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- #190685 - DOWN SYNDROME
- OMIM
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<span class="h4">#190685</span>
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<strong>Table of Contents</strong>
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<li role="presentation">
<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
</li>
<li role="presentation">
<a href="/clinicalSynopsis/190685"><strong>Clinical Synopsis</strong></a>
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<li role="presentation">
<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
<a href="#description">Description</a>
</li>
<li role="presentation" style="margin-left: 1em">
<a href="#clinicalFeatures">Clinical Features</a>
</li>
<li role="presentation" style="margin-left: 1em">
<a href="#diagnosis">Diagnosis</a>
</li>
<li role="presentation" style="margin-left: 1em">
<a href="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#populationGenetics">Population Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#pathogenesis">Pathogenesis</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#otherFeatures">Other Features</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#history">History</a>
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<li role="presentation">
<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
<a href="#references"><strong>References</strong></a>
</li>
<li role="presentation">
<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
<div style="display: table-row">
<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">&#9660;</div>
&nbsp;
<div style="display: table-cell;">External Links</div>
</div>
</a>
</h4>
</div>
</div>
<div id="mimExternalLinksFold" class="collapse in">
<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
<span class="panel-title">
<span class="small">
<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9660;</div>
&nbsp;
<div style="display: table-cell;">Clinical Resources</div>
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</div>
<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
<div class="panel-body small mim-panel-body">
<div><a href="https://clinicaltrials.gov/search?cond=DOWN SYNDROME" 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>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=116&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>
<div><a href="https://www.diseaseinfosearch.org/x/2327" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
<div><a href="#mimMedlinePlusGeneticsFold" id="mimMedlinePlusGeneticsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Consumer-friendly information about the effects of genetic variation on human health."><span id="mimMedlinePlusGeneticsToggleTriangle" class="small" style="margin-left: -0.8em;">&#9658;</span>MedlinePlus Genetics</div>
<div id="mimMedlinePlusGeneticsFold" class="collapse">
<div style="margin-left: 0.5em;"><a href="https://medlineplus.gov/genetics/condition/down-syndrome" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">Down syndrome&nbsp;</a></div><div style="margin-left: 0.5em;"><a href="https://medlineplus.gov/genetics/gene/mtr" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MTR gene&nbsp;</a></div>
</div>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=190685[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=870" 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>
<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/eb635148-a8b8-4f57-a243-2527ad5ead13/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</a></div>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
<span class="panel-title">
<span class="small">
<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Animal Models</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://www.alliancegenome.org/disease/DOID:14250" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
<div><a href="http://www.informatics.jax.org/disease/190685" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
<div><a href="https://wormbase.org/resources/disease/DOID:14250" 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>
</div>
</div>
</div>
<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
<span class="panel-title">
<span class="small">
<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
<div style="display: table-row">
<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
&nbsp;
<div style="display: table-cell;">Cell Lines</div>
</div>
</a>
</span>
</span>
</div>
<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
<div class="panel-body small mim-panel-body">
<div><a href="https://catalog.coriell.org/Search?q=OmimNum:190685" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
</div>
</div>
</div>
</div>
</div>
</div>
<span>
<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
&nbsp;
</span>
</span>
</div>
<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>SNOMEDCT:</strong> 737542000<br />
<strong>ICD10CM:</strong> Q90, Q90.9<br />
<strong>ICD9CM:</strong> 758.0<br />
<strong>ORPHA:</strong> 870<br />
<strong>DO:</strong> 14250<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
190685
</span>
</span>
</div>
</div>
<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
DOWN SYNDROME
</span>
</h3>
</div>
<div>
<br />
</div>
<div>
<a id="alternativeTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
<em>Alternative titles; symbols</em>
</span>
</p>
</div>
<div>
<h4>
<span class="mim-font">
TRISOMY 21
</span>
</h4>
</div>
</div>
<div>
<br />
</div>
<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
</div>
<div>
<span class="h3 mim-font">
DOWN SYNDROME CHROMOSOME REGION, INCLUDED; DCR, INCLUDED
</span>
</div>
<div>
<span class="h4 mim-font">
DOWN SYNDROME CRITICAL REGION, INCLUDED; DSCR, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="cytogeneticLocation" class="mim-anchor"></a>
<p>
<span class="mim-text-font">
<strong>
<em>
Cytogenetic location: <a href="/geneMap/21/119?start=-3&limit=10&highlight=119">21q22.3</a>
&nbsp;
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr21:41200001-46709983&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">21:41,200,001-46,709,983</a> </span>
</em>
</strong>
</span>
</p>
</div>
<div>
<br />
</div>
<div>
<a id="geneMap" class="mim-anchor"></a>
<div style="margin-bottom: 10px;">
<span class="h4 mim-font">
<strong>Gene-Phenotype Relationships</strong>
</span>
</div>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
</tr>
</thead>
<tbody>
<tr>
<td rowspan="1">
<span class="mim-font">
<a href="/geneMap/21/119?start=-3&limit=10&highlight=119">
21q22.3
</a>
</span>
</td>
<td>
<span class="mim-font">
Down syndrome
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/190685"> 190685 </a>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="Isolated cases">IC</abbr>
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="4 - A contiguous gene duplication or deletion syndrome in which multiple genes are involved">4</abbr>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<div class="btn-group mim-changed mim-change">
<a href="/clinicalSynopsis/190685" class="btn btn-warning" role="button"> Clinical Synopsis </a>
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
<span class="caret"></span>
<span class="sr-only">Toggle Dropdown</span>
</button>
</div>
&nbsp;
<div>
<p />
</div>
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
<div class="small" style="margin: 5px">
<div>
<div>
<span class="h5 mim-font">
<strong> INHERITANCE </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Isolated cases <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853237&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853237</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003745" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003745</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003745" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003745</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/398241000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">398241000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/413769002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">413769002</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> GROWTH </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Height </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Short stature <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/422065006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">422065006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237836003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237836003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/237837007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">237837007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E34.31" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E34.31</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/R62.52" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">R62.52</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/783.43" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">783.43</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0349588&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0349588</a>, <a href="https://bioportal.bioontology.org/search?q=C0013336&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0013336</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003510" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003510</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004322" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004322</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEAD & NECK </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Head </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Brachycephaly <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13649004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13649004</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0221356&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221356</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000248" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000248</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000248" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000248</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=9ccc4d161e106e4d5543286323f007ce" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Brachycephaly-Large-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=9ccc4d161e106e4d5543286323f007ce&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Face </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Flat facial profile <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1853241&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1853241</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012368" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012368</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012368" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012368</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Ears </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Small ears <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/35045004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">35045004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q17.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q17.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/744.23" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">744.23</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0152423&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0152423</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008551" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008551</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0008551" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0008551</a>]</span><br /> -
