</a>]
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David, T. J., Warin, R. P.
<strong>Waardenburg's syndrome in two siblings, both parents and their maternal grandmother.</strong>
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[<a href="https://doi.org/10.3928/0191-3913-19781101-03" target="_blank">Full Text</a>]
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DeStefano, A. L., Cupples, L. A., Arnos, K. S., Asher, J. H., Jr., Baldwin, C. T., Blanton, S., Carey, M. L., da Silva, E. O., Friedman, T. B., Greenberg, J., Lalwani, A. K., Milunsky, A., Nance, W. E., Pandya, A., Ramesar, R. S., Read, A. P., Tassabejhi, M., Wilcox, E. R., Farrer, L. A.
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[<a href="https://doi.org/10.1007/s004390050732" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0992-5" target="_blank">Full Text</a>]
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<p class="mim-text-font">
Farrer, L. A., Grundfast, K. M., Amos, J., Arnos, K. S., Asher, J. H., Jr., Beighton, P., Diehl, S. R., Fex, J., Foy, C., Friedman, T. B., Greenberg, J., Hoth, C., Marazita, M., Milunsky, A., Morell, R., Nance, W., Newton, V., Ramesar, R., San Agustin, T. B., Skare, J., Stevens, C. A., Wagner, R. G., Jr., Wilcox, E. R., Winship, I., Read, A. P.
<strong>Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS Consortium.</strong>
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<strong>Waardenburg's syndrome during the first year of life.</strong>
J. Pediat. 71: 874-876, 1967.
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[<a href="https://doi.org/10.1016/s0022-3476(67)80015-5" target="_blank">Full Text</a>]
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Foy, C., Newton, V., Wellesley, D., Harris, R., Read, A. P.
<strong>Assignment of the locus for Waardenburg syndrome type I to human chromosome 2q37 and possible homology to the Splotch mouse.</strong>
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Fraser, G. R.
<strong>Personal Communication.</strong>
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Fraser, G. R.
<strong>The Causes of Profound Deafness in Childhood.</strong>
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Giacoia, J. P., Klein, S. W.
<strong>Waardenburg's syndrome with bilateral cleft lip.</strong>
Am. J. Dis. Child. 117: 344-348, 1969.
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[<a href="https://doi.org/10.1001/archpedi.1969.02100030346020" target="_blank">Full Text</a>]
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<a id="Goldberg1966" class="mim-anchor"></a>
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Goldberg, M. F.
<strong>Waardenburg's syndrome with fundus and other anomalies.</strong>
Arch. Ophthal. 76: 797-810, 1966.
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[<a href="https://doi.org/10.1001/archopht.1966.03850010799005" target="_blank">Full Text</a>]
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<a id="Goodman1988" class="mim-anchor"></a>
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Goodman, R. M., Oelsner, G., Berkenstadt, M., Admon, D.
<strong>Absence of a vagina and right sided adnexa uteri in the Waardenburg syndrome: a possible clue to the embryological defect.</strong>
J. Med. Genet. 25: 355-357, 1988.
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[<a href="https://doi.org/10.1136/jmg.25.5.355" target="_blank">Full Text</a>]
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<a id="Grundfast1991" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Grundfast, K., Farrer, L., Amos, J., Arnos, K. S., Asher, J., Beighton, P., Diehl, S., Fex, J., Foy, C., Friedman, T., Greenberg, J., Hoth, C., Milunsky, A., Morell, R., Nance, W., Newton, V., Ramesar, R., Read, A., Skare, J., SanAgustin, T., Stevens, C., Wagner, R., Jr., Wilcox, E., Winship, I.
<strong>Waardenburg syndrome is caused by defects at multiple loci, one of which is tightly linked to ALPP on chromosome 2--first report of the WS consortium. (Abstract)</strong>
Am. J. Hum. Genet. 49 (suppl.): 17, 1991.
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Hageman, M. J.
<strong>Waardenburg's syndrome in Kenyan Africans.</strong>
Trop. Geogr. Med. 30: 45-55, 1978.
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<strong>Waardenburg's syndrome: report of a pedigree.</strong>
J. Nat. Med. Assoc. 57: 8-12, 1965.
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Hoth, C. F., Milunsky, A., Lipsky, N., Sheffer, R., Clarren, S. K., Baldwin, C. T.
<strong>Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I).</strong>
Am. J. Hum. Genet. 52: 455-462, 1993.
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<strong>Waardenburg's syndrome with deafness as the presenting symptom: report of two cases.</strong>
New Zeal. Med. J. 63: 83-89, 1964.
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Ishikiriyama, S., Tonoki, H., Shibuya, Y., Chin, S., Harada, N., Abe, K., Niikawa, N.
