3030 lines
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Entry
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- #300299 - NEUTROPENIA, SEVERE CONGENITAL, X-LINKED; SCNX
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- OMIM
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<p>
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<span class="h4">#300299</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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</li>
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<li role="presentation">
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<a href="/clinicalSynopsis/300299"><strong>Clinical Synopsis</strong></a>
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<li role="presentation">
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<a href="/phenotypicSeries/PS202700"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></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="#molecularGenetics">Molecular Genetics</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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<div><a href="https://clinicaltrials.gov/search?cond=NEUTROPENIA, SEVERE CONGENITAL, X-LINKED" 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=11727&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/NBK1178/" 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/6529" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=300299[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=86788" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:0112128" 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/300299" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 718882006<br />
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<strong>ORPHA:</strong> 86788<br />
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<strong>DO:</strong> 0112128<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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300299
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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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NEUTROPENIA, SEVERE CONGENITAL, X-LINKED; SCNX
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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XLN
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="phenotypeMap" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
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<strong>Phenotype-Gene Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
|
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<span class="mim-font">
|
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<a href="/geneMap/X/253?start=-3&limit=10&highlight=253">
|
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Xp11.23
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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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Neutropenia, severe congenital, X-linked
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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/300299"> 300299 </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="X-linked recessive">XLR</abbr>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</td>
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<td>
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<span class="mim-font">
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WAS
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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/300392"> 300392 </a>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<div class="btn-group ">
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<a href="/clinicalSynopsis/300299" class="btn btn-warning" role="button"> Clinical Synopsis </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<a href="/phenotypicSeries/PS202700" class="btn btn-info" role="button"> Phenotypic Series </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/300299" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/300299" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
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<p />
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- X-linked recessive <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845977&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845977</a>, <a href="https://bioportal.bioontology.org/search?q=C1279481&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1279481</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001419" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001419</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> SKIN, NAILS, & HAIR </strong>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<div>
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<div>
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<span class="h5 mim-font">
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<em> Skin </em>
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</span>
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</div>
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<div style="margin-left: 2em;">
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<span class="mim-font">
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- No eczema <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845991&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845991</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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</div>
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<div>
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<div>
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<span class="h5 mim-font">
|
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<strong> HEMATOLOGY </strong>