Folded helix <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860792&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860792</a>]</span><br /> -
Conductive hearing loss <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/44057004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">44057004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H90.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H90.2</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/389.00" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.00</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/389.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">389.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018777&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018777</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000405" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000405</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000405" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000405</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Eyes </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Upslanting palpebral fissures <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/246799009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">246799009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0423109&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0423109</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000582" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000582</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000582" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000582</a>]</span><br /> -
Epicanthal folds <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/74824007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">74824007</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0678230&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0678230</a>, <a href="https://bioportal.bioontology.org/search?q=C0229249&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0229249</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000286" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000286</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000286" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000286</a>]</span><br /> -
Iris Brushfield spots <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/400960002" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">400960002</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1303007&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1303007</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001088" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001088</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001088" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001088</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Mouth </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Protruding tongue <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/249872000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">249872000</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/285503005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">285503005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0241442&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0241442</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010808" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010808</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0010808" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0010808</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=a5aa73dcc42adf91162715d89977ff62" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/Tongue,Protruding-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=a5aa73dcc42adf91162715d89977ff62&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> CARDIOVASCULAR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Heart </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Congenital heart defect <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/13213009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">13213009</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q24.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q24.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/746.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">746.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0018798&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0018798</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001627" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001627</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001627" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001627</a>]</span><br /> -
Atrioventricular canal <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/77469004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">77469004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/360481003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">360481003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/15459006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">15459006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q21.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q21.2</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q21.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q21.20</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/Q21.23" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q21.23</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/745.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">745.6</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/745.60" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">745.60</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0231081&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0231081</a>, <a href="https://bioportal.bioontology.org/search?q=C0221215&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0221215</a>, <a href="https://bioportal.bioontology.org/search?q=C0014116&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0014116</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001674" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001674</a>, <a href="https://hpo.jax.org/app/browse/term/HP:0006695" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006695</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ABDOMEN </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Gastrointestinal </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Duodenal stenosis/atresia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860791&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860791</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100867" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100867</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0100867" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0100867</a>]</span><br /> -
Imperforate anus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/204712000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">204712000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q42.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q42.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003466&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003466</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002023" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002023</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002023" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002023</a>]</span><br /> -
Hirschsprung disease <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/204739008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">204739008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/Q43.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">Q43.1</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0019569&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0019569</a>, <a href="https://bioportal.bioontology.org/search?q=C3888239&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C3888239</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002251</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002251" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002251</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKELETAL </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Spine </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Atlantoaxial instability <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/202820009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">202820009</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0410653&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0410653</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003467" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003467</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003467" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003467</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Pelvis </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Hypoplastic iliac wings <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1865027&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1865027</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002866" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002866</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002866" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002866</a>]</span><br /> -
