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Entry
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- #600195 - VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL; VMCM
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- OMIM
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<p>
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<span class="h4">#600195</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="/clinicalSynopsis/600195"><strong>Clinical Synopsis</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#mapping">Mapping</a>
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<a href="#inheritance">Inheritance</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#otherFeatures">Other Features</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</h4>
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">▼</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</a>
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</span>
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</span>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://clinicaltrials.gov/search?cond=VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=2266&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK1967/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/8917" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/multiple-cutaneous-and-mucosal-venous-malformations" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600195[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=2451" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0050792" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/600195" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0050792" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="title" class="mim-anchor"></a>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 699301008<br />
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<strong>ORPHA:</strong> 2451<br />
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<strong>DO:</strong> 0050792<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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600195
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL; VMCM
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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VMCM1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
|
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<a href="/geneMap/9/113?start=-3&limit=10&highlight=113">
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9p21.2
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Venous malformations, multiple cutaneous and mucosal
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/600195"> 600195 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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TEK
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/600221"> 600221 </a>
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- Cutaneous and mucosal venous malformations<br />
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- Mucosal bleeding <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C2748540&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C2748540</a>]</span><br /> - Maxillary and mandibular deformity<br />
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- Autosomal dominant (9p) <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br />
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<p>A number sign (#) is used with this entry because of evidence that multiple cutaneous and mucosal venous malformations (VMCM) is caused by heterozygous mutation in the TIE2 gene (TEK; <a href="/entry/600221">600221</a>), which encodes the epithelial-specific tyrosine kinase receptor, on chromosome 9p21.</p>
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<p>Cutaneomucosal venous malformation (VMCM) is an uncommon, heritable form of venous malformation in which lesions tend to be multifocal and small. They are composed of grossly dilated vascular spaces lined by a single continuous layer of endothelial cells, with areas of relative lack of surrounding mural cells, suggesting a defect in their recruitment. Some VMCM patients have venous malformations located in internal organs, and some have additional anomalies, including cardiac malformations (summary by <a href="#11" class="mim-tip-reference" title="Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M. <strong>Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.</strong> Europ. J. Hum. Genet. 18: 414-420, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19888299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19888299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19888299[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2009.193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19888299">Wouters et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19888299" 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>Another form of autosomal dominant venous malformation, blue rubber bleb nevus (<a href="/entry/112200">112200</a>), is of uncertain relationship to VMCM. Multiple cerebrovenous anomalies without cutaneous lesions are also familial; see cerebral cavernous malformations (<a href="/entry/116860">116860</a>). Glomuvenous malformations (<a href="/entry/138000">138000</a>) are similar to but clinically distinguishable from VMCMs.</p>
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<p><a href="#9" class="mim-tip-reference" title="Pasyk, K. A., Argenta, L. C., Erickson, R. P. <strong>Familial vascular malformations: report of 25 members of one family.</strong> Clin. Genet. 26: 221-227, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6478643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6478643</a>]" pmid="6478643">Pasyk et al. (1984)</a> described a family in which multiple vascular malformations, including cavernous hemangiomas, arteriovenous malformations, and capillary hemangiomas, occurred in 25 persons over 5 generations in an autosomal dominant pattern. Slightly reduced penetrance was suggested by the fact that a clinically unaffected woman had a child with a hemangioma on the foot and that in the part of the pedigree with the most complete documentation, the ratio of affected to unaffected was 15:20. Histopathologic examination in most cases revealed typical cavernous hemangiomas, composed of large, lacunar vascular spaces forming compact masses. The walls of these dilated vessels were relatively thin, lined with a single layer of endothelium; no smooth muscle or elastic tissue surrounded the vessels. <a href="#9" class="mim-tip-reference" title="Pasyk, K. A., Argenta, L. C., Erickson, R. P. <strong>Familial vascular malformations: report of 25 members of one family.</strong> Clin. Genet. 