|
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</span>
|
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</div>
|
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<div style="margin-left: 2em;">
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<div>
|
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<span class="mim-font">
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|
|
- Severe congenital neutropenia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/89655007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">89655007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D70.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D70.0</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/288.01" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.01</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0340970&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0340970</a>, <a href="https://bioportal.bioontology.org/search?q=C1853118&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853118</a>]</span><br /> -
|
|
Low to low-normal platelet count <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275345&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275345</a>]</span><br /> -
|
|
Normal mean platelet volume (MPV) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845990&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845990</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
|
<strong> IMMUNOLOGY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Increased activated CD8+ T cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1845988&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1845988</a>]</span><br /> -
|
|
Decreased CD4+/CD8+ ratio <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0853905&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0853905</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0033222" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0033222</a>]</span><br /> -
|
|
Recurrent major bacterial infections <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/428875002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">428875002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1844383&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1844383</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002718</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002718" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002718</a>]</span><br /> -
|
|
Decreased CD3(-)CD16/15(+) natural killer cells <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275343&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275343</a>]</span><br /> -
|
|
Low-normal IgA levels <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C3275344&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3275344</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
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</div>
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|
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</div>
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|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Allelic to Wiskott-Aldrich syndrome (<a href="/entry/301000">301000</a>) and X-linked thrombocytopenia (<a href="/entry/313900">313900</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 WASP actin nucleation promoting factor gene (WAS, <a href="/entry/300392#0012">300392.0012</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
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|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Neutropenia, severe congenital
|
|
- <a href="/phenotypicSeries/PS202700">PS202700</a>
|
|
- 13 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/1/446?start=-3&limit=10&highlight=446"> 1p34.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/617014"> Neutropenia, severe congenital, 7, autosomal recessive </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/617014"> 617014 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/138971"> CSF3R </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/138971"> 138971 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/802?start=-3&limit=10&highlight=802"> 1p22.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613107"> Neutropenia, severe congenital 2, autosomal dominant </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/613107"> 613107 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600871"> GFI1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600871"> 600871 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1059?start=-3&limit=10&highlight=1059"> 1q21.2 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/615285"> Neutropenia, severe congenital, 5, autosomal recessive </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/615285"> 615285 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610035"> VPS45 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610035"> 610035 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1187?start=-3&limit=10&highlight=1187"> 1q21.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/610738"> Neutropenia, severe congenital 3, autosomal recessive </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">
|
|
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<a href="/entry/619813"> Neutropenia, severe congenital, 9, autosomal dominant </a>
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<a href="/entry/618752"> Neutropenia, severe congenital, 8, autosomal dominant </a>
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<a href="/entry/612541"> Neutropenia, severe congenital 4, autosomal recessive </a>
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<a href="/entry/611045"> 611045 </a>