<strong>Waardenburg syndrome type I in a child with de novo inversion (2)(q35q37.3).</strong>
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[<a href="https://doi.org/10.1002/ajmg.1320330419" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320460534" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(75)80709-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.1991.tb03011.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320440533" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(69)80206-4" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320440424" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.34.6.447" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.3109/01050398909042198" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320070108" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.10193" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.21211" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320150303" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.34.8.656" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM196103092641008" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00295681" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/cge.12631" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32189" target="_blank">Full Text</a>]
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<strong>Homozygosity for Waardenburg syndrome.</strong>
Am. J. Hum. Genet. 56: 1173-1178, 1995.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7726174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7726174</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7726174" 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 : 5/24/2016
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Cassandra L. Kniffin - updated : 3/8/2010<br>Victor A. McKusick - updated : 3/21/2003<br>Ada Hamosh - updated : 1/8/2002<br>Victor A. McKusick - updated : 12/27/2001<br>Victor A. McKusick - updated : 12/5/2001<br>George E. Tiller - updated : 10/20/2000<br>George E. Tiller - updated : 4/14/2000<br>Ada Hamosh - updated : 3/14/2000<br>Victor A. McKusick - updated : 6/12/1998<br>Victor A. McKusick - updated : 2/27/1998<br>Michael J. Wright - updated : 2/11/1998<br>Victor A. McKusick - updated : 8/13/1997
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Victor A. McKusick : 6/2/1986
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carol : 05/04/2022
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<strong>#</strong> 193500
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WAARDENBURG SYNDROME, TYPE 1; WS1
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<em>Alternative titles; symbols</em>
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WAARDENBURG SYNDROME WITH DYSTOPIA CANTHORUM
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<strong>SNOMEDCT:</strong> 1010606009; &nbsp;
<strong>ORPHA:</strong> 3440, 894; &nbsp;
<strong>DO:</strong> 0110948; &nbsp;
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<strong>Phenotype-Gene Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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2q36.1
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Waardenburg syndrome, type 1
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193500
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Autosomal dominant
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3
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PAX3
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606597
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that Waardenburg syndrome type 1 (WS1) is caused by heterozygous mutation in the PAX3 gene (606597) on chromosome 2q36.</p><p>Waardenburg syndrome type 3 (WS3; 148820) is also caused by mutation in the PAX3 gene.</p>
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<strong>Description</strong>
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<p>Waardenburg syndrome type 1 (WS1) is an autosomal dominant auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes; congenital sensorineural hearing loss; and 'dystopia canthorum,' the lateral displacement of the ocular inner canthi (reviews by Read and Newton, 1997, Tamayo et al., 2008, and Pingault et al., 2010). </p><p><strong><em>Clinical Variability of Waardenburg Syndrome Types 1-4</em></strong></p><p>
Waardenburg syndrome is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, including a white forelock and premature graying; pigmentary changes of the iris, such as heterochromia irides and brilliant blue eyes; and congenital sensorineural hearing loss. Waardenburg syndrome has been classified into 4 main phenotypes. WS type 1 is distinguished by the presence of dystopia canthorum. WS type 2 (WS2; see 193510) is distinguished from type 1 by the absence of dystopia canthorum. WS type 3 (WS3; 148820) has dystopia canthorum and upper limb abnormalities. WS type 4 (WS4; see 277580), also known as Waardenburg-Shah syndrome, has the additional feature of Hirschsprung disease (reviews by Read and Newton, 1997 and Tamayo et al., 2008). </p><p><strong><em>Genetic Heterogeneity of All Types of Waardenburg Syndrome</em></strong></p><p>
Waardenburg syndrome is genetically heterogeneous. WS1 and WS3 are both caused by mutation in the PAX3 gene. See WS2A (193510) for a discussion of genetic heterogeneity of WS type 2, and WS4A (277580) for a discussion of genetic heterogeneity of WS type 4.</p>
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<strong>Clinical Features</strong>
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<p>Waardenburg (1951) first delineated the syndrome that bears his name, describing it as a disorder combining anomalies of the eyelids, eyebrows, and nasal root with congenital deafness. </p><p>Feingold et al. (1967) noted that the white forelock may be present at birth and later disappear in patients with Waardenburg syndrome. Arias (1980) suggested that visceral and cranial malformations (such as Hirschsprung megacolon) are associated with Waardenburg syndrome type 1. </p><p>Yoshino et al. (1986) evaluated the incidence of dystopia canthorum in a 3-generation family with Waardenburg syndrome type 1 and concluded that it is the most frequently expressed sign of the condition.</p><p>Da-Silva (1991) reported 2 large multigenerational Brazilian kindreds with WS type 1. The total number of affected individuals was 73. The major manifestations were telecanthus, which was the only constant anomaly, prominent nasal root (78%), round or square tip of nose, hypoplastic alae, smooth philtrum, bushy eyebrows with synophrys (76%), sensorineural deafness (67%), heterochromia or hypoisochromia iridis, hypopigmented ocular fundus, white forelock (29%), premature graying (44%), and hypopigmented skin lesions (55%). </p><p>Winship and Beighton (1992) reviewed phenotypic variation of Waardenburg syndrome on the basis of an analysis of 68 affected children. </p><p>In a craniofacial anthropometric study of 51 WS type 1 individuals, da-Silva et al. (1993) concluded that the most discriminating parameters were, from clinical measurements, increased intercanthal distance and decreased philtrum length, and, from roentgenographic measurements, decreased nasal bone length and increased lower facial height. </p><p>Read and Newton (1997) provided a review of the clinical features and molecular basis of Waardenburg syndrome and other auditory pigmentary syndromes. </p><p>From a systematic literature search, Song et al. (2016) determined that the prevalence of hearing loss in patients with Waardenburg syndrome differed according to the genotype: the prevalence in those with WS1 due to PAX3 mutations was 52.3%. </p>
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<strong>Other Features</strong>
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<p>Giacoia and Klein (1969) documented the occurrence of bilateral cleft lip in Waardenburg syndrome. Arias (1971) observed a black forelock in place of white forelock. </p><p>Goodman et al. (1988) observed absence of vagina and of right-sided uterine adnexa in an 18-year-old woman with WS1. They postulated that these are related to Waardenburg syndrome because of altered invasion of neurons in early embryogenesis. </p><p>Carezani-Gavin et al. (1992) reported a patient with Waardenburg syndrome type 1 who also had a meningomyelocele at the L3-S1 level and Arnold-Chiari malformation. Characteristic features of WS1 were present, including hearing loss, dystopia canthorum, broad nasal root, and narrow nasal tip. There was a family history of the disorder, but none of the other affected individuals had neural tube defects. In the family reported by Carezani-Gavin et al. (1992), Hoth et al. (1993) identified a heterozygous mutation in the PAX3 gene (R56L; 606597.0014). </p><p>Chatkupt et al. (1993) stated that spina bifida had been noted in at least 4 patients with Waardenburg syndrome. They reported the cases of brothers with both Waardenburg syndrome and lumbosacral myelomeningocele. The mother had features of Waardenburg syndrome. Spina bifida occurs with the 'Splotch' mutation, which molecular studies indicate is the homologous disorder in the mouse (see 606597). </p>