26: 221-227, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6478643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6478643</a>]" pmid="6478643">Pasyk et al. (1984)</a> noted that none of the patients in this family had a history of any symptoms that would suggest intracranial involvement: there had been no seizure disorders in any of the generations, nor had there been a death from intracranial catastrophe. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6478643" 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 15 members of 3 generations of a kindred and by implication in a sixteenth member in an earlier generation, in a pedigree pattern consistent with autosomal dominant inheritance, <a href="#2" class="mim-tip-reference" title="Boon, L. M., Mulliken, J. B., Vikkula, M., Watkins, H., Seidman, J., Olsen, B. R., Warman, M. L. <strong>Assignment of a locus for dominantly inherited venous malformations to chromosome 9p.</strong> Hum. Molec. Genet. 3: 1583-1587, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7833915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7833915</a>] [<a href="https://doi.org/10.1093/hmg/3.9.1583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7833915">Boon et al. (1994)</a> described cutaneous and mucosal venous malformations. They pictured an 18-year-old male with a 'slow-flow' venous malformation in the tongue which bled intermittently and caused deformation of the maxilla and mandible. They also pictured characteristic small cutaneous venous malformations located on the posterior aspect of the ear in 1 member. The lesions varied in size from 0.5 to 2 cm, except for the lesion on the tongue which measured 5 cm. Lesions were located on the arms and legs, face, oral mucosa, or genitalia. Some were present at birth; most lesions appeared by puberty. None of the family members had a history of gastrointestinal bleeding and occult blood was not demonstrated by guaiac testing of the stool. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7833915" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Gallione, C. J., Pasyk, K. A., Boon, L. M., Lennon, F., Johnson, D. W., Helmbold, E. A., Markel, D. S., Vikkula, M., Mulliken, J. B., Warman, M. L., Pericak-Vance, M. A., Marchuk, D. A. <strong>A gene for familial venous malformations maps to chromosome 9p in a second large kindred.</strong> J. Med. Genet. 32: 197-199, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7783168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7783168</a>] [<a href="https://doi.org/10.1136/jmg.32.3.197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7783168">Gallione et al. (1995)</a> restudied the large family with multiple vascular malformations originally described by <a href="#9" class="mim-tip-reference" title="Pasyk, K. A., Argenta, L. C., Erickson, R. P. <strong>Familial vascular malformations: report of 25 members of one family.</strong> Clin. Genet. 26: 221-227, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6478643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6478643</a>]" pmid="6478643">Pasyk et al. (1984)</a>, noting that of 337 members over 7 generations, 56 individuals were affected. The location of the venous malformations was almost identical for several family members. In most cases, the lesions were small, enlarged with time, and were asymptomatic. A few of the females observed an increase in size of the vascular lesions approximately 1 week before menstruation and a subsequent decrease in size during menstruation. The lesions were present on the face and mucous membranes, including the lips, tongue, cheeks, tonsils, and larynx. Some members had venous malformations within internal organs. One developed 2 vascular tumors in the large intestine and required blood transfusions because of excessive bleeding. Two members of the family died from complications of these vascular abnormalities. Pathologic examination in one of these patients showed vascular tumors within the stomach, liver, pancreas, and spleen. <a href="#5" class="mim-tip-reference" title="Gallione, C. J., Pasyk, K. A., Boon, L. M., Lennon, F., Johnson, D. W., Helmbold, E. A., Markel, D. S., Vikkula, M., Mulliken, J. B., Warman, M. L., Pericak-Vance, M. A., Marchuk, D. A. <strong>A gene for familial venous malformations maps to chromosome 9p in a second large kindred.</strong> J. Med. Genet. 32: 197-199, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7783168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7783168</a>] [<a href="https://doi.org/10.1136/jmg.32.3.197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7783168">Gallione et al. (1995)</a> noted that the disorder in this family was similar to the blue rubber bleb nevus syndrome (<a href="/entry/112200">112200</a>), pointing out that the family originally described by <a href="#1" class="mim-tip-reference" title="Bean, W. B. <strong>Vascular Spiders and Related Lesions of the Skin.</strong> Springfield, Ill.: Charles C. Thomas (pub.) 1958. Pp. 178-185."None>Bean (1958)</a>, like their family, had gastrointestinal bleeding from vascular lesions. <a href="#5" class="mim-tip-reference" title="Gallione, C. J., Pasyk, K. A., Boon, L. M., Lennon, F., Johnson, D. W., Helmbold, E. A., Markel, D. S., Vikkula, M., Mulliken, J. B., Warman, M. L., Pericak-Vance, M. A., Marchuk, D. A. <strong>A gene for familial venous malformations maps to chromosome 9p in a second large kindred.</strong> J. Med. Genet. 32: 197-199, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7783168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7783168</a>] [<a href="https://doi.org/10.1136/jmg.32.3.197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7783168">Gallione et al. (1995)</a> suggested that blue rubber bleb nevus syndrome might be a subset in the general category of familial venous malformations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6478643+7783168" 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="Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M. <strong>Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.</strong> Europ. J. Hum. Genet. 18: 414-420, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19888299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19888299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19888299[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2009.193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19888299">Wouters et al. (2010)</a> studied 26 affected individuals from 12 unrelated families with VMCM. Cutaneous lesions were mostly located in the cervicofacial region (18 of 26) and/or limbs (21 of 26), and less often on the trunk (9 of 26). Lesions on the lips, tongue, and buccal mucosa were frequent (15 of 26). The venous malformations were generally small (less than 5 cm), and over 80% of patients had more than 2 lesions. Some individuals had venous malformations located in internal organs, including pulmonary, gastrointestinal, renal, and brain lesions. Localized intravascular coagulopathy was documented by elevated D-dimers in 5 of 13 patients tested, and appeared to be associated with overall lesion volume. Some patients had additional anomalies, including restrictive perimembranous ventricular septal defect, which was present in a mother and 2 daughters as well as a woman from an unrelated family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19888299" 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="Boon, L. M., Mulliken, J. B., Vikkula, M., Watkins, H., Seidman, J., Olsen, B. R., Warman, M. L. <strong>Assignment of a locus for dominantly inherited venous malformations to chromosome 9p.