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<a href="/entry/620534"> ?Neutropenia, severe congenital, 10, autosomal recessive </a>
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<a href="/entry/202700"> Neutropenia, severe congenital 1, autosomal dominant </a>
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<a href="/entry/300299"> Neutropenia, severe congenital, X-linked </a>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>A number sign (#) is used with this entry because X-linked severe congenital neutropenia (SCNX) is caused by hemizygous mutation in the WAS gene (<a href="/entry/300392">300392</a>) on chromosome Xp11.</p><p>See also Wiskott-Aldrich syndrome (WAS; <a href="/entry/301000">301000</a>), an allelic disorder.</p><p>For a discussion of genetic heterogeneity of severe congenital neutropenia, see <a href="/entry/202700">202700</a>.</p>
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<p>In a 3-generation family of European descent, <a href="#4" class="mim-tip-reference" title="Devriendt, K., Kim, A. S., Mathijs, G., Frints, S. G. M., Schwartz, M., Van den Oord, J. J., Verhoef, G. E. G., Boogaerts, M. A., Fryns, J.-P., You, D., Rosen, M. K., Vandenberghe, P. <strong>Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia.</strong> Nature Genet. 27: 313-317, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242115</a>] [<a href="https://doi.org/10.1038/85886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242115">Devriendt et al. (2001)</a> described 5 males who presented with a novel X-linked immunodeficiency syndrome characterized by recurrent major bacterial infections, severe congenital neutropenia, and monocytopenia. Although X-linked inheritance and shifts in lymphocyte subsets were not known to be features of severe congenital neutropenia (<a href="/entry/202700">202700</a>), affected males in this pedigree had increased numbers of activated CD8+ T cells in the peripheral blood resulting in decreased CD4+/CD8+ ratios of 0.5 or less. Immunoglobulin levels and T-lymphocyte activation were normal. Platelets were not decreased, and there was no history of eczema in affected individuals. Bone marrow examination demonstrated a maturation arrest at the promyelocyte/myelocyte stage, without gross abnormalities in megakaryopoiesis or erythropoiesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients with severe congenital neutropenia who were negative for mutation in the ELA2 gene (ELANE; <a href="/entry/130130">130130</a>), <a href="#1" class="mim-tip-reference" title="Ancliff, P. J., Blundell, M. P., Cory, G. O., Calle, Y., Worth, A., Kempski, H., Burns, S., Jones, G. E., Sinclair, J., Kinnon, C., Hann, I. M., Gale, R. E., Linch, D. C., Thrasher, A. J. <strong>Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia.</strong> Blood 108: 2182-2189, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804117</a>] [<a href="https://doi.org/10.1182/blood-2006-01-010249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804117">Ancliff et al. (2006)</a> identified mutations in the WAS gene (see MOLECULAR GENETICS). One patient presented in early infancy as a typical case of SCN, with severe neutropenia, maturation arrest at the promyelocyte stage in the bone marrow, and recurrent bacterial infections. His hemoglobin was low normal, and platelet numbers were usually within the normal range, although large-sized platelets were present. He had no bone marrow dysplasia. Immunologic analysis revealed low CD3(-)CD16/56(+) natural killer (NK) cell numbers and impaired lymphocyte proliferation responses to CD3 stimulation. The other patient was of Zairian parentage and presented at 4 years of age with fever of unknown origin, at which time he was found to have severe neutropenia with a normal hemoglobin level and platelet count, but with platelet anisocytosis including large platelets. Over 3 years, his lymphocyte numbers were intermittently reduced, but reversal of the normal CD4(+)/CD8(+) ratio, reduced CD3(-)CD16/56(+) NK cell numbers, and impaired lymphocyte proliferative responses to CD3 stimulation were invariably present. Subsequent bone marrow examination revealed trilineage dysplasia including bizarre megakaryocytic nuclear morphology with both abnormal giant megakaryocytes and micromegakaryocytes, hypogranular and markedly reduced granulopoiesis, and an excess of blasts, consistent with primary myelodysplasia. <a href="#1" class="mim-tip-reference" title="Ancliff, P. J., Blundell, M. P., Cory, G. O., Calle, Y., Worth, A., Kempski, H., Burns, S., Jones, G. E., Sinclair, J., Kinnon, C., Hann, I. M., Gale, R. E., Linch, D. C., Thrasher, A. J. <strong>Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia.</strong> Blood 108: 2182-2189, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804117</a>] [<a href="https://doi.org/10.1182/blood-2006-01-010249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804117">Ancliff et al. (2006)</a> noted that later bone marrow examinations displayed a considerably less dysplastic morphology than that originally observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16804117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Beel, K., Cotter, M. M., Blatny, J., Bond, J., Lucus, G., Green, F., Vanduppen, V., Leung, D. W., Rooney, S., Smith, O. P., Rosen, M. K., Vandenberghe, P. <strong>A large kindred with X-linked neutropenia with an I294T mutation of the Wiskott-Aldrich syndrome gene.</strong> Brit. J. Haemat. 144: 120-126, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19006568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19006568</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19006568[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/10.1111/j.1365-2141.2008.07416.