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<strong>Inheritance</strong>
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<p>Waardenburg syndrome type 1 is an autosomal dominant disorder (Pardono et al., 2003). </p><p>Jones et al. (1975) found evidence of paternal age effect in new mutations for autosomal dominant Waardenburg syndrome. </p><p>Kapur and Karam (1991) described a family in which 3 children with this disorder were born to normal, unrelated parents. Germline mosaicism was postulated. </p>
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<strong>Diagnosis</strong>
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<p>Laestadius et al. (1969) provided normal standards for the measurement of inner canthal and outer canthal distance. Standards were also presented by Christian et al. (1969). </p><p>In place of the measurement of inner canthal distance, the Waardenburg Consortium (Farrer et al., 1992) recommended the W index: a composite measure including the inner canthal, inner pupillary, and outer canthal distances. Normal and dystopic subjects had W values (mean +/- SD) of 1.76 +/- 0.16 and 2.61 +/- 0.19, respectively (Newton, 1989); the Waardenburg Consortium recommended a threshold W value of 2.07. </p><p>Pardono et al. (2003) studied 59 patients with Waardenburg syndrome from 37 families (30 with type 1, 21 with type 2, and 8 isolated individuals without telecanthus). All patients were examined for the presence of 8 cardinal diagnostic signs: telecanthus, synophrys, iris pigmentation disturbances, partial hair albinism, hearing impairment, hypopigmented skin spots, nasal root hyperplasia, and lower lacrimal dystopia. The authors noted that some patients with type 1 may not have dystopia canthorum, but that it is present in 95 to 99% of patients with WS type 1. Using their own data as well as those collected from the literature, the authors estimated the frequencies of these 8 cardinal signs of Waardenburg syndrome based on a sample of 461 affected individuals with type 1 and 121 with type 2. </p>
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<strong>Cytogenetics</strong>
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<p>Ishikiriyama et al. (1989, 1989) reported a 20-month-old boy with dystopia canthorum, sensorineural deafness, heterochromia iridis, partially albinotic ocular fundi, and partial leukoderma. Cytogenetic studies showed a paracentric inversion (2)(q35q37.3); his parents had normal chromosomes. Ishikiriyama et al. (1989) suggest that the gene for Waardenburg syndrome type 1 may be located on chromosome 2q35 or 2q37.3. Kirkpatrick et al. (1992) described WS type 1 in a child with del(2)(q35q36.2). Because of this report and that of Lin et al. (1992) of deletion of 2q37 without features of WS1, Ishikiriyama (1993) concluded that the WS1 gene is located at 2q35. </p>
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<strong>Mapping</strong>
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<p>On the basis of an analysis of mouse and hamster mutants as models for Waardenburg syndrome(s), Asher and Friedman (1990) predicted that the gene(s) would be found to be on chromosome 2q near fibronectin-1 (135600), on chromosome 3p near the protooncogene RAF1 (164760) or 3q near rhodopsin, (RHO; 180380), or on chromosome 4p near the protooncogene KIT (164920). </p><p>Foy et al. (1990) demonstrated linkage of the Waardenburg syndrome to placental alkaline phosphatase (ALPP; 171800), which had previously been assigned to 2q37; the peak lod score was 4.76 at a recombination fraction of 0.023. These findings suggest that the distal breakpoint responsible for the paracentric inversion is at the site of the Waardenburg syndrome, namely, 2q37.3. This region of chromosome 2 is homologous to mouse chromosome 1, which contains the 'Splotch' locus (Sp) (PAX3). This patchy pigment mutation is accompanied by a malformation of the inner ear and severe CNS malformation in the homozygote. Whether the heterozygote is deaf is unclear. </p><p>In a family with 11 affected individuals spanning 4 generations, Asher et al. (1991) confirmed the assignment of WS1 to 2q. No recombination was found with ALPP at 2q37 or with FN1 (135600) at 2q34-q36. Grundfast et al. (1991) found no obligatory crossovers between WS1 and ALPP. For a collection of families, they obtained a maximum lod of 12.5 at theta = 0.31 for the WS1/ALPP linkage. </p>
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<strong>Molecular Genetics</strong>
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<p>Tassabehji et al. (1992) identified variations in the PAX3 gene in 6 of 17 unrelated patients with Waardenburg syndrome type 1 using primers to amplify exons followed by testing for heteroduplex formation on polyacrylamide gels. No variants were seen in any exon in 50 normal controls. In 3 families that were tested, the variant was found to be familial in 2 and apparently de novo in the third. The variant bands showed perfect linkage to WS in the families studied. One family was found to have a heterozygous 18-bp deletion in the central region of exon 2, resulting in loss of amino acids 29 to 34 (606597.0001). </p><p>Simultaneously and independently, Baldwin et al. (1992) identified a heterozygous mutation in the PAX3 gene (P50L; 606597.0002) in affected members of a large Brazilian family with Waardenburg syndrome type 1 reported by da-Silva (1991). There were 49 affected persons in 6 generations, and more than 78% of the affected individuals had hearing loss. </p><p>Baldwin et al. (1995) described 10 additional mutations in the PAX3 gene in families with WS type 1. Eight of these mutations were in a region of PAX3 where only 1 mutation had previously been described. Taken together with previously reported mutations, these mutations covered essentially the entire PAX3 gene. All but 1 of the mutations were 'private;' only 1 mutation had been reported in 2 apparently unrelated families. Baldwin et al. (1995) also cataloged 16 previously reported mutations and 5 chromosomal abnormalities affecting the 2q35 region that were associated with WS. </p><p><strong><em>Modifier Genes</em></strong></p><p>
Work in the hamster model for Waardenburg syndrome suggested to Asher and Friedman (1990) that modifier genes may account for the intrafamilial variation in phenotype in Waardenburg syndrome. </p><p>Reynolds et al. (1996) sought to determine whether the W-index is influenced primarily by allelic variation in the PAX3 disease gene or other major loci, by polygenic background effects, or by all of these potential sources of genetic variation. They studied both WS1-affected individuals and their WS1 unaffected relatives. After adjustment of the W-index for WS1 disease status, segregation analyses by the regression approach indicated major-locus control of this variation, although residual parent-offspring and sib-sib correlations were consistent with additional (possibly polygenic) effects. Separate analyses of WS1-affected and WS1-unaffected individuals suggested that epistatic interactions between disease alleles at the PAX3 WS1 locus and a second major locus influenced variation in dystopia canthorum. Reynolds et al. (1996) suggested that their approach should be applicable for assessing the 'genetic architecture' of variation associated with other genetic diseases. </p><p>While mutations in PAX3 seem to be responsible for most, if not all, WS1 cases, it is not clear what accounts for the reduced penetrance of deafness. Stochastic events during development may be the factors that determine whether a person with a PAX3 mutation will be congenitally deaf or not. Alternatively, genetic background, nonrandom environmental factors, or both may be significant. Morell et al. (1997) compared the likelihood for deafness in affected subjects from 24 families with PAX3 mutations and in 7 of the families originally described by Waardenburg. They found evidence that stochastic variation alone does not explain the differences in penetrance of deafness among WS families. Their analyses suggested that genetic background in combination with certain PAX3 alleles may be important factors in the etiology of deafness in WS1. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>In a series of patients with Waardenburg syndrome, Tassabehji et al. (1994) found a number of previously unidentified PAX3 mutations. These included a chromosomal deletion, a splice site mutation, and an amino acid substitution that closely corresponded to the molecular changes seen in the 'Splotch-retarded' and 'Splotch-delayed' mouse mutants, respectively. These mutations confirmed that Waardenburg syndrome is produced by gene dosage effects and showed that the phenotypic differences between 'Splotch' mice and humans with Waardenburg syndrome are caused by differences in genetic background rather than different primary effects of the mutations. </p><p>Chalepakis et al. (1994) studied the functional consequence of the mutations described in 606597.0001 and 606597.0006 on DNA binding and compared the results with those in the 'Splotch' mouse. Combining the phenotypic features of heterozygous mutants and considering that molecular defects ranging from single point mutations to large deletions cause similar phenotypes, they excluded the possibility that the mutated allele in heterozygotes interferes with the function of the wildtype allele. Contrariwise, they considered both WS and 'Splotch' mutants to represent loss-of-function mutations. </p><p>Zlotogora et al. (1995) reported a large kindred in which many individuals had Waardenburg syndrome type 1 caused by a heterozygous mutation in the PAX3 gene (S84F; 606597.0009). However, there was 1 child, born of consanguineous parents, who had a severe phenotype consistent with WS type 3 (148820): this patient was found to be homozygous for the S84F mutation. The child presented with dystopia canthorum, partial albinism, and very severe upper limb defects. Since all Pax3 mutations in mice lead to severe neural tube defects and intrauterine or neonatal death, the survival of the homozygote in this case and the absence of neural tube defects were unexpected. </p><p>Ayme and Philip (1995) observed exencephaly in a fetus with possible homozygous Waardenburg syndrome. The fetus was the product of a mating between a gypsy brother and sister, both of whom had Waardenburg syndrome. </p><p>Baldwin et al. (1995) stated that their analysis of a total of 30 PAX3 mutations causing WS type 1 or type 3 demonstrated little correlation between genotype and phenotype. Deletions of the entire PAX3 gene resulted in phenotypes indistinguishable from those associated with single-base substitutions in the paired domain or homeodomain of the gene. Moreover, 2 similar mutations in close proximity could result in significantly different phenotypes, WS type 1 in 1 family and WS type 3 in another. </p><p>DeStefano et al. (1998) assessed the relationship between phenotype and gene defect in 48 families containing 271 individuals with WS collected by members of the Waardenburg Consortium. They grouped the 42 unique mutations previously identified in the PAX3 gene in these families into 5 mutation categories: amino acid substitution in the paired domain, amino acid substitution in the homeodomain, deletion of the ser-thr-pro-rich region, deletion of the homeodomain and the ser-thr-pro-rich region, and deletion of the entire gene. This classification of mutations was based on the structure of the PAX3 gene and was chosen to group mutations predicted to have similar defects in the gene product. They found that odds for the presence of eye pigment abnormality, white forelock, and skin hypopigmentation were 2, 8, and 5 times greater, respectively, for individuals with deletions of the homeodomain and the pro-ser-thr-rich region compared to individuals with an amino acid substitution in the homeodomain. Odds ratios that differed significantly from 1.0 for these traits may indicate that the gene products resulting from different classes of mutations act differently in the expression of WS. Although a suggestive association was detected for hearing loss with an odds ratio of 2.6 for amino acid substitution in the paired domain compared with amino acid substitution in the homeodomain, this odds ratio did not differ significantly from 1.0. </p>
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<strong>Pathogenesis</strong>
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<p>Watanabe et al. (1998) showed that PAX3 transactivates the MITF (156845) promoter. They further showed that PAX3 proteins associated with WS1 in either the paired domain or the homeodomain failed to recognize and transactivate the MITF promoter. These results provided evidence that PAX3 directly regulates MITF, and suggested that the failure of this regulation due to PAX3 mutations causes the auditory-pigmentary symptoms in at least some individuals with WS1. </p><p>Bondurand et al. (2000) showed that SOX10 (602229), in synergy with PAX3, strongly activates MITF expression in transfection assays. Transfection experiments revealed that PAX3 and SOX10 interact directly by binding to a proximal region of the MITF promoter containing binding sites for both factors. Mutant SOX10 or PAX3 proteins failed to transactivate this promoter, providing further evidence that the 2 genes act in concert to directly regulate expression of MITF. In situ hybridization experiments carried out in the dominant megacolon (Dom) mouse confirmed that SOX10 dysfunction impaired Mitf expression as well as melanocytic development and survival. The authors hypothesized that interaction between 3 of the genes that are altered in WS could explain the auditory/pigmentary symptoms of this disease. </p>
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<strong>Population Genetics</strong>
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</div>
<span class="mim-text-font">
<p>Waardenburg syndrome has been described in American blacks (Hansen et al., 1965) and in Maoris (Houghton, 1964) as well as in Europeans. </p><p>In the state of South Australia, Waardenburg syndrome is a leading cause of deafness and has a position comparable to porphyria in South Africa, having been introduced by early settlers who had many descendants (Fraser, 1967).</p><p>An affected Chinese family was reported by Chew et al. (1968). </p><p>In a report from a consortium, Grundfast et al. (1991) concluded that about 56% of WS families are linked to 2q markers. Farrer et al. (1992) estimated that the WS1 gene on chromosome 2 was responsible for approximately 45% of the 44 families in their sample. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Nomenclature</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Arias (1971) proposed the delineation of Waardenburg syndrome type 1 and 2 based on the presence or absence of dystopia canthorum. Thus, descriptions of the disorder before this time refer only to 'Waardenburg syndrome' and not to a specific subtype (Pardono et al., 2003; Tamayo et al., 2008). </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Simpson et al. (1974) and Arias et al. (1975) found a weak suggestion of linkage between Waardenburg syndrome and the ABO locus (110300), known to be located in 9q34. However, Read et al. (1989) excluded linkage to ABO. In a study of 2 large kindreds in northeastern Brazil, da-Silva et al. (1990) could not confirm linkage to ABO. Since a plausible mouse model is 'Steel' (Sl), a dominant mutation on mouse chromosome 10 closely linked to Pep-2, Read et al. (1989) studied polymorphic probes for loci on human chromosome 12 close to PEPB (169900), the human homolog, in 7 families. They excluded a sizable region of 12q as the site of this gene. </p><p>Quoting William Harvey's famous observation that 'Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path,' Duyk et al. (1992) reviewed the forms of deafness, syndromal and nonsyndromal, for which linkage has been established. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
David and Warin (1972); Delleman and Hageman (1978); Fraser (1976);
Goldberg (1966); Hageman (1978); Opitz (1980); Preus et al. (1983);
Settelmayer and Hogan (1961)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Arias, S., Mota, M., de Yanez, A., Bolivar, M.