</strong> Hum. Molec. Genet. 3: 1583-1587, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7833915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7833915</a>] [<a href="https://doi.org/10.1093/hmg/3.9.1583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7833915">Boon et al. (1994)</a> demonstrated that the disorder did not map to 9q, the site of the mutation in hereditary hemorrhagic telangiectasia type 1 (HHT1; <a href="/entry/187300">187300</a>). On the other hand, they were able to demonstrate that the locus for multiple cutaneous and mucosal venous malformations in this family lies within a 24-cM interval on 9p, defined by the markers D9S157 and D9S163. <a href="#5" class="mim-tip-reference" title="Gallione, C. J., Pasyk, K. A., Boon, L. M., Lennon, F., Johnson, D. W., Helmbold, E. A., Markel, D. S., Vikkula, M., Mulliken, J. B., Warman, M. L., Pericak-Vance, M. A., Marchuk, D. A. <strong>A gene for familial venous malformations maps to chromosome 9p in a second large kindred.</strong> J. Med. Genet. 32: 197-199, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7783168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7783168</a>] [<a href="https://doi.org/10.1136/jmg.32.3.197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7783168">Gallione et al. (1995)</a> confirmed linkage to 9p in a second family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7833915+7783168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Heterogeneity</em></strong></p><p>
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<a href="#3" class="mim-tip-reference" title="Calvert, J. T., Riney, T. J., Kontos, C. D., Cha, E. H., Prieto, V. G., Shea, C. R., Berg, J. N., Nevin, N. C., Simpson, S. A., Pasyk, K. A., Speer, M. C., Peters, K. G., Marchuk, D. A. <strong>Allelic and locus heterogeneity in inherited venous malformations.</strong> Hum. Molec. Genet. 8: 1279-1289, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369874</a>] [<a href="https://doi.org/10.1093/hmg/8.7.1279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10369874">Calvert et al. (1999)</a> excluded linkage to 9p21 in at least 1 VMCM family, thus providing evidence that this disorder displays genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10369874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The transmission pattern of VMCM in the families studied by <a href="#10" class="mim-tip-reference" title="Vikkula, M., Boon, L. M., Carraway, K. L., III, Calvert, J. T., Diamonti, A. J., Goumnerov, B., Pasyk, K. A., Marchuk, D. A., Warman, M. L., Cantley, L. C., Mulliken, J. B., Olsen, B. R. <strong>Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2.</strong> Cell 87: 1181-1190, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8980225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8980225</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81814-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8980225">Vikkula et al. (1996)</a> was consistent with autosomal dominant inheritance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8980225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The endothelial cell-specific receptor tyrosine kinase gene TIE2 had been mapped to 9p21. To test whether TIE2 is localized to the interval where the VMCM1 locus is situated, <a href="#10" class="mim-tip-reference" title="Vikkula, M., Boon, L. M., Carraway, K. L., III, Calvert, J. T., Diamonti, A. J., Goumnerov, B., Pasyk, K. A., Marchuk, D. A., Warman, M. L., Cantley, L. C., Mulliken, J. B., Olsen, B. R. <strong>Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2.</strong> Cell 87: 1181-1190, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8980225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8980225</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81814-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8980225">Vikkula et al. (1996)</a> used 2 human melanoma cell lines containing previously defined homozygous deletions of 9p and a YAC contig covering the 8-cM region from the IFN gene cluster to the marker D9S161. They showed that indeed the TIE2 gene lies within the linked interval. They then analyzed TIE2 as a candidate gene in the 2 large VMCM pedigrees previously linked to 9p by <a href="#2" class="mim-tip-reference" title="Boon, L. M., Mulliken, J. B., Vikkula, M., Watkins, H., Seidman, J., Olsen, B. R., Warman, M. L. <strong>Assignment of a locus for dominantly inherited venous malformations to chromosome 9p.</strong> Hum. Molec. Genet. 3: 1583-1587, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7833915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7833915</a>] [<a href="https://doi.org/10.1093/hmg/3.9.1583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7833915">Boon et al. (1994)</a> and <a href="#5" class="mim-tip-reference" title="Gallione, C. J., Pasyk, K. A., Boon, L. M., Lennon, F., Johnson, D. W., Helmbold, E. A., Markel, D. S., Vikkula, M., Mulliken, J. B., Warman, M. L., Pericak-Vance, M. A., Marchuk, D. A. <strong>A gene for familial venous malformations maps to chromosome 9p in a second large kindred.</strong> J. Med. Genet. 32: 197-199, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7783168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7783168</a>] [<a href="https://doi.org/10.1136/jmg.32.3.197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7783168">Gallione et al. (1995)</a>, and identified a heterozygous missense mutation (R849W; <a href="/entry/600221#0001">600221.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7783168+8980225+7833915" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Calvert, J. T., Riney, T. J., Kontos, C. D., Cha, E. H., Prieto, V. G., Shea, C. R., Berg, J. N., Nevin, N. C., Simpson, S. A., Pasyk, K. A., Speer, M. C., Peters, K. G., Marchuk, D. A. <strong>Allelic and locus heterogeneity in inherited venous malformations.</strong> Hum. Molec. Genet. 