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19006568">Beel et al. (2008)</a> described a large 3-generation Irish kindred with X-linked severe congenital neutropenia, originally reported by <a href="#3" class="mim-tip-reference" title="Cryan, E. F., Deasy, P. F., Buckley, R. J., Greally, J. F. <strong>Congenital neutropenia and low serum immunoglobulin A: description and investigation of a large kindred.</strong> Thymus 11: 185-199, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3284030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3284030</a>]" pmid="3284030">Cryan et al. (1988)</a>, in which there were 10 affected males and 8 female carriers. Affected individuals showed considerable variation in infectious history, and the severity of neutropenia did not seem to correlate closely with susceptibility to infections. Five of the 10 affected males had monocytopenia. All had low or low-normal numbers of lymphocytes, with the most strikingly decreased subset being CD3(-)CD16/56(+) NK cells. Absolute B-lymphocyte counts were decreased in all 10 affected males. In contrast to previously studied SCNX patients, an inverted CD4/CD8 ratio was not a feature in this family. Platelet counts were low-normal or mildly reduced, with normal mean platelet volume. Female carriers showed intermediate findings, with low-normal neutrophil and platelet counts, and NK cell counts were higher than in affected males, but still below the normal range. The mean IgA level in affected adult males was significantly lower than in unaffected adult family members; <a href="#2" class="mim-tip-reference" title="Beel, K., Cotter, M. M., Blatny, J., Bond, J., Lucus, G., Green, F., Vanduppen, V., Leung, D. W., Rooney, S., Smith, O. P., Rosen, M. K., Vandenberghe, P. <strong>A large kindred with X-linked neutropenia with an I294T mutation of the Wiskott-Aldrich syndrome gene.</strong> Brit. J. Haemat. 144: 120-126, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19006568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19006568</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19006568[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/10.1111/j.1365-2141.2008.07416.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19006568">Beel et al. (2008)</a> stated that IgA levels were also decreased in 2 of the 3 patients studied by <a href="#4" class="mim-tip-reference" title="Devriendt, K., Kim, A. S., Mathijs, G., Frints, S. G. M., Schwartz, M., Van den Oord, J. J., Verhoef, G. E. G., Boogaerts, M. A., Fryns, J.-P., You, D., Rosen, M. K., Vandenberghe, P. <strong>Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia.</strong> Nature Genet. 27: 313-317, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242115</a>] [<a href="https://doi.org/10.1038/85886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242115">Devriendt et al. (2001)</a>, and suggested that low-normal IgA levels appear to be a feature of SCNX. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19006568+3284030+11242115" 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="#4" class="mim-tip-reference" title="Devriendt, K., Kim, A. S., Mathijs, G., Frints, S. G. M., Schwartz, M., Van den Oord, J. J., Verhoef, G. E. G., Boogaerts, M. A., Fryns, J.-P., You, D., Rosen, M. K., Vandenberghe, P. <strong>Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia.</strong> Nature Genet. 27: 313-317, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242115</a>] [<a href="https://doi.org/10.1038/85886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242115">Devriendt et al. (2001)</a> performed linkage studies with polymorphic markers spanning the entire X chromosome and markers spanning chromosome 19p13.3, the region containing the neutrophil elastase gene (ELANE; <a href="/entry/130130">130130</a>), which is mutant in many cases of severe congenital neutropenia (<a href="/entry/202700">202700</a>). No evidence for linkage with 19p13.3 was found; evidence pointing to linkage to the proximal Xp region containing the Wiskott-Aldrich syndrome locus was found. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242115" 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>Mutation analysis of the WAS gene by <a href="#4" class="mim-tip-reference" title="Devriendt, K., Kim, A. S., Mathijs, G., Frints, S. G. M., Schwartz, M., Van den Oord, J. J., Verhoef, G. E. G., Boogaerts, M. A., Fryns, J.-P., You, D., Rosen, M. K., Vandenberghe, P. <strong>Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia.</strong> Nature Genet. 27: 313-317, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242115</a>] [<a href="https://doi.org/10.1038/85886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242115">Devriendt et al. (2001)</a> revealed a missense mutation (L270P; <a href="/entry/300392#0012">300392.0012</a>) in all affected males and carrier females. Preferential inactivation of the X chromosome carrying the mutated WAS gene was found in some carriers, indicating that selection operates against the L270P allele in vivo. Noncarrier females had random X inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Ancliff, P. J., Blundell, M. P., Cory, G. O., Calle, Y., Worth, A., Kempski, H., Burns, S., Jones, G. E., Sinclair, J., Kinnon, C., Hann, I. M., Gale, R. E., Linch, D. C., Thrasher, A. J. <strong>Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia.</strong> Blood 108: 2182-2189, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804117</a>] [<a href="https://doi.org/10.1182/blood-2006-01-010249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804117">Ancliff et al. (2006)</a> analyzed the WAS gene in 14 boys with severe congenital neutropenia who were negative for mutation in the ELA2 gene, 8 with classic SCN and 6 with evidence of myelodysplasia and/or immunologic abnormalities in addition to neutropenia, and identified 2 different mutations in 2 probands (S272P, <a href="/entry/300392#0024">300392.0024</a>; I294T, <a href="/entry/300392#0025">300392.0025</a>, respectively). Both patients had defects of immunologic function including a generalized reduction of lymphoid and NK cell numbers, reduced lymphocyte proliferation, and abrogated phagocyte activity. In vitro culture of bone marrow progenitors demonstrated a profound reduction in neutrophil production and increased levels of apoptosis, consistent with an intrinsic disturbance of normal myeloid differentiation as the cause of their neutropenia. Female carriers from both families showed nonrandom X inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16804117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Beel, K., Cotter, M. M., Blatny, J., Bond, J., Lucus, G., Green, F., Vanduppen, V., Leung, D. W., Rooney, S., Smith, O. P., Rosen, M. K., Vandenberghe, P. <strong>A large kindred with X-linked neutropenia with an I294T mutation of the Wiskott-Aldrich syndrome gene.</strong> Brit. J. Haemat. 144: 120-126, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19006568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19006568</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19006568[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/10.1111/j.1365-2141.2008.07416.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19006568">Beel et al. (2008)</a> analyzed the WAS gene in 60 members of a large Irish kindred segregating X-linked congenital neutropenia, originally reported by <a href="#3" class="mim-tip-reference" title="Cryan, E. F., Deasy, P. F., Buckley, R. J., Greally, J. F. <strong>Congenital neutropenia and low serum immunoglobulin A: description and investigation of a large kindred.</strong> Thymus 11: 185-199, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3284030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3284030</a>]" pmid="3284030">Cryan et al. (1988)</a>, and identified the I294T mutation in 10 affected males and 8 female carriers. Four of 6 female carriers showed random X-chromosome inactivation, and 2 female carriers showed no consistent pattern of asymmetric X-chromosome inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19006568+3284030" 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="#4" class="mim-tip-reference" title="Devriendt, K., Kim, A. S., Mathijs, G., Frints, S. G. M., Schwartz, M., Van den Oord, J. J., Verhoef, G. E. G., Boogaerts, M. A., Fryns, J.-P., You, D., Rosen, M. K., Vandenberghe, P. <strong>Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia.</strong> Nature Genet. 27: 313-317, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242115</a>] [<a href="https://doi.org/10.1038/85886" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11242115">Devriendt et al. (2001)</a> showed that the L270P mutation is located in the region of the WAS gene encoding the conserved GTPase binding domain. In vitro, the mutant protein was constitutively activated through disruption of an autoinhibitory domain in the wildtype protein, indicating that loss of WAS autoinhibition is a key event in X-linked severe congenital neutropenia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Westerberg, L. S., Meelu, P., Baptista, M., Eston, M. A., Adamovich, D. A., Cotta-de-Almeida, V., Seed, B., Rosen, M. K., Vandenberghe, P., Thrasher, A. J., Klein, C., Alt, F. W., Snapper, S. B. <strong>Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes.</strong> J. Exp. Med. 207: 1145-1152, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513746</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20513746[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/10.1084/jem.20091245" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20513746">Westerberg et al. (2010)</a> created mice with mutations in the mouse Wasp gene corresponding to the human leu270-to-pro (L270P; <a href="/entry/300392#0012">300392.0012</a>) and ile294-to-thr (I294T; <a href="/entry/300392#0025">300392.0025</a>) mutations, which cause X-linked neutropenia. These mutations interfered with normal lymphocyte activation by inducing a marked increase in polymerized actin, decreased cell spreading, and increased apoptosis associated with increased genomic instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20513746" 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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Ancliff, P. J., Blundell, M. P., Cory, G. O., Calle, Y., Worth, A., Kempski, H., Burns, S., Jones, G. E., Sinclair, J., Kinnon, C., Hann, I. M., Gale, R. E., Linch, D. C., Thrasher, A. J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804117</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16804117" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<p class="mim-text-font">
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Beel, K., Cotter, M. M., Blatny, J., Bond, J., Lucus, G., Green, F., Vanduppen, V., Leung, D. W., Rooney, S., Smith, O. P., Rosen, M. K., Vandenberghe, P.
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<strong>A large kindred with X-linked neutropenia with an I294T mutation of the Wiskott-Aldrich syndrome gene.</strong>
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Brit. J. Haemat. 144: 120-126, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19006568/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19006568</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19006568[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=19006568" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2141.2008.07416.x" target="_blank">Full Text</a>]
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<a id="Cryan1988" class="mim-anchor"></a>
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<p class="mim-text-font">
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Cryan, E. F., Deasy, P. F., Buckley, R. J., Greally, J. F.