Shallow acetabulum <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860796&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860796</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003182" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003182</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0003182" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0003182</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Limbs </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Joint laxity <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/298203008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">298203008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/788453008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">788453008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1862377&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1862377</a>, <a href="https://bioportal.bioontology.org/search?q=C0086437&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0086437</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001382" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001382</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001382" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001382</a>]</span><br />
</span>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<em> Hands </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Short, broad hands <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1849956&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1849956</a>]</span><br /> -
Fifth finger mid-phalanx hypoplasia <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1834060&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1834060</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004220" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004220</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0004220" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0004220</a>]</span><br /> -
Single transverse palmar crease <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248409006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248409006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424731&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424731</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000954" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000954</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000954" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000954</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=6933e8f04e93713c6c05a6e701badf6a" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/U5EUWeuZTbrrCpHgZPeZ3ZeG36uxxNme-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=6933e8f04e93713c6c05a6e701badf6a&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> SKIN, NAILS, & HAIR </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Skin </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
- Excess nuchal skin <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1836940&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1836940</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000474" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000474</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000474" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000474</a>]</span><br /> -
Single transverse palmar crease <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/248409006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">248409006</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0424731&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0424731</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000954" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000954</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000954" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000954</a>]</span> <a href="https://elementsofmorphology.nih.gov/index.cgi?tid=6933e8f04e93713c6c05a6e701badf6a" target="_blank" class="small mim-tip-eom" title="&lt;img src=&quot;https://elementsofmorphology.nih.gov/images/terms/U5EUWeuZTbrrCpHgZPeZ3ZeG36uxxNme-small.jpg&quot;&gt; &lt;br/&gt;Further Information: &lt;a href=&quot;https://elementsofmorphology.nih.gov/index.cgi?tid=6933e8f04e93713c6c05a6e701badf6a&quot target=&quot;_blank&quot onclick=&quot;gtag(\'event\', \'mim_outbound\', {\'name\': \'EOM\', \'domain\': \'elementsofmorphology.nih.gov\'})&quot;&gt;Elements of Morphology&lt;/a&gt;"><span class="glyphicon glyphicon-user" aria-hidden="true"></span></a><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEUROLOGIC </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<div>
<span class="h5 mim-font">
<em> Central Nervous System </em>
</span>
</div>
<div style="margin-left: 2em;">
<span class="mim-font">
<div class="mim-changed mim-change"> - Impaired intellectual development <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C4747273&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C4747273</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001249" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001249</a>]</span><br /></div>
- Alzheimer disease <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/26929004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">26929004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/G30.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G30.9</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/G30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">G30</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/331.0" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">331.0</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1364818&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1364818</a>, <a href="https://bioportal.bioontology.org/search?q=C0002395&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0002395</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002511" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002511</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0002511" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0002511</a>]</span><br />
- Hypotonia, poor Moro reflex <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860790&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860790</a>]</span><br />
</span>
</div>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> ENDOCRINE FEATURES </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Hypothyroidism <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/40930008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">40930008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/E03.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">E03.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/244.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">244.9</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0020676&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0020676</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000821" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000821</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000821" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000821</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> HEMATOLOGY </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Leukemoid reactions <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/56478004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">56478004</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/D72.823" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">D72.823</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/288.62" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">288.62</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023501&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023501</a>]</span><br />
</span>
</div>
</div>
</div>
<div>
<div>
<span class="h5 mim-font">
<strong> NEOPLASIA </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Leukemia (both ALL and AML) <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1860794&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1860794</a>]</span> <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/93143009" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">93143009</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/1162768007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">1162768007</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/C95" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C95</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/C95.90" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C95.90</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/C95.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C95.9</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/208.9" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">208.9</a>, <a href="https://purl.bioontology.org/ontology/ICD9CM/208" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">208</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001909" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001909</a>]</span><br /> -
Acute megakaryocytic leukemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/52220008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">52220008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/277602003" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">277602003</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/188754005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">188754005</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/C94.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C94.2</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/C94.20" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C94.20</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/207.2" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">207.2</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0023462&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0023462</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006733" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006733</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0006733" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0006733</a>]</span><br />
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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">
- Meiotic origin >95% maternal, mostly meiosis I<br /> -
Increased recurrence risk with parental translocation<br /> -
Incidence, 1 in 650-1000 live births<br />
</span>
</div>
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</div>
<div>
<div>
<span class="h5 mim-font">
<strong> MOLECULAR BASIS </strong>
</span>
</div>
<div style="margin-left: 2em;">
<div>
<span class="mim-font">
- Full trisomy 21, 94%<br /> -
Mosaic trisomy 21, 2.4%<br /> -
Translocation 21, 3.3%<br />
</span>
</div>
</div>
</div>
<div class="text-right">
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">&#9650;&nbsp;Close</a>
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<div class="mim-changed mim-change"><p>A number sign (#) is used with this entry because Down syndrome is caused by a chromosomal aberration, trisomy 21, and many genes are involved in the phenotype.</p></div>
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<a id="description" class="mim-anchor"></a>
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<div class="mim-changed mim-change"><p>Down syndrome, the most frequent form of impaired intellectual development caused by a microscopically demonstrable chromosomal aberration, is characterized by well-defined and distinctive phenotypic features and natural history. It is caused by triplicate state (trisomy) of all or a critical portion of chromosome 21.</p></div>