8: 1279-1289, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369874</a>] [<a href="https://doi.org/10.1093/hmg/8.7.1279" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10369874">Calvert et al. (1999)</a> found the R849W mutation in an unrelated VMCM family, and identified heterozygosity for a different missense mutation within the same domain of TIE2 in another kindred (Y897S; <a href="/entry/600221#0002">600221.0002</a>). Cell transfection experiments using constructs containing either the R849W or the Y897S mutation demonstrated that the receptors containing either mutation showed ligand-independent hyperphosphorylation, suggesting a gain-of-function mechanism for development of venous malformations in these families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10369874" 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="Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M. <strong>Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.</strong> Europ. J. Hum. Genet. 18: 414-420, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19888299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19888299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19888299[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2009.193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19888299">Wouters et al. (2010)</a> analyzed the TEK gene in 26 affected members of 12 families with VMCM, and identified heterozygosity for the R849W mutation in 14 patients from 6 of the families. In the remaining families, 6 different heterozygous missense mutations were identified, respectively (see, e.g., <a href="/entry/600221#0003">600221.0003</a> and <a href="/entry/600221#0004">600221.0004</a>). All of the VMCM-associated mutations resulted in ligand-independent hyperphosphorylation of TEK2; although the levels of hyperphosphorylation were highly variable, <a href="#11" class="mim-tip-reference" title="Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M. <strong>Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.</strong> Europ. J. Hum. Genet. 18: 414-420, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19888299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19888299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19888299[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2009.193" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19888299">Wouters et al. (2010)</a> observed no genotype-phenotype correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19888299" 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>Sporadic Venous Malformations</em></strong></p><p>
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<a href="#7" class="mim-tip-reference" title="Limaye, N., Wouters, V., Uebelhoer, M., Tuominen, M., Wirkkala, R., Mulliken, J. B., Eklund, L., Boon, L. M., Vikkula, M. <strong>Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.</strong> Nature Genet. 41: 118-124, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19079259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19079259</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19079259[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19079259">Limaye et al. (2009)</a> assessed whether localized tissue-specific events have a role in the etiology of sporadic venous malformations, which are far more common than mucocutaneous venous malformations. <a href="#7" class="mim-tip-reference" title="Limaye, N., Wouters, V., Uebelhoer, M., Tuominen, M., Wirkkala, R., Mulliken, J. B., Eklund, L., Boon, L. M., Vikkula, M. <strong>Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.</strong> Nature Genet. 41: 118-124, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19079259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19079259</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19079259[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19079259">Limaye et al. (2009)</a> identified 8 somatic TEK mutations in lesions from 28 of 57 individuals (49.1%) with sporadic venous malformations. The somatic mutations included one causing a frequent L914F substitution (leu914 to phe) and several double mutations in cis, all of which resulted in ligand-independent TIE2 hyperphosphorylation in vitro. When overexpressed in human umbilical vein endothelial cells, the L914F mutant was abnormally localized and responded to ligand, in contrast to wildtype TIE2 and the common, inherited R849W (<a href="/entry/600221#0001">600221.0001</a>) mutant, suggesting that the mutations have distinct effects. The presence of the same mutations in multifocal sporadic venous malformations in 2 individuals suggested a common origin for the abnormal endothelial cells at the distant sites. <a href="#7" class="mim-tip-reference" title="Limaye, N., Wouters, V., Uebelhoer, M., Tuominen, M., Wirkkala, R., Mulliken, J. B., Eklund, L., Boon, L. M., Vikkula, M. <strong>Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.</strong> Nature Genet. 41: 118-124, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19079259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19079259</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19079259[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19079259">Limaye et al. (2009)</a> concluded that their data showed that a sporadic disease may be explained by somatic changes in a gene causing rare, inherited forms and pinpointed TIE2 pathways as potential therapeutic targets for venous malformations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19079259" 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>DNA pooling is a powerful and efficient method for rapid genomewide linkage scans in autosomal recessive diseases in inbred populations, where affected individuals are likely to be homozygous for alleles at loci surrounding the disease gene. This strategy exploits the fact that affected individuals in inbred families share a chromosomal region inherited from a common ancestor surrounding the disease locus. Traditionally, genotype results are generated for individual DNA samples using a given marker or markers. In the DNA pooling strategy, DNA from multiple affected and unaffected individuals from each family, as well as population controls, are pooled in separate lanes and simultaneously amplified by PCR with a given marker. Markers linked to and in association with the disease gene will show loss of heterozygosity and hence a different pattern of alleles from appropriate control groups. Unlinked markers should demonstrate an allele distribution that is similar to control lanes. <a href="#4" class="mim-tip-reference" title="Damji, K. F., Gallione, C. J., Allingham, R. R., Slotterbeck, B., Guttmacher, A. E., Pasyk, K. A., Vance, J. M., Pericak-Vance, M. A., Speer, M. C., Marchuk, D. A. <strong>Quantitative DNA pooling to increase the efficiency of linkage analysis in autosomal dominant disease.</strong> Hum. Genet. 102: 207-212, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521591</a>] [<a href="https://doi.org/10.1007/s004390050679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521591">Damji et al. (1998)</a> investigated whether this approach would detect linkage in autosomal dominant disorders, as suggested by <a href="#6" class="mim-tip-reference" title="Kanis, A. B., Beck, J. S., Rokhlina, T., Tchida, C., Stone, E. M., Sheffield, V. C. <strong>Use of DNA pooling strategies for mapping dominant disorders and the potential application to mapping complex diseases.