<strong>Probable loose linkage between the ABO locus and Waardenburg syndrome type I.</strong>
Humangenetik 27: 145-149, 1975.
[PubMed: 1150237]
[Full Text: https://doi.org/10.1007/BF00273330]
</p>
</li>
<li>
<p class="mim-text-font">
Arias, S.
<strong>Genetic heterogeneity in the Waardenburg syndrome.</strong>
Birth Defects Orig. Art. Ser. 7(4): 87-101, 1971.
</p>
</li>
<li>
<p class="mim-text-font">
Arias, S.
<strong>Waardenburg syndrome--two distinct types. (Letter)</strong>
Am. J. Med. Genet. 6: 99-100, 1980.
[PubMed: 7187610]
[Full Text: https://doi.org/10.1002/ajmg.1320060109]
</p>
</li>
<li>
<p class="mim-text-font">
Asher, J. H., Jr., Friedman, T. B.
<strong>Mouse and hamster mutants as models for Waardenburg syndromes in humans.</strong>
J. Med. Genet. 27: 618-626, 1990.
[PubMed: 2246770]
[Full Text: https://doi.org/10.1136/jmg.27.10.618]
</p>
</li>
<li>
<p class="mim-text-font">
Asher, J. H., Jr., Morell, R., Friedman, T. B.
<strong>Waardenburg syndrome (WS): the analysis of a single family with a WS1 mutation showing linkage to RFLP markers on human chromosome 2q.</strong>
Am. J. Hum. Genet. 48: 43-52, 1991.
[PubMed: 1670751]
</p>
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<li>
<p class="mim-text-font">
Ayme, S., Philip, N.
<strong>Possible homozygous Waardenburg syndrome in a fetus with exencephaly. (Letter)</strong>
Am. J. Med. Genet. 59: 263-265, 1995.
[PubMed: 8588597]
[Full Text: https://doi.org/10.1002/ajmg.1320590227]
</p>
</li>
<li>
<p class="mim-text-font">
Baldwin, C. T., Hoth, C. F., Amos, J. A., da-Silva, E. O., Milunsky, A.
<strong>An exonic mutation in the HuP2 paired domain gene causes Waardenburg&#x27;s syndrome.</strong>
Nature 355: 637-638, 1992.
[PubMed: 1347149]
[Full Text: https://doi.org/10.1038/355637a0]
</p>
</li>
<li>
<p class="mim-text-font">
Baldwin, C. T., Hoth, C. F., Macina, R. A., Milunsky, A.
<strong>Mutations in PAX3 that cause Waardenburg syndrome type I: ten new mutations and review of the literature.</strong>
Am. J. Med. Genet. 58: 115-122, 1995.
[PubMed: 8533800]
[Full Text: https://doi.org/10.1002/ajmg.1320580205]
</p>
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<li>
<p class="mim-text-font">
Bondurand, N., Pingault, V., Goerich, D. E., Lemort, N., Sock, E., Le Caignec, C., Wegner, M., Goossens, M.
<strong>Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.</strong>
Hum. Molec. Genet. 9: 1907-1917, 2000.
[PubMed: 10942418]
[Full Text: https://doi.org/10.1093/hmg/9.13.1907]
</p>
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<li>
<p class="mim-text-font">
Carezani-Gavin, M., Clarren, S. K., Steege, T.
<strong>Waardenburg syndrome associated with meningomyelocele. (Letter)</strong>
Am. J. Med. Genet. 42: 135-136, 1992.
[PubMed: 1308353]
[Full Text: https://doi.org/10.1002/ajmg.1320420127]
</p>
</li>
<li>
<p class="mim-text-font">
Chalepakis, G., Goulding, M., Read, A., Strachan, T., Gruss, P.
<strong>Molecular basis of Splotch and Waardenburg Pax-3 mutations.</strong>
Proc. Nat. Acad. Sci. 91: 3685-3689, 1994.
[PubMed: 7909605]
[Full Text: https://doi.org/10.1073/pnas.91.9.3685]
</p>
</li>
<li>
<p class="mim-text-font">
Chatkupt, S., Chatkupt, S., Johnson, W. G.
<strong>Waardenburg syndrome and myelomeningocele in a family.</strong>
J. Med. Genet. 30: 83-84, 1993.
[PubMed: 8423616]
[Full Text: https://doi.org/10.1136/jmg.30.1.83]
</p>
</li>
<li>
<p class="mim-text-font">
Chew, K. L., Chen, A. J., Tan, K. H.
<strong>A Chinese family with Waardenburg&#x27;s syndrome.</strong>
Am. J. Ophthal. 65: 174-182, 1968.
[PubMed: 4966266]
</p>
</li>
<li>
<p class="mim-text-font">
Christian, J. C., Bixler, D., Blythe, S. C., Merritt, A. D.
<strong>Familial telecanthus with associated congenital anomalies.</strong>
Birth Defects Orig. Art. Ser. V(2): 82-85, 1969.
</p>
</li>
<li>
<p class="mim-text-font">
da-Silva, E. O., Batista, J. E. M., Medeiros, M. A. B., Fonteles, S. M. S.
<strong>Craniofacial anthropometric studies in Waardenburg syndrome type I.</strong>
Clin. Genet. 44: 20-25, 1993.
[PubMed: 8403450]
[Full Text: https://doi.org/10.1111/j.1399-0004.1993.tb03836.x]
</p>
</li>
<li>
<p class="mim-text-font">
da-Silva, E. O., Salzano, F. M., Weimer, T. A.