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<strong>Clinical Features</strong>
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<div class="mim-changed mim-change"><p>Down syndrome (<a href="#20" class="mim-tip-reference" title="Down, J. L. H. &lt;strong&gt;Observations on an ethnic classification of idiots.&lt;/strong&gt; London Hosp. Clin. Lect. Rep. 3: 259 only, 1866."None>Down, 1866</a>), a particular combination of phenotypic features that includes impaired intellectual development and characteristic facies, is caused by trisomy 21 (<a href="#42" class="mim-tip-reference" title="Lejeune, J., Gautier, M., Turpin, R. &lt;strong&gt;Etude des chromosomes somatiques de neuf enfants mongoliens.&lt;/strong&gt; C. R. Acad. Sci. 248: 1721-1722, 1959.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/13639368/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;13639368&lt;/a&gt;]" pmid="13639368">Lejeune et al., 1959</a>), one of the most common chromosomal abnormalities in liveborn children. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=13639368" 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></div>
<p>It has long been recognized that the risk of having a child with trisomy 21 increases with maternal age (<a href="#64" class="mim-tip-reference" title="Penrose, L. S. &lt;strong&gt;The relative effects of paternal and maternal age in mongolism.&lt;/strong&gt; J. Genet. 27: 219 only, 1933. Note: Classic Article. J. Genet. 88: 9-14, 2009."None>Penrose, 1933</a>). For example, the risk of having a liveborn with Down syndrome at maternal age 30 is 1 in 1,000 and at maternal age 40 is 9 in 1,000 (<a href="#36" class="mim-tip-reference" title="Hook, E. G. &lt;strong&gt;Epidemiology of Down syndrome. In: Pueschel, S. M.; Rynders, J. E. (eds.): Down Syndrome. Advances in Biomedicine and the Behavioral Sciences.&lt;/strong&gt; Cambridge: Ware Press (pub.) 1982. P. 11 only."None>Hook, 1982</a>; <a href="#35" class="mim-tip-reference" title="Hook, E. B., Cross, P. K., Schreinemachers, D. M. &lt;strong&gt;Chromosomal abnormality rates at amniocentesis and in live-born infants.&lt;/strong&gt; JAMA 249: 2034-2038, 1983.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6220164/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6220164&lt;/a&gt;]" pmid="6220164">Hook et al., 1983</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6220164" 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>Individuals with Down syndrome often have specific major congenital malformations such as those of the heart (30-40% in some studies), particularly atrioventricular septal defect (AVSD), and of the gastrointestinal tract, such as duodenal stenosis or atresia, imperforate anus, and Hirschsprung disease (<a href="/entry/142623">142623</a>). Some of these clinical features have been incorporated into the preliminary phenotypic maps of chromosome 21 developed by <a href="#41" class="mim-tip-reference" title="Korenberg, J. R. &lt;strong&gt;Toward a molecular understanding of Down syndrome.&lt;/strong&gt; Prog. Clin. Biol. Res. 384: 87-115, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8115409/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8115409&lt;/a&gt;]" pmid="8115409">Korenberg (1993)</a>, <a href="#38" class="mim-tip-reference" title="Korenberg, J., Bradley, C., Disteche, C. &lt;strong&gt;Down syndrome: molecular mapping of congenital heart disease and duodenal stenosis.&lt;/strong&gt; Am. J. Hum. Genet. 50: 294-302, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1531166/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1531166&lt;/a&gt;]" pmid="1531166">Korenberg et al. (1992)</a>, and <a href="#19" class="mim-tip-reference" title="Delabar, J. M., Theophile, D., Rahmani, Z., Chettouh, Z., Blouin, J. L., Prieur, M., Noel, B., Sinet, P. M. &lt;strong&gt;Molecular mapping of twenty-four features of Down syndrome on chromosome 21.&lt;/strong&gt; Europ. J. Hum. Genet. 1: 114-124, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8055322/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8055322&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000472398&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8055322">Delabar et al. (1993)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1531166+8055322+8115409" 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>Leukemia (both ALL and AML) and leukemoid reactions show increased incidence in Down syndrome (<a href="#24" class="mim-tip-reference" title="Fong, C.-T., Brodeur, G. M. &lt;strong&gt;Down&#x27;s syndrome and leukemia: epidemiology, genetics, cytogenetics and mechanisms of leukemogenesis.&lt;/strong&gt; Cancer Genet. Cytogenet. 28: 55-76, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2955886/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2955886&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0165-4608(87)90354-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2955886">Fong and Brodeur, 1987</a>; <a href="#73" class="mim-tip-reference" title="Robison, L. L. &lt;strong&gt;Down syndrome and leukemia.&lt;/strong&gt; Leukemia 6 (Suppl. 1): 5-7, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1532221/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1532221&lt;/a&gt;]" pmid="1532221">Robison, 1992</a>). Estimates of the relative risk have ranged from 10 to 20 times higher than the normal population; in particular, acute megakaryocytic leukemia occurs 200 to 400 times more frequently in the Down syndrome than in the chromosomally normal population (<a href="#98" class="mim-tip-reference" title="Zipursky, A., Peeters, M., Poon, A. &lt;strong&gt;Megakaryoblastic leukemia and Down syndrome--A review. In: McCoy, E. E.; Epstein, C. J. (eds.): Oncology and Immunology of Down Syndrome.&lt;/strong&gt; New York: Alan R. Liss (pub.) 1987. Pp. 33-56."None>Zipursky et al., 1987</a>). Transient leukemoid reactions have been reported repeatedly in the neonatal period (<a href="#60" class="mim-tip-reference" title="Niikawa, N., Deng, H. X., Abe, K., Harada, N., Okada, T., Tsuchiya, H., Akaboshi, I., Matsuda, I., Fukushima, Y., Kaneko, Y. &lt;strong&gt;Possible mapping of the gene for transient myeloproliferative syndrome at 21q11.2.&lt;/strong&gt; Hum. Genet. 87: 561-566, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1680787/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1680787&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00209012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1680787">Niikawa et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1680787+2955886+1532221" 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>Ninety percent of all Down syndrome patients have a significant hearing loss, usually of the conductive type (<a href="#50" class="mim-tip-reference" title="Mazzoni, D. S., Ackley, R. S., Nash, D. J. &lt;strong&gt;Abnormal pinna type and hearing loss correlations in Down&#x27;s syndrome.&lt;/strong&gt; J. Intellect. Disabil. Res. 38: 549-560, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7881226/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7881226&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1365-2788.1994.tb00456.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7881226">Mazzoni et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7881226" 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>For additional defects and phenotypic characteristics, see <a href="#23" class="mim-tip-reference" title="Epstein, C. J. &lt;strong&gt;Down syndrome, trisomy 21. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): Metabolic Basis of Inherited Disease.&lt;/strong&gt; New York: McGraw-Hill (pub.) 1989. Pp. 291-326."None>Epstein (1989)</a>.</p>
<p>Patients with Down syndrome develop the neuropathologic hallmarks of Alzheimer disease at a much earlier age than individuals with Alzheimer disease without trisomy 21 (<a href="#94" class="mim-tip-reference" title="Wisniewski, K. E., Wisniewski, H. M., Wen, G. Y. &lt;strong&gt;Occurrence of neuropathological changes and dementia of Alzheimer&#x27;s disease in Down&#x27;s syndrome.&lt;/strong&gt; Ann. Neurol. 17: 278-282, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3158266/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3158266&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410170310&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3158266">Wisniewski et al., 1985</a>). Characteristic senile plaques and neurofibrillary tangles are present in the brain of all individuals with Down syndrome over the age of 40 years (<a href="#94" class="mim-tip-reference" title="Wisniewski, K. E., Wisniewski, H. M., Wen, G. Y. &lt;strong&gt;Occurrence of neuropathological changes and dementia of Alzheimer&#x27;s disease in Down&#x27;s syndrome.&lt;/strong&gt; Ann. Neurol. 17: 278-282, 1985.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/3158266/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;3158266&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ana.410170310&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="3158266">Wisniewski et al., 1985</a>). The triplication of the amyloid precursor protein gene (APP; <a href="/entry/104760">104760</a>) may be the cause of this phenomenon. Several mutations in the APP gene have been described in families with early-onset Alzheimer disease without trisomy 21 (e.g., <a href="#29" class="mim-tip-reference" title="Goate, A., Chartier-Harlin, M. C., Mullan, M., Brown, J., Crawford, F., Fidayi, L., Giuffra, L., Haynes, A., Irvine, N., James, L., Mant, R., Newton, P., Rooke, K., Roques, P., Talbot, C., Pericak-Vance, M., Roses, A., Williamson, R., Rorsov, M., Owen, M., Hardy, J. &lt;strong&gt;Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer disease.&lt;/strong&gt; Nature 349: 704-706, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1671712/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1671712&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/349704a0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1671712">Goate et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3158266+1671712" 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="#16" class="mim-tip-reference" title="Castilla, E. E., Lugarinho, R., de Garcia Dutra, M., Salgado, L. J. &lt;strong&gt;Associated anomalies in individuals with polydactyly.&lt;/strong&gt; Am. J. Med. Genet. 