(Abstract)</strong> Am. J. Hum. Genet. 57 (suppl.): A195 only, 1995."None>Kanis et al. (1995)</a>, where affected individuals within a given family may share 1 allele identical by descent at loci tightly linked to the disease. They used 2 outbred pedigrees in which familial venous malformations and hereditary hemorrhagic telangiectasia type 1 are linked to sites at opposite ends of chromosome 9. These were the kindreds reported by <a href="#5" class="mim-tip-reference" title="Gallione, C. J., Pasyk, K. A., Boon, L. M., Lennon, F., Johnson, D. W., Helmbold, E. A., Markel, D. S., Vikkula, M., Mulliken, J. B., Warman, M. L., Pericak-Vance, M. A., Marchuk, D. A. <strong>A gene for familial venous malformations maps to chromosome 9p in a second large kindred.</strong> J. Med. Genet. 32: 197-199, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7783168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7783168</a>] [<a href="https://doi.org/10.1136/jmg.32.3.197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7783168">Gallione et al. (1995)</a> and <a href="#8" class="mim-tip-reference" title="McDonald, M. T., Papenberg, K. A., Ghosh, S., Glatfelter, A. A., Biesecker, B. B., Helmbold, E. A., Markel, D. S., Zolotor, A., McKinnon, W. C., Vanderstoep, J. L., Jackson, C. E., Iannuzzi, M., Collins, F. S., Boehnke, M., Porteous, M. E., Guttmacher, A. E., Marchuk, D. A. <strong>A disease locus for hereditary haemorrhagic telangiectasia maps to chromosome 9q33-34.</strong> Nature Genet. 6: 197-204, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162075</a>] [<a href="https://doi.org/10.1038/ng0294-197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8162075">McDonald et al. (1994)</a>, respectively. Separate pools of DNA from 21 family members affected with VMCM and 17 with HHT1, 9 unaffected family members, and 25 unrelated population controls were established. In both autosomal dominant diseases investigated, quantitative DNA pooling detected shifts in allele frequency, thus identifying areas of known linkage. Although the false-positive rate appeared to be high, the approach was thought still to serve the purpose of reducing the amount of genotyping required. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8162075+7783168+9521591" 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 href="https://doi.org/10.1093/hmg/3.9.1583" target="_blank">Full Text</a>]
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Calvert, J. T., Riney, T. J., Kontos, C. D., Cha, E. H., Prieto, V. G., Shea, C. R., Berg, J. N., Nevin, N. C., Simpson, S. A., Pasyk, K. A., Speer, M. C., Peters, K. G., Marchuk, D. A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369874</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10369874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/8.7.1279" target="_blank">Full Text</a>]
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Damji, K. F., Gallione, C. J., Allingham, R. R., Slotterbeck, B., Guttmacher, A. E., Pasyk, K. A., Vance, J. M., Pericak-Vance, M. A., Speer, M. C., Marchuk, D. A.
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<strong>Quantitative DNA pooling to increase the efficiency of linkage analysis in autosomal dominant disease.</strong>
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Hum. Genet. 102: 207-212, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521591</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9521591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390050679" target="_blank">Full Text</a>]
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Gallione, C. J., Pasyk, K. A., Boon, L. M., Lennon, F., Johnson, D. W., Helmbold, E. A., Markel, D. S., Vikkula, M., Mulliken, J. B., Warman, M. L., Pericak-Vance, M. A., Marchuk, D. A.
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<strong>A gene for familial venous malformations maps to chromosome 9p in a second large kindred.</strong>
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J. Med. Genet. 32: 197-199, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7783168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7783168</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7783168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Kanis, A. B., Beck, J. S., Rokhlina, T., Tchida, C., Stone, E. M., Sheffield, V. C.
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<strong>Use of DNA pooling strategies for mapping dominant disorders and the potential application to mapping complex diseases.(Abstract)</strong>
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Am. J. Hum. Genet. 57 (suppl.): A195 only, 1995.
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Limaye, N., Wouters, V., Uebelhoer, M., Tuominen, M., Wirkkala, R., Mulliken, J. B., Eklund, L., Boon, L. M., Vikkula, M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19079259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19079259</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19079259[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19079259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng.272" target="_blank">Full Text</a>]
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McDonald, M. T., Papenberg, K. A., Ghosh, S., Glatfelter, A. A., Biesecker, B. B., Helmbold, E. A., Markel, D. S., Zolotor, A., McKinnon, W. C., Vanderstoep, J. L., Jackson, C. E., Iannuzzi, M., Collins, F. S., Boehnke, M., Porteous, M. E., Guttmacher, A. E., Marchuk, D. A.
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<strong>A disease locus for hereditary haemorrhagic telangiectasia maps to chromosome 9q33-34.</strong>
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Nature Genet. 6: 197-204, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8162075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8162075</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8162075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng0294-197" target="_blank">Full Text</a>]
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Pasyk, K. A., Argenta, L. C., Erickson, R. P.
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Vikkula, M., Boon, L. M., Carraway, K. L., III, Calvert, J. T., Diamonti, A. J., Goumnerov, B., Pasyk, K. A., Marchuk, D. A., Warman, M. L., Cantley, L. C., Mulliken, J. B., Olsen, B. R.
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<strong>Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8980225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8980225</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8980225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)81814-0" target="_blank">Full Text</a>]
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Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M.