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<strong>Congenital neutropenia and low serum immunoglobulin A: description and investigation of a large kindred.</strong>
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Thymus 11: 185-199, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3284030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3284030</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3284030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Devriendt2001" class="mim-anchor"></a>
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<p class="mim-text-font">
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Devriendt, K., Kim, A. S., Mathijs, G., Frints, S. G. M., Schwartz, M., Van den Oord, J. J., Verhoef, G. E. G., Boogaerts, M. A., Fryns, J.-P., You, D., Rosen, M. K., Vandenberghe, P.
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<strong>Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia.</strong>
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Nature Genet. 27: 313-317, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11242115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11242115</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11242115" 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/10.1038/85886" target="_blank">Full Text</a>]
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<a id="Westerberg2010" class="mim-anchor"></a>
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Westerberg, L. S., Meelu, P., Baptista, M., Eston, M. A., Adamovich, D. A., Cotta-de-Almeida, V., Seed, B., Rosen, M. K., Vandenberghe, P., Thrasher, A. J., Klein, C., Alt, F. W., Snapper, S. B.
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<strong>Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes.</strong>
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J. Exp. Med. 207: 1145-1152, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20513746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20513746</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20513746[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=20513746" 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/10.1084/jem.20091245" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Paul J. Converse - updated : 11/9/2012
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<div class="row collapse" id="mimCollapseContributors">
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Marla J. F. O'Neill - updated : 5/20/2011<br>Cassandra L. Kniffin - reorganized : 5/13/2002
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 3/1/2001
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carol : 10/25/2016
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alopez : 09/22/2016<br>mgross : 11/19/2012<br>terry : 11/9/2012<br>carol : 6/23/2011<br>wwang : 6/8/2011<br>wwang : 6/7/2011<br>wwang : 6/7/2011<br>wwang : 5/25/2011<br>terry : 5/20/2011<br>carol : 5/13/2002<br>ckniffin : 5/10/2002<br>alopez : 3/1/2001
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<strong>#</strong> 300299
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NEUTROPENIA, SEVERE CONGENITAL, X-LINKED; SCNX
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XLN
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<strong>SNOMEDCT:</strong> 718882006;
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<strong>ORPHA:</strong> 86788;
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<strong>DO:</strong> 0112128;
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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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<span class="mim-font">
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Xp11.23
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<span class="mim-font">
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Neutropenia, severe congenital, X-linked
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300299
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<span class="mim-font">
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X-linked recessive
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<span class="mim-font">
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3
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WAS
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300392
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because X-linked severe congenital neutropenia (SCNX) is caused by hemizygous mutation in the WAS gene (300392) on chromosome Xp11.</p><p>See also Wiskott-Aldrich syndrome (WAS; 301000), an allelic disorder.</p><p>For a discussion of genetic heterogeneity of severe congenital neutropenia, see 202700.</p>
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<strong>Clinical Features</strong>