80: 459-465, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9880209/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9880209&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/(sici)1096-8628(19981228)80:5&lt;459::aid-ajmg5&gt;3.0.co;2-g&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9880209">Castilla et al. (1998)</a> performed an epidemiologic analysis of the association of polydactyly with other congenital anomalies in 5,927 consecutively born polydactyly cases. Trisomy 13, Meckel syndrome (<a href="/entry/249000">249000</a>), and Down syndrome explained 255 of the 338 syndromic polydactyly cases. Down syndrome was strongly associated with first-digit duplication, and negatively associated with postaxial polydactyly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9880209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<p>In a retrospective study of high-altitude pulmonary edema performed at Children's Hospital in Denver, <a href="#21" class="mim-tip-reference" title="Durmowicz, A. G. &lt;strong&gt;Pulmonary edema in 6 children with Down syndrome during travel to moderate altitudes.&lt;/strong&gt; Pediatrics 108: 443-447, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11483813/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11483813&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1542/peds.108.2.443&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11483813">Durmowicz (2001)</a> identified 6 of 52 patients as having Down syndrome. Five of the 6 children had preexisting illnesses including chronic pulmonary hypertension, existing cardiac defects with left-to-right shunt, or previous defects of left-to-right shunt that had been repaired. One child had Eisenmenger syndrome. <a href="#21" class="mim-tip-reference" title="Durmowicz, A. G. &lt;strong&gt;Pulmonary edema in 6 children with Down syndrome during travel to moderate altitudes.&lt;/strong&gt; Pediatrics 108: 443-447, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11483813/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11483813&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1542/peds.108.2.443&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11483813">Durmowicz (2001)</a> suggested caution in traveling to even moderate altitudes with children with Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11483813" 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>To determine whether newborns with DS have decreased blood T4 (thyroxine; tetraiodothyronine) concentrations at the time of the neonatal screening, <a href="#87" class="mim-tip-reference" title="van Trotsenburg, A. S. P., Vulsma, T., van Santen, H. M., Cheung, W., de Vijlder, J. J. M. &lt;strong&gt;Lower neonatal screening thyroxine concentrations in Down syndrome newborns.&lt;/strong&gt; J. Clin. Endocr. Metab. 88: 1512-1515, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12679431/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12679431&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1210/jc.2002-021303&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12679431">van Trotsenburg et al. (2003)</a> conducted an observational study in a large and representative cohort of Dutch children with DS born in 1996 and 1997. Results of congenital hypothyroidism (CH) screening measuring T4, TSH (see <a href="/entry/188540">188540</a>), and T4-binding globulin (<a href="/entry/314200">314200</a>) concentrations were analyzed in comparison with clinical information obtained by interviewing the parents and data from the general newborn population and a large control group. The mean T4 concentration of the 284 studied children with DS was significantly decreased. The individual T4 concentrations were normally (Gaussian) distributed but shifted to lower concentrations. Mean TSH and T4-binding globulin concentrations were significantly increased and normal, respectively. The decreased T4 concentration, left-shifted normal distribution, and mildly elevated TSH concentrations pointed to a mild hypothyroid state in newborns with DS and supported the existence of a DS-specific thyroid (regulation) disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12679431" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<p>In a case-control study, <a href="#86" class="mim-tip-reference" title="Tyler, C. V., Jr., Zyzanski, S. J., Runser, L. &lt;strong&gt;Increased risk of symptomatic gallbladder disease in adults with Down syndrome.&lt;/strong&gt; Am. J. Med. Genet. 130A: 351-353, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15386474/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15386474&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30243&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15386474">Tyler et al. (2004)</a> found that the rate of symptomatic gallbladder disease was 25% among 28 index cases of adults with Down syndrome compared to 4.5% among sex-matched controls (p = 0.002). The adjusted relative risk for gallbladder disease among individuals with Down syndrome was 3.52. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15386474" 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="#33" class="mim-tip-reference" title="Henry, E., Walker, D., Wiedmeier, S. E., Christensen, R. D. &lt;strong&gt;Hematological abnormalities during the first week of life among neonates with Down syndrome: data from a multihospital healthcare system.&lt;/strong&gt; Am. J. Med. Genet. 143A: 42-50, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17163522/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17163522&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31442&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17163522">Henry et al. (2007)</a> examined complete blood counts obtained in the first week of life from 158 consecutive neonates with Down syndrome and found that neutrophilia, thrombocytopenia, and polycythemia were the most common hematologic abnormalities, occurring in 80%, 66%, and 33% of patients, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17163522" 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>Survival</em></strong>
</p>
<p><a href="#97" class="mim-tip-reference" title="Zhu, J. L., Hasle, H., Correa, A., Schendel, D., Friedman, J. M., Olsen, J., Rasmussen, S. A. &lt;strong&gt;Survival among people with Down syndrome: a nationwide population-based study in Denmark.&lt;/strong&gt; Genet. Med. 15: 64-69, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22878506/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22878506&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/gim.2012.93&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22878506">Zhu et al. (2013)</a> studied survival among individuals with Down syndrome from the Danish population using a national cohort of 3,530 persons with Down syndrome identified from the Danish Cytogenetic Register and a reference cohort of persons without Down syndrome randomly selected from the general population followed from 1 April 1968 to 15 January 2009 by linkages to the Register of Causes of Death and the Civil Registration System. Overall, persons with Down syndrome had higher mortality than the reference cohort but to a lesser degree for persons with mosaic trisomy 21 than for persons with standard trisomy 21 or with Robertsonian translocations (hazard ratio 4.98 (95% CI 3.52-7.08), 8.94 (8.32-9.60) and 10.23 (7.50-13.97), respectively). Among persons with Down syndrome born after April 1968, more recent birth cohorts had lower mortality rates than older birth cohorts, which was largely due to declining mortality among persons with Down syndrome who also had congenital heart defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22878506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="diagnosis" class="mim-anchor"></a>
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<strong>Diagnosis</strong>
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<p>During the second trimester of pregnancy, serum alpha-feto protein (AFP; <a href="/entry/104150">104150</a>) is commonly used for evaluating the risk of Down syndrome. Decreased levels of AFP are indicative of Down syndrome. However, <a href="#67" class="mim-tip-reference" title="Petit, F. M., Hebert, M., Picone, O., Brisset, S., Maurin, M.-L., Parisot, F., Capel, L., Benattar, C., Senat, M.-V., Tachdjian, G., Labrune, P. &lt;strong&gt;A new mutation in the AFP gene responsible for a total absence of alpha feto-protein on second trimester maternal serum screening for Down syndrome.&lt;/strong&gt; Europ. J. Hum. Genet. 17: 387-390, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18854864/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18854864&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ejhg.2008.186&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18854864">Petit et al. (2009)</a> noted that a congenital deficiency of AFP may result in decreased AFP in the maternal serum and amniotic fluid. They reported a male fetus with congenital absence of AFP, due to a truncating mutation (<a href="/entry/104150#0003">104150.0003</a>), who showed normal growth and development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18854864" 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="#85" class="mim-tip-reference" title="Tsui, N. B. Y., Akolekar, R., Chiu, R. W. K., Chow, K. C. K., Leung, T. Y., Lau, T. K., Nicolaides, K. H., Lo, Y. M. D. &lt;strong&gt;Synergy of total PLAC4 RNA concentration and measurement of the RNA single-nucleotide polymorphism allelic ratio for the noninvasive prenatal detection of trisomy 21.&lt;/strong&gt; Clin. Chem. 56: 73-81, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19892844/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19892844&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1373/clinchem.2009.132662&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19892844">Tsui et al. (2010)</a> showed that analysis of PLAC4 (<a href="/entry/613770">613770</a>) can aid in the noninvasive prenatal detection of trisomy 21 using maternal plasma samples. PLAC4 is transcribed from chromosome 21 in the placenta and is specific for the fetus in maternal plasma. One analytic method, termed the RNA-SNP approach, measures the ratio of alleles for a SNP in placenta-derived mRNA molecules in maternal plasma. The RNA-SNP approach detected the deviated RNA-SNP allelic ratio in PLAC4 mRNA caused by an imbalance in chromosome 21 dosage. In a study of 153 pregnant women, the diagnostic sensitivity and specificity using this method was 100% and 89.7%, respectively. In fetuses homozygous for the SNP, a second analytic approach was used, which quantifies circulating PLAC4 mRNA concentrations. Trisomy 21 pregnancies showed significantly increased plasma PLAC mRNA compared to unaffected pregnancies. The sensitivity and specificity of this method were 91.7% and 81.0% using real-time PCR, and 83.3% and 83.5% using digital PCR. The overall findings suggested that the synergistic use of these 2 methods will increase the yield of correct diagnosis of trisomy 21 using noninvasive methods. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19892844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="cytogenetics" class="mim-anchor"></a>
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<strong>Cytogenetics</strong>