<strong>Is the Waardenburg I syndrome gene located on chromosome 9?</strong>
Rev. Brasil. Genet. 13: 551-556, 1990.
</p>
</li>
<li>
<p class="mim-text-font">
da-Silva, E. O.
<strong>Waardenburg I syndrome: a clinical and genetic study of two large Brazilian kindreds, and literature review.</strong>
Am. J. Med. Genet. 40: 65-74, 1991.
[PubMed: 1887852]
[Full Text: https://doi.org/10.1002/ajmg.1320400113]
</p>
</li>
<li>
<p class="mim-text-font">
David, T. J., Warin, R. P.
<strong>Waardenburg&#x27;s syndrome in two siblings, both parents and their maternal grandmother.</strong>
Proc. Roy. Soc. Med. 65: 601-602, 1972.
[PubMed: 5085935]
</p>
</li>
<li>
<p class="mim-text-font">
Delleman, J. W., Hageman, M. J.
<strong>Ophthalmological findings in 34 patients with Waardenburg syndrome.</strong>
J. Pediat. Ophthal. Strabismus 15: 341-345, 1978.
[PubMed: 105123]
[Full Text: https://doi.org/10.3928/0191-3913-19781101-03]
</p>
</li>
<li>
<p class="mim-text-font">
DeStefano, A. L., Cupples, L. A., Arnos, K. S., Asher, J. H., Jr., Baldwin, C. T., Blanton, S., Carey, M. L., da Silva, E. O., Friedman, T. B., Greenberg, J., Lalwani, A. K., Milunsky, A., Nance, W. E., Pandya, A., Ramesar, R. S., Read, A. P., Tassabejhi, M., Wilcox, E. R., Farrer, L. A.
<strong>Correlation between Waardenburg syndrome phenotype and genotype in a population of individuals with identified PAX3 mutations.</strong>
Hum. Genet. 102: 499-506, 1998.
[PubMed: 9654197]
[Full Text: https://doi.org/10.1007/s004390050732]
</p>
</li>
<li>
<p class="mim-text-font">
Duyk, G., Gastier, J. M., Mueller, R. F.
<strong>Traces of her workings.</strong>
Nature Genet. 2: 5-8, 1992.
[PubMed: 1303249]
[Full Text: https://doi.org/10.1038/ng0992-5]
</p>
</li>
<li>
<p class="mim-text-font">
Farrer, L. A., Grundfast, K. M., Amos, J., Arnos, K. S., Asher, J. H., Jr., Beighton, P., Diehl, S. R., Fex, J., Foy, C., Friedman, T. B., Greenberg, J., Hoth, C., Marazita, M., Milunsky, A., Morell, R., Nance, W., Newton, V., Ramesar, R., San Agustin, T. B., Skare, J., Stevens, C. A., Wagner, R. G., Jr., Wilcox, E. R., Winship, I., Read, A. P.
<strong>Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS Consortium.</strong>
Am. J. Hum. Genet. 50: 902-913, 1992.
[PubMed: 1349198]
</p>
</li>
<li>
<p class="mim-text-font">
Feingold, M., Robinson, M. J., Gellis, S. S.
<strong>Waardenburg&#x27;s syndrome during the first year of life.</strong>
J. Pediat. 71: 874-876, 1967.
[PubMed: 6059431]
[Full Text: https://doi.org/10.1016/s0022-3476(67)80015-5]
</p>
</li>
<li>
<p class="mim-text-font">
Foy, C., Newton, V., Wellesley, D., Harris, R., Read, A. P.
<strong>Assignment of the locus for Waardenburg syndrome type I to human chromosome 2q37 and possible homology to the Splotch mouse.</strong>
Am. J. Hum. Genet. 46: 1017-1023, 1990.
[PubMed: 2339698]
</p>
</li>
<li>
<p class="mim-text-font">
Fraser, G. R.
<strong>Personal Communication.</strong>
Adelaide, Australia 1967.
</p>
</li>
<li>
<p class="mim-text-font">
Fraser, G. R.
<strong>The Causes of Profound Deafness in Childhood.</strong>
Baltimore: Johns Hopkins Univ. Press (pub.) 1976. P. 106.
</p>
</li>
<li>
<p class="mim-text-font">
Giacoia, J. P., Klein, S. W.
<strong>Waardenburg&#x27;s syndrome with bilateral cleft lip.</strong>
Am. J. Dis. Child. 117: 344-348, 1969.
[PubMed: 5765156]
[Full Text: https://doi.org/10.1001/archpedi.1969.02100030346020]
</p>
</li>
<li>
<p class="mim-text-font">
Goldberg, M. F.
<strong>Waardenburg&#x27;s syndrome with fundus and other anomalies.</strong>
Arch. Ophthal. 76: 797-810, 1966.
[PubMed: 4958935]
[Full Text: https://doi.org/10.1001/archopht.1966.03850010799005]
</p>
</li>
<li>
<p class="mim-text-font">
Goodman, R. M., Oelsner, G., Berkenstadt, M., Admon, D.
<strong>Absence of a vagina and right sided adnexa uteri in the Waardenburg syndrome: a possible clue to the embryological defect.</strong>
J. Med. Genet. 25: 355-357, 1988.
[PubMed: 3385746]
[Full Text: https://doi.org/10.1136/jmg.25.5.355]
</p>
</li>
<li>
<p class="mim-text-font">
Grundfast, K., Farrer, L., Amos, J., Arnos, K. S., Asher, J., Beighton, P., Diehl, S., Fex, J., Foy, C., Friedman, T., Greenberg, J., Hoth, C., Milunsky, A., Morell, R., Nance, W., Newton, V., Ramesar, R., Read, A., Skare, J., SanAgustin, T., Stevens, C., Wagner, R., Jr., Wilcox, E., Winship, I.
<strong>Waardenburg syndrome is caused by defects at multiple loci, one of which is tightly linked to ALPP on chromosome 2--first report of the WS consortium. (Abstract)</strong>
Am. J. Hum. Genet. 49 (suppl.): 17, 1991.
</p>
</li>
<li>
<p class="mim-text-font">
Hageman, M. J.
<strong>Waardenburg&#x27;s syndrome in Kenyan Africans.</strong>
Trop. Geogr. Med. 30: 45-55, 1978.