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<p>In a 3-generation family of European descent, Devriendt et al. (2001) described 5 males who presented with a novel X-linked immunodeficiency syndrome characterized by recurrent major bacterial infections, severe congenital neutropenia, and monocytopenia. Although X-linked inheritance and shifts in lymphocyte subsets were not known to be features of severe congenital neutropenia (202700), affected males in this pedigree had increased numbers of activated CD8+ T cells in the peripheral blood resulting in decreased CD4+/CD8+ ratios of 0.5 or less. Immunoglobulin levels and T-lymphocyte activation were normal. Platelets were not decreased, and there was no history of eczema in affected individuals. Bone marrow examination demonstrated a maturation arrest at the promyelocyte/myelocyte stage, without gross abnormalities in megakaryopoiesis or erythropoiesis. </p><p>In 2 patients with severe congenital neutropenia who were negative for mutation in the ELA2 gene (ELANE; 130130), Ancliff et al. (2006) identified mutations in the WAS gene (see MOLECULAR GENETICS). One patient presented in early infancy as a typical case of SCN, with severe neutropenia, maturation arrest at the promyelocyte stage in the bone marrow, and recurrent bacterial infections. His hemoglobin was low normal, and platelet numbers were usually within the normal range, although large-sized platelets were present. He had no bone marrow dysplasia. Immunologic analysis revealed low CD3(-)CD16/56(+) natural killer (NK) cell numbers and impaired lymphocyte proliferation responses to CD3 stimulation. The other patient was of Zairian parentage and presented at 4 years of age with fever of unknown origin, at which time he was found to have severe neutropenia with a normal hemoglobin level and platelet count, but with platelet anisocytosis including large platelets. Over 3 years, his lymphocyte numbers were intermittently reduced, but reversal of the normal CD4(+)/CD8(+) ratio, reduced CD3(-)CD16/56(+) NK cell numbers, and impaired lymphocyte proliferative responses to CD3 stimulation were invariably present. Subsequent bone marrow examination revealed trilineage dysplasia including bizarre megakaryocytic nuclear morphology with both abnormal giant megakaryocytes and micromegakaryocytes, hypogranular and markedly reduced granulopoiesis, and an excess of blasts, consistent with primary myelodysplasia. Ancliff et al. (2006) noted that later bone marrow examinations displayed a considerably less dysplastic morphology than that originally observed. </p><p>Beel et al. (2008) described a large 3-generation Irish kindred with X-linked severe congenital neutropenia, originally reported by Cryan et al. (1988), in which there were 10 affected males and 8 female carriers. Affected individuals showed considerable variation in infectious history, and the severity of neutropenia did not seem to correlate closely with susceptibility to infections. Five of the 10 affected males had monocytopenia. All had low or low-normal numbers of lymphocytes, with the most strikingly decreased subset being CD3(-)CD16/56(+) NK cells. Absolute B-lymphocyte counts were decreased in all 10 affected males. In contrast to previously studied SCNX patients, an inverted CD4/CD8 ratio was not a feature in this family. Platelet counts were low-normal or mildly reduced, with normal mean platelet volume. Female carriers showed intermediate findings, with low-normal neutrophil and platelet counts, and NK cell counts were higher than in affected males, but still below the normal range. The mean IgA level in affected adult males was significantly lower than in unaffected adult family members; Beel et al. (2008) stated that IgA levels were also decreased in 2 of the 3 patients studied by Devriendt et al. (2001), and suggested that low-normal IgA levels appear to be a feature of SCNX. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>Devriendt et al. (2001) performed linkage studies with polymorphic markers spanning the entire X chromosome and markers spanning chromosome 19p13.3, the region containing the neutrophil elastase gene (ELANE; 130130), which is mutant in many cases of severe congenital neutropenia (202700). No evidence for linkage with 19p13.3 was found; evidence pointing to linkage to the proximal Xp region containing the Wiskott-Aldrich syndrome locus was found. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>Mutation analysis of the WAS gene by Devriendt et al. (2001) revealed a missense mutation (L270P; 300392.0012) in all affected males and carrier females. Preferential inactivation of the X chromosome carrying the mutated WAS gene was found in some carriers, indicating that selection operates against the L270P allele in vivo. Noncarrier females had random X inactivation. </p><p>Ancliff et al. (2006) analyzed the WAS gene in 14 boys with severe congenital neutropenia who were negative for mutation in the ELA2 gene, 8 with classic SCN and 6 with evidence of myelodysplasia and/or immunologic abnormalities in addition to neutropenia, and identified 2 different mutations in 2 probands (S272P, 300392.0024; I294T, 300392.0025, respectively). Both patients had defects of immunologic function including a generalized reduction of lymphoid and NK cell numbers, reduced lymphocyte proliferation, and abrogated phagocyte activity. In vitro culture of bone marrow progenitors demonstrated a profound reduction in neutrophil production and increased levels of apoptosis, consistent with an intrinsic disturbance of normal myeloid differentiation as the cause of their neutropenia. Female carriers from both families showed nonrandom X inactivation. </p><p>Beel et al. (2008) analyzed the WAS gene in 60 members of a large Irish kindred segregating X-linked congenital neutropenia, originally reported by Cryan et al. (1988), and identified the I294T mutation in 10 affected males and 8 female carriers. Four of 6 female carriers showed random X-chromosome inactivation, and 2 female carriers showed no consistent pattern of asymmetric X-chromosome inactivation. </p>