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<p>Most individuals (95%) with trisomy 21 have 3 free copies of chromosome 21; in about 5% of patients, 1 copy is translocated to another acrocentric chromosome, most often chromosome 14 or 21 (<a href="#84" class="mim-tip-reference" title="Thuline, H. C., Pueschel, S. M. &lt;strong&gt;Cytogenetics in Down syndrome. In: Pueschel, S. M.; Rynders, J. E.: Down Syndrome. Advances in Biomedicine and the Behavioral Sciences.&lt;/strong&gt; Cambridge: Ware Press (pub.) 1982. P. 133."None>Thuline and Pueschel, 1982</a>; <a href="#36" class="mim-tip-reference" title="Hook, E. G. &lt;strong&gt;Epidemiology of Down syndrome. In: Pueschel, S. M.; Rynders, J. E. (eds.): Down Syndrome. Advances in Biomedicine and the Behavioral Sciences.&lt;/strong&gt; Cambridge: Ware Press (pub.) 1982. P. 11 only."None>Hook, 1982</a>). In 2 to 4% of cases with free trisomy 21 there is recognizable mosaicism for a trisomic and a normal cell line (<a href="#52" class="mim-tip-reference" title="Mikkelsen, M. &lt;strong&gt;Down&#x27;s syndrome cytogenetic epidemiology.&lt;/strong&gt; Hereditas 86: 45-59, 1977.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/143464/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;143464&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1601-5223.1977.tb01211.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="143464">Mikkelsen, 1977</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=143464" 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>Origin of Free Trisomy 21</em></strong></p><p>
The availability of highly informative DNA markers has allowed the parental origin of the extra chromosome 21 and the meiotic/mitotic origin to be determined. More than 400 families have been studied (Antonarakis et al. (<a href="#6" class="mim-tip-reference" title="Antonarakis, S. E., Lewis, J. G., Adelsberger, P. A., Petersen, M. B., Schinzel, A. A., Binkert, F., Schmid, W., Pangalos, C., Raoul, O., Chakravarti, A., Hafez, M., Cohen, M. M., Roulston, D., Schwartz, S., Mikkelsen, M., Tranebjaerg, L., Greenberg, F., Hoar, D. I., Rudd, N. L., Warren, A. C., Metaxotou, C., Bartsocas, C., Down Syndrome Collaborative Group. &lt;strong&gt;Parental origin of the extra chromosome in trisomy 21 using DNA polymorphism analysis.&lt;/strong&gt; New Eng. J. Med. 324: 872-876, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1825697/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1825697&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199103283241302&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1825697">1991</a>, <a href="#7" class="mim-tip-reference" title="Antonarakis, S. E., Petersen, M. B., McInnis, M. G., Adelsberger, P. A., Schinzel, A. A., Binkert, F., Pangalos, C., Raoul, O., Slaugenhaupt, S. A., Hafez, M., Cohen, M. M., Roulson, D., Schwartz, S., Mikkelsen, M., Tranebjaerg, L., Greenberg, F., Hoar, D. I., Rudd, N. L., Warren, A. C., Metaxotou, C., Bartsocas, C., Chakravarti, A. &lt;strong&gt;The meiotic stage of nondisjunction in trisomy 21: determination using DNA polymorphisms.&lt;/strong&gt; Am. J. Hum. Genet. 50: 544-550, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1347192/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1347192&lt;/a&gt;]" pmid="1347192">1992</a>); <a href="#8" class="mim-tip-reference" title="Antonarakis, S. E. &lt;strong&gt;Human chromosome 21: genome mapping and exploration circa 1993.&lt;/strong&gt; Trends Genet. 9: 142-148, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8516850/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8516850&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0168-9525(93)90210-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8516850">Antonarakis, 1993</a>; Sherman et al. (<a href="#79" class="mim-tip-reference" title="Sherman, S. L., Takaesu, N., Freeman, S. B., Grantham, M., Phillips, C., Blackston, R. D., Jacobs, P. A., Cockwell, A. E. &lt;strong&gt;Association between reduced recombination and nondisjunction.&lt;/strong&gt; Am. J. Hum. Genet. 49: 608-620, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1831960/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1831960&lt;/a&gt;]" pmid="1831960">1991</a>, <a href="#78" class="mim-tip-reference" title="Sherman, S. L., Freeman, S. B., Grantham, M., Peters, J., Jacobs, P. A., Kurnit, D. M., Uchida, I., Petersen, M. B., Mikkelsen, M., Hassold, T. J. &lt;strong&gt;Non-disjunction of trisomy 21: comparison of centromere maps resulting from maternal meiosis I and II non-disjunction. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 51 (suppl.): A24 only, 1992."None>1992</a>)) and the results are as follows: (1) Errors in meiosis that lead to trisomy 21 are overwhelmingly of maternal origin; only about 5% occur during spermatogenesis. (2) Most errors in maternal meiosis occur in meiosis I and the mean maternal age associated with these is 32 years (the mean maternal age of the general population is approximately 27 years). Thus, meiosis I errors account for 76 to 80% of maternal meiotic errors and 67 to 73% of all instances of free trisomy 21. (3) Maternal meiosis II errors constitute 20 to 24% of maternal errors and 18 to 20% of all cases of free trisomy 21. The mean maternal age is also advanced and is 31.4 in one study and 34.1 in another. (4) In rare families in which there is paternal nondisjunction, most of the errors occur in meiosis II. The mean maternal and paternal ages are similar to the mean reproductive age in western societies. (5) In 5% of trisomic individuals the supernumerary chromosome 21 appears to result from an error in mitosis. In these cases there is no advanced maternal age and there is no preference for which chromosome 21 is duplicated in the mitotic error. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1347192+1825697+8516850+1831960" 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="#91" class="mim-tip-reference" title="Warren, A. C., Chakravarti, A., Wong, C., Slaugenhaupt, S. A., Halloran, S. L., Watkins, P. C., Metaxotou, C., Antonarakis, S. E. &lt;strong&gt;Evidence for reduced recombination on the nondisjoined chromosomes 21 in Down syndrome.&lt;/strong&gt; Science 237: 652-654, 1987.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2955519/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2955519&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.2955519&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2955519">Warren et al. (1987)</a> and <a href="#79" class="mim-tip-reference" title="Sherman, S. L., Takaesu, N., Freeman, S. B., Grantham, M., Phillips, C., Blackston, R. D., Jacobs, P. A., Cockwell, A. E. &lt;strong&gt;Association between reduced recombination and nondisjunction.&lt;/strong&gt; Am. J. Hum. Genet. 49: 608-620, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1831960/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1831960&lt;/a&gt;]" pmid="1831960">Sherman et al. (1991)</a> have described an association between trisomy 21 and reduced recombination in meioses. A significant proportion (at least 30%) of maternal meiosis I nondisjunctions of chromosome 21 is associated with failure to recombine. It is not known whether the paucity of recombination is related to maternal age; moreover, the mechanism of recombination failure (asynapsis vs abnormalities during or after synapsis) is as yet unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1831960+2955519" 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>There is a well-established association between altered recombination patterns and nondisjunction of human chromosomes. <a href="#13" class="mim-tip-reference" title="Brown, A. S., Feingold, E., Broman, K. W., Sherman, S. L. &lt;strong&gt;Genome-wide variation in recombination in female meiosis: a risk factor for non-disjunction of chromosome 21.&lt;/strong&gt; Hum. Molec. Genet. 9: 515-523, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10699174/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10699174&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/9.4.515&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10699174">Brown et al. (2000)</a> investigated the possibility of reduced recombination in the total genome of an egg with a nondisjoined chromosome 21 and no detectable recombination. By genotyping 15 patients (at 366 autosomal markers) with trisomy 21, as well as their parents and maternal grandparents, the authors found a statistically significant genomewide reduction (p less than 0.05) in the mean recombination rate in these eggs with nondisjoined chromosomes 21. This reduction was felt to be consistent with normal variation in recombination observed among eggs. The authors hypothesized that when the number of genomewide recombination events is less than some threshold, specific chromosomes may be at an increased risk for nondisjunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10699174" 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>Origin of Translocation Trisomy 21</em></strong></p><p>
All de novo t(14;21) trisomies studied have originated in maternal germ cells (<a href="#66" class="mim-tip-reference" title="Petersen, M. B., Adelsberger, P. A., Schinzel, A. A., Binkert, F., Hinkel, G. K., Antonarakis, S. E. &lt;strong&gt;Down syndrome due to de novo Robertsonian translocation t14;21: DNA polymorphism analysis suggests that the origin of the extra 21q is maternal.&lt;/strong&gt; Am. J. Hum. Genet. 49: 529-536, 1991.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1831959/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1831959&lt;/a&gt;]" pmid="1831959">Petersen et al., 1991</a>; <a href="#77" class="mim-tip-reference" title="Shaffer, L. G., Jackson-Cook, C. K., Stasiowski, B. A., Spence, J. E., Brown, J. A. &lt;strong&gt;Parental origin determination in 30 de novo Robertsonian translocations.&lt;/strong&gt; Am. J. Med. Genet. 43: 957-963, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1357969/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1357969&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320430611&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1357969">Shaffer et al., 1992</a>). The mean maternal age was 29.2 years. In de novo t(21;21) Down syndrome the situation is different (<a href="#30" class="mim-tip-reference" title="Grasso, M., Giovannucci Uzielli, M. L., Pierluigi, M., Tavellini, F., Perroni, L., Dagna-Bricarelli, F. &lt;strong&gt;Isochromosome, not translocation in trisomy 21q21q.&lt;/strong&gt; Hum. Genet. 84: 63-65, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2532615/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2532615&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/BF00210673&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2532615">Grasso et al., 1989</a>; <a href="#5" class="mim-tip-reference" title="Antonarakis, S. E., Adelsberger, P. A., Petersen, M. B., Binkert, F., Schinzel, A. A. &lt;strong&gt;Analysis of DNA polymorphism suggests that most de novo dup(21q) chromosomes in patients with Down syndrome are isochromosomes and not translocations.&lt;/strong&gt; Am. J. Hum. Genet. 47: 968-972, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1978562/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1978562&lt;/a&gt;]" pmid="1978562">Antonarakis et al., 1990</a>; <a href="#77" class="mim-tip-reference" title="Shaffer, L. G., Jackson-Cook, C. K., Stasiowski, B. A., Spence, J. E., Brown, J. A. &lt;strong&gt;Parental origin determination in 30 de novo Robertsonian translocations.&lt;/strong&gt; Am. J. Med. Genet. 43: 957-963, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1357969/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1357969&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.1320430611&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1357969">Shaffer et al., 1992</a>). In most cases (14 out of 17) the t(21;21) is an isochromosome (dup21q) rather than the result of a Robertsonian translocation caused by a fusion between 2 heterologous chromatids. About half were of paternal and half of maternal origin. In the 3 de novo t(21;21) true Robertsonian trisomy 21 cases, the extra chromosome 21 was maternal. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2532615+1978562+1831959+1357969" 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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<strong>Mapping</strong>