[PubMed: 675827]
</p>
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<li>
<p class="mim-text-font">
Hansen, A. C., Ackaouy, G., Crump, E. P.
<strong>Waardenburg&#x27;s syndrome: report of a pedigree.</strong>
J. Nat. Med. Assoc. 57: 8-12, 1965.
[PubMed: 14269024]
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<li>
<p class="mim-text-font">
Hoth, C. F., Milunsky, A., Lipsky, N., Sheffer, R., Clarren, S. K., Baldwin, C. T.
<strong>Mutations in the paired domain of the human PAX3 gene cause Klein-Waardenburg syndrome (WS-III) as well as Waardenburg syndrome type I (WS-I).</strong>
Am. J. Hum. Genet. 52: 455-462, 1993.
[PubMed: 8447316]
</p>
</li>
<li>
<p class="mim-text-font">
Houghton, N. I.
<strong>Waardenburg&#x27;s syndrome with deafness as the presenting symptom: report of two cases.</strong>
New Zeal. Med. J. 63: 83-89, 1964.
[PubMed: 14124244]
</p>
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<li>
<p class="mim-text-font">
Ishikiriyama, S., Tonoki, H., Shibuya, Y., Chin, S., Harada, N., Abe, K., Niikawa, N.
<strong>A sporadic case of Waardenburg syndrome type I associated with de novo inv(2)(q35q37.3). (Abstract)</strong>
Cytogenet. Cell Genet. 51: 1018, 1989.
</p>
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<li>
<p class="mim-text-font">
Ishikiriyama, S., Tonoki, H., Shibuya, Y., Chin, S., Harada, N., Abe, K., Niikawa, N.
<strong>Waardenburg syndrome type I in a child with de novo inversion (2)(q35q37.3).</strong>
Am. J. Med. Genet. 33: 505-507, 1989.
[PubMed: 2596512]
[Full Text: https://doi.org/10.1002/ajmg.1320330419]
</p>
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<li>
<p class="mim-text-font">
Ishikiriyama, S.
<strong>Gene for Waardenburg syndrome type I is located at 2q35, not at 2q37.3. (Letter)</strong>
Am. J. Med. Genet. 46: 608, 1993.
[PubMed: 8322830]
[Full Text: https://doi.org/10.1002/ajmg.1320460534]
</p>
</li>
<li>
<p class="mim-text-font">
Jones, K. L., Smith, D. W., Harvey, M. A. S., Hall, B. D., Quan, L.
<strong>Older paternal age and fresh gene mutation: data on additional disorders.</strong>
J. Pediat. 86: 84-88, 1975.
[PubMed: 1110452]
[Full Text: https://doi.org/10.1016/s0022-3476(75)80709-8]
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<p class="mim-text-font">
Kapur, S., Karam, S.
<strong>Germ-line mosaicism in Waardenburg syndrome.</strong>
Clin. Genet. 39: 194-198, 1991.
[PubMed: 2036740]
[Full Text: https://doi.org/10.1111/j.1399-0004.1991.tb03011.x]
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<p class="mim-text-font">
Kirkpatrick, S. J., Kent, C. M., Laxova, R., Sekhon, G. S.
<strong>Waardenburg syndrome type I in a child with deletion (2)(q35q36.2). (Letter)</strong>
Am. J. Med. Genet. 44: 699-700, 1992.
[PubMed: 1481835]
[Full Text: https://doi.org/10.1002/ajmg.1320440533]
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<p class="mim-text-font">
Laestadius, N. D., Aase, J. M., Smith, D. W.
<strong>Normal inner canthal and outer orbital dimensions.</strong>
J. Pediat. 74: 465-468, 1969.
[PubMed: 5764779]
[Full Text: https://doi.org/10.1016/s0022-3476(69)80206-4]
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<p class="mim-text-font">
Lin, S.-P., Petty, E. M., Gibson, L. H., Inserra, J., Seashore, M. R., Yang-Feng, T. L.
<strong>Smallest terminal deletion of the long arm of chromosome 2 in a mildly affected boy.</strong>
Am. J. Med. Genet. 44: 500-502, 1992.
[PubMed: 1442895]
[Full Text: https://doi.org/10.1002/ajmg.1320440424]
</p>
</li>
<li>
<p class="mim-text-font">
Morell, R., Friedman, T. B., Asher, J. H., Jr., Robbins, L. G.
<strong>The incidence of deafness is non-randomly distributed among families segregating for Waardenburg syndrome type 1 (WS1).</strong>
J. Med. Genet. 34: 447-452, 1997.
[PubMed: 9192262]
[Full Text: https://doi.org/10.1136/jmg.34.6.447]
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<li>
<p class="mim-text-font">
Newton, V. E.
<strong>Waardenburg&#x27;s syndrome: a comparison of biometric indices used to diagnose lateral displacement of the inner canthi.</strong>
Scand. Audiol. 18: 221-223, 1989.
[PubMed: 2609099]
[Full Text: https://doi.org/10.3109/01050398909042198]
</p>
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<li>
<p class="mim-text-font">
Opitz, J. M.
<strong>In memoriam: Petrus Johannes Waardenburg, 1886-1979.</strong>
Am. J. Med. Genet. 7: 35-39, 1980.
[PubMed: 7011029]
[Full Text: https://doi.org/10.1002/ajmg.1320070108]
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<li>
<p class="mim-text-font">
Pardono, E., van Bever, Y., van den Ende, J., Havrenne, P. C., Iughetti, P., Maestrelli, S. R. P., Costa F, O., Richieri-Costa, A., Frota-Pessoa, O., Otto, P. A.
<strong>Waardenburg syndrome: clinical differentiation between types I and II.</strong>
Am. J. Med. Genet. 117A: 223-235, 2003.
[PubMed: 12599185]
[Full Text: https://doi.org/10.1002/ajmg.a.10193]
</p>
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<li>
<p class="mim-text-font">
Pingault, V., Ente, D., Dastot-Le Moal, F., Goossens, M., Marlin, S., Bondurand, N.
<strong>Review and update of mutations causing Waardenburg syndrome.</strong>
Hum. Mutat. 31: 391-406, 2010.
[PubMed: 20127975]
[Full Text: https://doi.org/10.1002/humu.21211]
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<li>
<p class="mim-text-font">
Preus, M., Linstrom, C., Polomeno, R. C., Milot, J.