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<strong>Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.</strong>
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Europ. J. Hum. Genet. 18: 414-420, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19888299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19888299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19888299[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19888299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ejhg.2009.193" target="_blank">Full Text</a>]
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Marla J. F. O'Neill - updated : 11/30/2011
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Ada Hamosh - updated : 1/15/2010<br>George E. Tiller - updated : 1/17/2000<br>Victor A. McKusick - updated : 4/1/1998<br>Victor A. McKusick - updated : 2/6/1997
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Victor A. McKusick : 11/16/1994
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carol : 12/14/2022
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carol : 01/07/2021<br>carol : 02/06/2020<br>alopez : 09/29/2016<br>carol : 11/30/2011<br>alopez : 1/27/2010<br>alopez : 1/27/2010<br>terry : 1/15/2010<br>wwang : 7/29/2009<br>carol : 4/29/2004<br>alopez : 1/17/2000<br>dholmes : 4/17/1998<br>alopez : 4/1/1998<br>terry : 3/23/1998<br>terry : 3/23/1998<br>alopez : 7/8/1997<br>terry : 2/6/1997<br>terry : 2/6/1997<br>terry : 2/3/1997<br>joanna : 1/15/1997<br>mimadm : 9/23/1995<br>terry : 4/19/1995<br>terry : 11/16/1994
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<span class="mim-font">
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<strong>#</strong> 600195
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<h3>
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VENOUS MALFORMATIONS, MULTIPLE CUTANEOUS AND MUCOSAL; VMCM
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</h3>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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VMCM1
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</h4>
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<strong>SNOMEDCT:</strong> 699301008;
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<strong>ORPHA:</strong> 2451;
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<strong>DO:</strong> 0050792;
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<h4>
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<strong>Phenotype-Gene Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<th>
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Location
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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<th>
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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9p21.2
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<span class="mim-font">
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Venous malformations, multiple cutaneous and mucosal
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<span class="mim-font">
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600195
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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TEK
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<span class="mim-font">
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600221
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because of evidence that multiple cutaneous and mucosal venous malformations (VMCM) is caused by heterozygous mutation in the TIE2 gene (TEK; 600221), which encodes the epithelial-specific tyrosine kinase receptor, on chromosome 9p21.</p>
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<strong>Description</strong>
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</h4>
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<p>Cutaneomucosal venous malformation (VMCM) is an uncommon, heritable form of venous malformation in which lesions tend to be multifocal and small. They are composed of grossly dilated vascular spaces lined by a single continuous layer of endothelial cells, with areas of relative lack of surrounding mural cells, suggesting a defect in their recruitment. Some VMCM patients have venous malformations located in internal organs, and some have additional anomalies, including cardiac malformations (summary by Wouters et al., 2010). </p><p>Another form of autosomal dominant venous malformation, blue rubber bleb nevus (112200), is of uncertain relationship to VMCM. Multiple cerebrovenous anomalies without cutaneous lesions are also familial; see cerebral cavernous malformations (116860). Glomuvenous malformations (138000) are similar to but clinically distinguishable from VMCMs.</p>
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<strong>Clinical Features</strong>
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<p>Pasyk et al. (1984) described a family in which multiple vascular malformations, including cavernous hemangiomas, arteriovenous malformations, and capillary hemangiomas, occurred in 25 persons over 5 generations in an autosomal dominant pattern. Slightly reduced penetrance was suggested by the fact that a clinically unaffected woman had a child with a hemangioma on the foot and that in the part of the pedigree with the most complete documentation, the ratio of affected to unaffected was 15:20. Histopathologic examination in most cases revealed typical cavernous hemangiomas, composed of large, lacunar vascular spaces forming compact masses. The walls of these dilated vessels were relatively thin, lined with a single layer of endothelium; no smooth muscle or elastic tissue surrounded the vessels. Pasyk et al. (1984) noted that none of the patients in this family had a history of any symptoms that would suggest intracranial involvement: there had been no seizure disorders in any of the generations, nor had there been a death from intracranial catastrophe. </p><p>In 15 members of 3 generations of a kindred and by implication in a sixteenth member in an earlier generation, in a pedigree pattern consistent with autosomal dominant inheritance, Boon et al. (1994) described cutaneous and mucosal venous malformations. They pictured an 18-year-old male with a 'slow-flow' venous malformation in the tongue which bled intermittently and caused deformation of the maxilla and mandible. They also pictured characteristic small cutaneous venous malformations located on the posterior aspect of the ear in 1 member. The lesions varied in size from 0.5 to 2 cm, except for the lesion on the tongue which measured 5 cm. Lesions were located on the arms and legs, face, oral mucosa, or genitalia. Some were present at birth; most lesions appeared by puberty. None of the family members had a history of gastrointestinal bleeding and occult blood was not demonstrated by guaiac testing of the stool. </p><p>Gallione et al. (1995) restudied the large family with multiple vascular malformations originally described by Pasyk et al. (1984), noting that of 337 members over 7 generations, 56 individuals were affected. The location of the venous malformations was almost identical for several family members. In most cases, the lesions were small, enlarged with time, and were asymptomatic. A few of the females observed an increase in size of the vascular lesions approximately 1 week before menstruation and a subsequent decrease in size during menstruation. The lesions were present on the face and mucous membranes, including the lips, tongue, cheeks, tonsils, and larynx. Some members had venous malformations within internal organs. One developed 2 vascular tumors in the large intestine and required blood transfusions because of excessive bleeding. Two members of the family died from complications of these vascular abnormalities. Pathologic examination in one of these patients showed vascular tumors within the stomach, liver, pancreas, and spleen. Gallione et al. (1995) noted that the disorder in this family was similar to the blue rubber bleb nevus syndrome (112200), pointing out that the family originally described by Bean (1958), like their family, had gastrointestinal bleeding from vascular lesions. Gallione et al. (1995) suggested that blue rubber bleb nevus syndrome might be a subset in the general category of familial venous malformations. </p><p>Wouters et al. (2010) studied 26 affected individuals from 12 unrelated families with VMCM. Cutaneous lesions were mostly located in the cervicofacial region (18 of 26) and/or limbs (21 of 26), and less often on the trunk (9 of 26). Lesions on the lips, tongue, and buccal mucosa were frequent (15 of 26). The venous malformations were generally small (less than 5 cm), and over 80% of patients had more than 2 lesions. Some individuals had venous malformations located in internal organs, including pulmonary, gastrointestinal, renal, and brain lesions. Localized intravascular coagulopathy was documented by elevated D-dimers in 5 of 13 patients tested, and appeared to be associated with overall lesion volume. Some patients had additional anomalies, including restrictive perimembranous ventricular septal defect, which was present in a mother and 2 daughters as well as a woman from an unrelated family. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Boon et al. (1994) demonstrated that the disorder did not map to 9q, the site of the mutation in hereditary hemorrhagic telangiectasia type 1 (HHT1; 187300). On the other hand, they were able to demonstrate that the locus for multiple cutaneous and mucosal venous malformations in this family lies within a 24-cM interval on 9p, defined by the markers D9S157 and D9S163. Gallione et al. (1995) confirmed linkage to 9p in a second family. </p><p><strong><em>Heterogeneity</em></strong></p><p>
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Calvert et al. (1999) excluded linkage to 9p21 in at least 1 VMCM family, thus providing evidence that this disorder displays genetic heterogeneity. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Inheritance</strong>
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</h4>
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<span class="mim-text-font">
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<p>The transmission pattern of VMCM in the families studied by Vikkula et al. (1996) was consistent with autosomal dominant inheritance. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>The endothelial cell-specific receptor tyrosine kinase gene TIE2 had been mapped to 9p21. To test whether TIE2 is localized to the interval where the VMCM1 locus is situated, Vikkula et al. (1996) used 2 human melanoma cell lines containing previously defined homozygous deletions of 9p and a YAC contig covering the 8-cM region from the IFN gene cluster to the marker D9S161. They showed that indeed the TIE2 gene lies within the linked interval. They then analyzed TIE2 as a candidate gene in the 2 large VMCM pedigrees previously linked to 9p by Boon et al. (1994) and Gallione et al. (1995), and identified a heterozygous missense mutation (R849W; 600221.0001). </p><p>Calvert et al. (1999) found the R849W mutation in an unrelated VMCM family, and identified heterozygosity for a different missense mutation within the same domain of TIE2 in another kindred (Y897S; 600221.0002). Cell transfection experiments using constructs containing either the R849W or the Y897S mutation demonstrated that the receptors containing either mutation showed ligand-independent hyperphosphorylation, suggesting a gain-of-function mechanism for development of venous malformations in these families. </p><p>Wouters et al. (2010) analyzed the TEK gene in 26 affected members of 12 families with VMCM, and identified heterozygosity for the R849W mutation in 14 patients from 6 of the families. In the remaining families, 6 different heterozygous missense mutations were identified, respectively (see, e.g., 600221.0003 and 600221.0004). All of the VMCM-associated mutations resulted in ligand-independent hyperphosphorylation of TEK2; although the levels of hyperphosphorylation were highly variable, Wouters et al. (2010) observed no genotype-phenotype correlation. </p><p><strong><em>Sporadic Venous Malformations</em></strong></p><p>
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Limaye et al. (2009) assessed whether localized tissue-specific events have a role in the etiology of sporadic venous malformations, which are far more common than mucocutaneous venous malformations. Limaye et al. (2009) identified 8 somatic TEK mutations in lesions from 28 of 57 individuals (49.1%) with sporadic venous malformations. The somatic mutations included one causing a frequent L914F substitution (leu914 to phe) and several double mutations in cis, all of which resulted in ligand-independent TIE2 hyperphosphorylation in vitro. When overexpressed in human umbilical vein endothelial cells, the L914F mutant was abnormally localized and responded to ligand, in contrast to wildtype TIE2 and the common, inherited R849W (600221.0001) mutant, suggesting that the mutations have distinct effects. The presence of the same mutations in multifocal sporadic venous malformations in 2 individuals suggested a common origin for the abnormal endothelial cells at the distant sites. Limaye et al. (2009) concluded that their data showed that a sporadic disease may be explained by somatic changes in a gene causing rare, inherited forms and pinpointed TIE2 pathways as potential therapeutic targets for venous malformations. </p>
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<h4>
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<span class="mim-font">
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<strong>Other Features</strong>
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<span class="mim-text-font">
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<p>DNA pooling is a powerful and efficient method for rapid genomewide linkage scans in autosomal recessive diseases in inbred populations, where affected individuals are likely to be homozygous for alleles at loci surrounding the disease gene. This strategy exploits the fact that affected individuals in inbred families share a chromosomal region inherited from a common ancestor surrounding the disease locus. Traditionally, genotype results are generated for individual DNA samples using a given marker or markers. In the DNA pooling strategy, DNA from multiple affected and unaffected individuals from each family, as well as population controls, are pooled in separate lanes and simultaneously amplified by PCR with a given marker. Markers linked to and in association with the disease gene will show loss of heterozygosity and hence a different pattern of alleles from appropriate control groups. Unlinked markers should demonstrate an allele distribution that is similar to control lanes. Damji et al. (1998) investigated whether this approach would detect linkage in autosomal dominant disorders, as suggested by Kanis et al. (1995), where affected individuals within a given family may share 1 allele identical by descent at loci tightly linked to the disease. They used 2 outbred pedigrees in which familial venous malformations and hereditary hemorrhagic telangiectasia type 1 are linked to sites at opposite ends of chromosome 9. These were the kindreds reported by Gallione et al. (1995) and McDonald et al. (1994), respectively. Separate pools of DNA from 21 family members affected with VMCM and 17 with HHT1, 9 unaffected family members, and 25 unrelated population controls were established. In both autosomal dominant diseases investigated, quantitative DNA pooling detected shifts in allele frequency, thus identifying areas of known linkage. Although the false-positive rate appeared to be high, the approach was thought still to serve the purpose of reducing the amount of genotyping required. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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<ol>
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<li>
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<p class="mim-text-font">
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Bean, W. B.