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<p><strong><em>Down Syndrome Critical Region</em></strong>
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<div class="mim-changed mim-change"><p>Mapping of the chromosomal region that, if triplicated, results in the phenotypic characteristics of Down syndrome has been facilitated by the use of DNA samples from individuals who have partial trisomy 21 with or without features of the Down syndrome phenotype (<a href="#70" class="mim-tip-reference" title="Rahmani, Z., Blouin, J., Creau-Goldberg, N., Watkins, P., Mattei, J., Poissonnier, M., Prieur, M., Chettouh, Z., Nicole, A., Aurias, A., Sinet, P., Delabar, J. &lt;strong&gt;Critical role of D21S55 region on chromosome 21 in the pathogenesis of Down syndrome.&lt;/strong&gt; Proc. Nat. Acad. Sci. 86: 5958-5962, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2527368/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2527368&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.86.15.5958&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2527368">Rahmani et al., 1989</a>; <a href="#51" class="mim-tip-reference" title="McCormick, M., Schinzel, A., Petersen, M., Stetten, G., Driscoll, D., Cantu, E., Tranebjaerg, L., Mikkelsen, M., Watkins, P., Antonarakis, S. &lt;strong&gt;Molecular genetic approach to the characterization of the Down syndrome region of chromosome 21.&lt;/strong&gt; Genomics 5: 325-331, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2529205/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2529205&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0888-7543(89)90065-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2529205">McCormick et al., 1989</a>; <a href="#39" class="mim-tip-reference" title="Korenberg, J., Kawashima, H., Pulst, S., Ikeuchi, T., Ogasawara, N., Yamamoto, K., Schonberg, S., Kojis, T., Allen, L., Magenis, E., Ikawa, H., Taniguchi, N., Epstein, C. &lt;strong&gt;Molecular definition of the region of chromosome 21 that causes features of the Down syndrome phenotype.&lt;/strong&gt; Am. J. Hum. Genet. 47: 236-246, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2143053/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2143053&lt;/a&gt;]" pmid="2143053">Korenberg et al., 1990</a>; <a href="#19" class="mim-tip-reference" title="Delabar, J. M., Theophile, D., Rahmani, Z., Chettouh, Z., Blouin, J. L., Prieur, M., Noel, B., Sinet, P. M. &lt;strong&gt;Molecular mapping of twenty-four features of Down syndrome on chromosome 21.&lt;/strong&gt; Europ. J. Hum. Genet. 1: 114-124, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8055322/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8055322&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000472398&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8055322">Delabar et al., 1993</a>; <a href="#41" class="mim-tip-reference" title="Korenberg, J. R. &lt;strong&gt;Toward a molecular understanding of Down syndrome.&lt;/strong&gt; Prog. Clin. Biol. Res. 384: 87-115, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8115409/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8115409&lt;/a&gt;]" pmid="8115409">Korenberg, 1993</a>). Although detailed analysis of these DNAs is still under way, an area of approximately 5 Mb between loci D21S58 and D21S42 has been identified that is associated with impaired intellectual development and most of the facial features of the syndrome. In particular, a subregion that includes D21S55 and MX1 (interferon-induced protein p78; <a href="/entry/147150">147150</a>), the latter being located in band 21q22.3, has been associated with impaired intellectual development and several morphologic features, including oblique eye fissure, epicanthus, flat nasal bridge, protruding tongue, short broad hands, clinodactyly of the fifth finger, gap between first and second toes, hypotonia, short stature, Brushfield spots, and characteristic dermatoglyphics (<a href="#19" class="mim-tip-reference" title="Delabar, J. M., Theophile, D., Rahmani, Z., Chettouh, Z., Blouin, J. L., Prieur, M., Noel, B., Sinet, P. M. &lt;strong&gt;Molecular mapping of twenty-four features of Down syndrome on chromosome 21.&lt;/strong&gt; Europ. J. Hum. Genet. 1: 114-124, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8055322/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8055322&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000472398&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8055322">Delabar et al., 1993</a>). Additional phenotypic characteristics may map outside the minimum critical region (symbolized DCR). Material from other rare patients who have features of Down syndrome but no visible chromosomal abnormality may help to narrow down the critical region. In several such studies, however, no triplicated region has been identified (<a href="#51" class="mim-tip-reference" title="McCormick, M., Schinzel, A., Petersen, M., Stetten, G., Driscoll, D., Cantu, E., Tranebjaerg, L., Mikkelsen, M., Watkins, P., Antonarakis, S. &lt;strong&gt;Molecular genetic approach to the characterization of the Down syndrome region of chromosome 21.&lt;/strong&gt; Genomics 5: 325-331, 1989.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2529205/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2529205&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/0888-7543(89)90065-7&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2529205">McCormick et al., 1989</a>; <a href="#19" class="mim-tip-reference" title="Delabar, J. M., Theophile, D., Rahmani, Z., Chettouh, Z., Blouin, J. L., Prieur, M., Noel, B., Sinet, P. M. &lt;strong&gt;Molecular mapping of twenty-four features of Down syndrome on chromosome 21.&lt;/strong&gt; Europ. J. Hum. Genet. 1: 114-124, 1993.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8055322/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8055322&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000472398&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8055322">Delabar et al., 1993</a>). It is possible that these patients do not have any chromosome 21 abnormality and their phenotype is a phenocopy of Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2529205+8115409+8055322+2527368+2143053" 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></div>
<p><a href="#39" class="mim-tip-reference" title="Korenberg, J., Kawashima, H., Pulst, S., Ikeuchi, T., Ogasawara, N., Yamamoto, K., Schonberg, S., Kojis, T., Allen, L., Magenis, E., Ikawa, H., Taniguchi, N., Epstein, C. &lt;strong&gt;Molecular definition of the region of chromosome 21 that causes features of the Down syndrome phenotype.&lt;/strong&gt; Am. J. Hum. Genet. 47: 236-246, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2143053/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2143053&lt;/a&gt;]" pmid="2143053">Korenberg et al. (1990)</a> defined the critical region for AVSD as involving D21S39, D21S42, and D21S43. Their subsequent publications further refined the minimum region for the major phenotypic features, although it remains unclear whether the region essential for AVSD is the same, since many clinical reports give insufficient information about the nature of the heart defect (<a href="#38" class="mim-tip-reference" title="Korenberg, J., Bradley, C., Disteche, C. &lt;strong&gt;Down syndrome: molecular mapping of congenital heart disease and duodenal stenosis.&lt;/strong&gt; Am. J. Hum. Genet. 50: 294-302, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1531166/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1531166&lt;/a&gt;]" pmid="1531166">Korenberg et al., 1992</a>). <a href="#38" class="mim-tip-reference" title="Korenberg, J., Bradley, C., Disteche, C. &lt;strong&gt;Down syndrome: molecular mapping of congenital heart disease and duodenal stenosis.&lt;/strong&gt; Am. J. Hum. Genet. 50: 294-302, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1531166/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1531166&lt;/a&gt;]" pmid="1531166">Korenberg et al. (1992)</a> correlated the human and mouse chromosome maps and suggested that the area of greatest interest extends from D21S55 to MX1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1531166+2143053" 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>By analysis of a 3-generation Japanese family containing 4 Down syndrome individuals with partial trisomy 21 (<a href="#39" class="mim-tip-reference" title="Korenberg, J., Kawashima, H., Pulst, S., Ikeuchi, T., Ogasawara, N., Yamamoto, K., Schonberg, S., Kojis, T., Allen, L., Magenis, E., Ikawa, H., Taniguchi, N., Epstein, C. &lt;strong&gt;Molecular definition of the region of chromosome 21 that causes features of the Down syndrome phenotype.&lt;/strong&gt; Am. J. Hum. Genet. 47: 236-246, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2143053/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2143053&lt;/a&gt;]" pmid="2143053">Korenberg et al., 1990</a>), <a href="#62" class="mim-tip-reference" title="Ohira, M., Ichikawa, H., Suzuki, E., Iwaki, M., Suzuki, K., Saito-Ohara F., Ikeuchi, T., Chumakov, I., Tanahashi, H., Tashiro, K., Sakaki, Y. &lt;strong&gt;A 1.6-Mb P1-based physical map of the Down syndrome region on chromosome 21.&lt;/strong&gt; Genomics 33: 65-74, 1996.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8617511/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8617511&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/geno.1996.0160&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8617511">Ohira et al. (1996)</a> defined a 1.6-Mb region between LA68 and ERG (<a href="/entry/165080">165080</a>) in 21q22 as the Down syndrome critical region. They constructed a contig map covering more than 95% of this 1.6-Mb region. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8617511+2143053" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="molecularGenetics" class="mim-anchor"></a>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Genes Within the Down Syndrome Critical Region</em></strong>