<strong>Waardenburg syndrome--penetrance of major signs.</strong>
Am. J. Med. Genet. 15: 383-388, 1983.
[PubMed: 6881207]
[Full Text: https://doi.org/10.1002/ajmg.1320150303]
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<li>
<p class="mim-text-font">
Read, A. P., Foy, C., Newton, V.
<strong>Exclusion mapping in Waardenburg syndrome. (Abstract)</strong>
Cytogenet. Cell Genet. 51: 1064, 1989.
</p>
</li>
<li>
<p class="mim-text-font">
Read, A. P., Newton, V. E.
<strong>Waardenburg syndrome.</strong>
J. Med. Genet. 34: 656-665, 1997.
[PubMed: 9279758]
[Full Text: https://doi.org/10.1136/jmg.34.8.656]
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<li>
<p class="mim-text-font">
Reynolds, J. E., Marazita, M. L., Meyer, J. M., Stevens, C. A., Eaves, L. J., Arnos, K. S., Ploughman, L. M., MacLean, C., Nance, W. E., Diehl, S. R.
<strong>Major-locus contributions to variability of the craniofacial feature dystopia canthorum in Waardenburg syndrome.</strong>
Am. J. Hum. Genet. 58: 384-392, 1996.
[PubMed: 8571965]
</p>
</li>
<li>
<p class="mim-text-font">
Settelmayer, J. R., Hogan, M.
<strong>Waardenburg&#x27;s syndrome--report of a case in a non-Dutch family.</strong>
New Eng. J. Med. 264: 500-501, 1961.
[PubMed: 13750394]
[Full Text: https://doi.org/10.1056/NEJM196103092641008]
</p>
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<li>
<p class="mim-text-font">
Simpson, J. L., Falk, C. T., Morillo-Cucci, G., Allen, F. H., Jr., German, J.
<strong>Analysis for possible linkage between the loci for the Waardenburg syndrome and various blood groups and serological traits.</strong>
Humangenetik 23: 45-50, 1974.
[PubMed: 4211154]
[Full Text: https://doi.org/10.1007/BF00295681]
</p>
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<p class="mim-text-font">
Song, J., Feng, Y., Acke, F. R., Coucke, P., Vleminckx, K., Dhooge, I. J.
<strong>Hearing loss in Waardenburg syndrome: a systematic review.</strong>
Clin. Genet. 89: 416-425, 2016.
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[Full Text: https://doi.org/10.1111/cge.12631]
</p>
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<p class="mim-text-font">
Tamayo, M. L., Gelvez, N., Rodriguez, M., Florez, S., Varon, C., Medina, D., Bernal, J. E.
<strong>Screening program for Waardenburg syndrome in Colombia: clinical definition and phenotypic variability.</strong>
Am. J. Med. Genet. 146A: 1026-1031, 2008.
[PubMed: 18241065]
[Full Text: https://doi.org/10.1002/ajmg.a.32189]
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<p class="mim-text-font">
Tassabehji, M., Newton, V. E., Leverton, K., Turnbull, K., Seemanova, E., Kunze, J., Sperling, K., Strachan, T., Read, A. P.
<strong>PAX3 gene structure and mutations: close analogies between Waardenburg syndrome and the &#x27;Splotch&#x27; mouse.</strong>
Hum. Molec. Genet. 3: 1069-1074, 1994.
[PubMed: 7981674]
[Full Text: https://doi.org/10.1093/hmg/3.7.1069]
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<li>
<p class="mim-text-font">
Tassabehji, M., Read, A. P., Newton, V. E., Harris, R., Balling, R., Gruss, P., Strachan, T.
<strong>Waardenburg&#x27;s syndrome patients have mutations in the human homologue of the Pax-3 paired box gene.</strong>
Nature 355: 635-636, 1992.
[PubMed: 1347148]
[Full Text: https://doi.org/10.1038/355635a0]
</p>
</li>
<li>
<p class="mim-text-font">
Waardenburg, P.
<strong>A new syndrome combining developmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness.</strong>
Am. J. Hum. Genet. 3: 195-253, 1951.
[PubMed: 14902764]
</p>
</li>
<li>
<p class="mim-text-font">
Watanabe, A., Takeda, K., Ploplis, B., Tachibana, M.
<strong>Epistatic relationship between Waardenburg syndrome genes MITF and PAX3.</strong>
Nature Genet. 18: 283-286, 1998.
[PubMed: 9500554]
[Full Text: https://doi.org/10.1038/ng0398-283]
</p>
</li>
<li>
<p class="mim-text-font">
Winship, I., Beighton, P.
<strong>Phenotypic discriminants in the Waardenburg syndrome.</strong>
Clin. Genet. 41: 181-188, 1992.
[PubMed: 1576755]
</p>
</li>
<li>
<p class="mim-text-font">
Yoshino, M., Nakao, M., Shiotsuki, Y., Nishiyori, A., Yamashita, F., Karukaya, S., Yoshimura, H., Nishida, H., Shiotani, N., Sugita, A.
<strong>Incidences of dystopia canthorum and some other signs in a family with Waardenburg syndrome type I.</strong>
Jpn. J. Hum. Genet. 31: 373-378, 1986.
</p>
</li>
<li>
<p class="mim-text-font">
Zlotogora, J., Lerer, I., Bar-David, S., Ergaz, Z., Abeliovich, D.
<strong>Homozygosity for Waardenburg syndrome.</strong>
Am. J. Hum. Genet. 56: 1173-1178, 1995.
[PubMed: 7726174]
</p>
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Cassandra L. Kniffin - updated : 5/24/2016<br>Cassandra L. Kniffin - updated : 3/8/2010<br>Victor A. McKusick - updated : 3/21/2003<br>Ada Hamosh - updated : 1/8/2002<br>Victor A. McKusick - updated : 12/27/2001<br>Victor A. McKusick - updated : 12/5/2001<br>George E. Tiller - updated : 10/20/2000<br>George E. Tiller - updated : 4/14/2000<br>Ada Hamosh - updated : 3/14/2000<br>Victor A. McKusick - updated : 6/12/1998<br>Victor A. McKusick - updated : 2/27/1998<br>Michael J. Wright - updated : 2/11/1998<br>Victor A. McKusick - updated : 8/13/1997
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Victor A. McKusick : 6/2/1986
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