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<p>Devriendt et al. (2001) showed that the L270P mutation is located in the region of the WAS gene encoding the conserved GTPase binding domain. In vitro, the mutant protein was constitutively activated through disruption of an autoinhibitory domain in the wildtype protein, indicating that loss of WAS autoinhibition is a key event in X-linked severe congenital neutropenia. </p>
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<strong>Animal Model</strong>
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<p>Westerberg et al. (2010) created mice with mutations in the mouse Wasp gene corresponding to the human leu270-to-pro (L270P; 300392.0012) and ile294-to-thr (I294T; 300392.0025) mutations, which cause X-linked neutropenia. These mutations interfered with normal lymphocyte activation by inducing a marked increase in polymerized actin, decreased cell spreading, and increased apoptosis associated with increased genomic instability. </p>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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Ancliff, P. J., Blundell, M. P., Cory, G. O., Calle, Y., Worth, A., Kempski, H., Burns, S., Jones, G. E., Sinclair, J., Kinnon, C., Hann, I. M., Gale, R. E., Linch, D. C., Thrasher, A. J.
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<strong>Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia.</strong>
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Blood 108: 2182-2189, 2006.
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[PubMed: 16804117]
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[Full Text: https://doi.org/10.1182/blood-2006-01-010249]
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Beel, K., Cotter, M. M., Blatny, J., Bond, J., Lucus, G., Green, F., Vanduppen, V., Leung, D. W., Rooney, S., Smith, O. P., Rosen, M. K., Vandenberghe, P.
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<strong>A large kindred with X-linked neutropenia with an I294T mutation of the Wiskott-Aldrich syndrome gene.</strong>
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Brit. J. Haemat. 144: 120-126, 2008.
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[PubMed: 19006568]
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[Full Text: https://doi.org/10.1111/j.1365-2141.2008.07416.x]
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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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Cryan, E. F., Deasy, P. F., Buckley, R. J., Greally, J. F.
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<strong>Congenital neutropenia and low serum immunoglobulin A: description and investigation of a large kindred.</strong>
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Thymus 11: 185-199, 1988.
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[PubMed: 3284030]
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</p>
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Devriendt, K., Kim, A. S., Mathijs, G., Frints, S. G. M., Schwartz, M., Van den Oord, J. J., Verhoef, G. E. G., Boogaerts, M. A., Fryns, J.-P., You, D., Rosen, M. K., Vandenberghe, P.
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<strong>Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia.</strong>
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Nature Genet. 27: 313-317, 2001.
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[PubMed: 11242115]
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[Full Text: https://doi.org/10.1038/85886]
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</p>
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<li>
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<p class="mim-text-font">
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Westerberg, L. S., Meelu, P., Baptista, M., Eston, M. A., Adamovich, D. A., Cotta-de-Almeida, V., Seed, B., Rosen, M. K., Vandenberghe, P., Thrasher, A. J., Klein, C., Alt, F. W., Snapper, S. B.
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<strong>Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes.</strong>
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J. Exp. Med. 207: 1145-1152, 2010.
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[PubMed: 20513746]
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[Full Text: https://doi.org/10.1084/jem.20091245]
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Paul J. Converse - updated : 11/9/2012<br>Marla J. F. O'Neill - updated : 5/20/2011<br>Cassandra L. Kniffin - reorganized : 5/13/2002
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