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<strong>Vascular Spiders and Related Lesions of the Skin.</strong>
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Springfield, Ill.: Charles C. Thomas (pub.) 1958. Pp. 178-185.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Boon, L. M., Mulliken, J. B., Vikkula, M., Watkins, H., Seidman, J., Olsen, B. R., Warman, M. L.
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<strong>Assignment of a locus for dominantly inherited venous malformations to chromosome 9p.</strong>
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Hum. Molec. Genet. 3: 1583-1587, 1994.
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[PubMed: 7833915]
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[Full Text: https://doi.org/10.1093/hmg/3.9.1583]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Calvert, J. T., Riney, T. J., Kontos, C. D., Cha, E. H., Prieto, V. G., Shea, C. R., Berg, J. N., Nevin, N. C., Simpson, S. A., Pasyk, K. A., Speer, M. C., Peters, K. G., Marchuk, D. A.
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<strong>Allelic and locus heterogeneity in inherited venous malformations.</strong>
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Hum. Molec. Genet. 8: 1279-1289, 1999.
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[PubMed: 10369874]
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[Full Text: https://doi.org/10.1093/hmg/8.7.1279]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Damji, K. F., Gallione, C. J., Allingham, R. R., Slotterbeck, B., Guttmacher, A. E., Pasyk, K. A., Vance, J. M., Pericak-Vance, M. A., Speer, M. C., Marchuk, D. A.
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<strong>Quantitative DNA pooling to increase the efficiency of linkage analysis in autosomal dominant disease.</strong>
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Hum. Genet. 102: 207-212, 1998.
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[PubMed: 9521591]
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[Full Text: https://doi.org/10.1007/s004390050679]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Gallione, C. J., Pasyk, K. A., Boon, L. M., Lennon, F., Johnson, D. W., Helmbold, E. A., Markel, D. S., Vikkula, M., Mulliken, J. B., Warman, M. L., Pericak-Vance, M. A., Marchuk, D. A.
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<strong>A gene for familial venous malformations maps to chromosome 9p in a second large kindred.</strong>
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J. Med. Genet. 32: 197-199, 1995.
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[PubMed: 7783168]
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[Full Text: https://doi.org/10.1136/jmg.32.3.197]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kanis, A. B., Beck, J. S., Rokhlina, T., Tchida, C., Stone, E. M., Sheffield, V. C.
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<strong>Use of DNA pooling strategies for mapping dominant disorders and the potential application to mapping complex diseases.(Abstract)</strong>
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Am. J. Hum. Genet. 57 (suppl.): A195 only, 1995.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Limaye, N., Wouters, V., Uebelhoer, M., Tuominen, M., Wirkkala, R., Mulliken, J. B., Eklund, L., Boon, L. M., Vikkula, M.
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<strong>Somatic mutations in angiopoietin receptor gene TEK cause solitary and multiple sporadic venous malformations.</strong>
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Nature Genet. 41: 118-124, 2009.
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[PubMed: 19079259]
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McDonald, M. T., Papenberg, K. A., Ghosh, S., Glatfelter, A. A., Biesecker, B. B., Helmbold, E. A., Markel, D. S., Zolotor, A., McKinnon, W. C., Vanderstoep, J. L., Jackson, C. E., Iannuzzi, M., Collins, F. S., Boehnke, M., Porteous, M. E., Guttmacher, A. E., Marchuk, D. A.
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<strong>A disease locus for hereditary haemorrhagic telangiectasia maps to chromosome 9q33-34.</strong>
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Pasyk, K. A., Argenta, L. C., Erickson, R. P.
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<strong>Familial vascular malformations: report of 25 members of one family.</strong>
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Vikkula, M., Boon, L. M., Carraway, K. L., III, Calvert, J. T., Diamonti, A. J., Goumnerov, B., Pasyk, K. A., Marchuk, D. A., Warman, M. L., Cantley, L. C., Mulliken, J. B., Olsen, B. R.
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Wouters, V., Limaye, N., Uebelhoer, M., Irrthum, A., Boon, L. M., Mulliken, J. B., Enjolras, O., Baselga, E., Berg, J., Dompmartin, A., Ivarsson, S. A., Kangesu, L., Lacassie, Y., Murphy, J., Teebi, A. S., Penington, A., Rieu, P., Vikkula, M.
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<strong>Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.</strong>
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[PubMed: 19888299]
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Marla J. F. O'Neill - updated : 11/30/2011<br>Ada Hamosh - updated : 1/15/2010<br>George E. Tiller - updated : 1/17/2000<br>Victor A. McKusick - updated : 4/1/1998<br>Victor A. McKusick - updated : 2/6/1997
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Victor A. McKusick : 11/16/1994
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