</p>
<div class="mim-changed mim-change"><p><a href="#26" class="mim-tip-reference" title="Fuentes, J.-J., Pritchard, M. A., Planas, A. M., Bosch, A., Ferrer, I., Estivill, X. &lt;strong&gt;A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart.&lt;/strong&gt; Hum. Molec. Genet. 4: 1935-1944, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8595418/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8595418&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/4.10.1935&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8595418">Fuentes et al. (1995)</a> cloned a gene (RCAN1; <a href="/entry/602917">602917</a>), which they designated DSCR1, from the Down syndrome critical region that is highly expressed in brain and heart, and suggested it as a candidate for involvement in the pathogenesis of DS, in particular impaired intellectual development and/or cardiac defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8595418" 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></div>
<p><a href="#57" class="mim-tip-reference" title="Nakamura, A., Hattori, M., Sakaki, Y. &lt;strong&gt;A novel gene isolated from human placenta located in Down syndrome critical region on chromosome 21.&lt;/strong&gt; DNA Res. 4: 321-324, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9455479/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9455479&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/dnares/4.5.321&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9455479">Nakamura et al. (1997)</a> identified DSCR4 (<a href="/entry/604829">604829</a>) as 2 ESTs that map to the 1.6-Mb Down syndrome critical region. DSCR4 is predominantly expressed in placenta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9455479" 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="#88" class="mim-tip-reference" title="Vidal-Taboada, J. M., Sanz, S., Egeo, A., Scartezzini, P., Oliva, R. &lt;strong&gt;Identification and characterization of a new gene from human chromosome 21 between markers D21S343 and D21S268 encoding a leucine-rich protein.&lt;/strong&gt; Biochem. Biophys. Res. Commun. 250: 547-554, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9784380/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9784380&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1006/bbrc.1998.9352&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9784380">Vidal-Taboada et al. (1998)</a> identified DSCR2 (<a href="/entry/605296">605296</a>) within the Down syndrome critical region 2 between DNA marker D21S55 and MX1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9784380" 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="#58" class="mim-tip-reference" title="Nakamura, A., Hattori, M., Sakaki, Y. &lt;strong&gt;Isolation of a novel human gene from the Down syndrome critical region of chromosome 21q22.2.&lt;/strong&gt; J. Biochem. 122: 872-877, 1997.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9399594/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9399594&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/oxfordjournals.jbchem.a021835&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9399594">Nakamura et al. (1997)</a> identified DSCR3 (<a href="/entry/605298">605298</a>) within the Down syndrome critical region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9399594" 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>Using indexing-based differential display PCR on neuronal precursor cells to study gene expression in Down syndrome, <a href="#10" class="mim-tip-reference" title="Bahn, S., Mimmack, M., Ryan, M., Caldwell, M. A., Jauniaux, E., Starkey, M., Svendsen, C. N., Emson, P. &lt;strong&gt;Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down&#x27;s syndrome: a gene expression study.&lt;/strong&gt; Lancet 359: 310-315, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11830198/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11830198&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(02)07497-4&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11830198">Bahn et al. (2002)</a> found that genes regulated by the REST (<a href="/entry/600571">600571</a>) transcription factor were selectively repressed. One of these genes, SCG10 (<a href="/entry/600621">600621</a>), which encodes a neuron-specific growth-associated protein, was almost undetectable. The REST factor itself was also downregulated by 49% compared to controls. In cell culture, the Down syndrome cells showed a reduction of neurogenesis, as well as decreased neurite length and abnormal changes in neuron morphology. The authors noted that REST-regulated genes play an important part in brain development, plasticity, and synapse formation, and they suggested a link between dysregulation of REST and some of the neurologic deficits seen in Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11830198" 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="#22" class="mim-tip-reference" title="Eggermann, T., Schonherr, N., Spengler, S., Jager, S., Denecke, B., Binder, G., Baudis, M. &lt;strong&gt;Identification of a 21q22 duplication in a Silver-Russell syndrome patient further narrows down the Down syndrome critical region.&lt;/strong&gt; Am. J. Med. Genet. 152A: 356-359, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20101688/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20101688&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33217&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20101688">Eggermann et al. (2010)</a> reported a patient with a paternally inherited 0.46-Mb duplication of chromosome 21q22, including the KCNE1 (<a href="/entry/176261">176261</a>) and RCAN1 genes, who did not have typical facial or cardiac features of Down syndrome. The patient had a clinical phenotype resembling Silver-Russell syndrome (SRS; <a href="/entry/180860">180860</a>), which is characterized by poor growth, but typical epigenetic changes associated with SRS were excluded. The duplication was inherited from the unaffected father. <a href="#22" class="mim-tip-reference" title="Eggermann, T., Schonherr, N., Spengler, S., Jager, S., Denecke, B., Binder, G., Baudis, M. &lt;strong&gt;Identification of a 21q22 duplication in a Silver-Russell syndrome patient further narrows down the Down syndrome critical region.&lt;/strong&gt; Am. J. Med. Genet. 152A: 356-359, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20101688/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20101688&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33217&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20101688">Eggermann et al. (2010)</a> concluded that the RCAN1 gene is not sufficient for generating the phenotypic features associated with Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20101688" 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>Acute Megakaryoblastic Leukemia of Down Syndrome</em></strong>
</p>
<p>Children with Down syndrome have a 10- to 20-fold elevated risk of developing leukemia, particularly acute megakaryoblastic leukemia (AMKL). <a href="#92" class="mim-tip-reference" title="Wechsler, J., Greene, M., McDevitt, M. A., Anastasi, J., Karp, J. E., Le Beau, M. M., Crispino, J. D. &lt;strong&gt;Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome.&lt;/strong&gt; Nature Genet. 32: 148-152, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12172547/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12172547&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng955&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12172547">Wechsler et al. (2002)</a> showed that leukemic cells from individuals with Down syndrome-related AMKL had mutations in the GATA1 gene (<a href="/entry/305371">305371</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12172547" 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="#45" class="mim-tip-reference" title="Look, A. T. &lt;strong&gt;A leukemogenic twist for GATA1.&lt;/strong&gt; Nature Genet. 32: 83-84, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12172549/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12172549&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng960&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12172549">Look (2002)</a> reviewed the mechanism by which GATA1 mutations might interact with trisomy 21 to result in AMKL. He pointed out that several lines of evidence indicated that at least 2 classes of mutations are needed to transform a normal hematopoietic stem cell into a clonal acute myeloid leukemia. One class imparts a myeloproliferative or survival advantage, as illustrated by activating mutations in FLT3 (<a href="/entry/136351">136351</a>), encoding a receptor tyrosine kinase, or the increased dosage of genes in chromosome 21 in persons with Down syndrome. To generate overt leukemia, a second class of genetic alterations must produce lineage-specific blocks in differentiation. The mutations responsible for this step have been demonstrated mainly in genes encoding chimeric transcription factors produced by chromosomal translocation. GATA1 is a transcription factor that plays a pivotal role in myeloid lineage commitment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12172549" 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>Transient Myeloproliferative Disorder of Down Syndrome</em></strong>
</p>
<p>As many as 10% of infants with Down syndrome present with transient myeloproliferative disorder (TMD; <a href="/entry/159595">159595</a>) at or shortly after birth. TMD is characterized by an abundance of blasts within peripheral blood and liver, and undergoes spontaneous remission in a majority of cases. TMD may be a precursor to AMKL, with an estimated 30% of TMD patients developing AMKL within 3 years. Mutations in GATA1 are associated with AMKL of Down syndrome. To determine whether the acquisition of GATA1 mutations is a late event restricted to acute leukemia, <a href="#56" class="mim-tip-reference" title="Mundschau, G., Gurbuxani, S., Gamis, A. S., Greene, M. E., Arceci, R. J., Crispino, J. D. &lt;strong&gt;Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis.&lt;/strong&gt; Blood 101: 4298-4300, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12560215/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12560215&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2002-12-3904&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12560215">Mundschau et al. (2003)</a> analyzed GATA1 in DNA from TMD patients. They found that GATA1 was mutated in the TMD blasts from every infant examined. These results demonstrated that GATA1 is likely to play a critical role in the etiology of TMD, and mutagenesis of GATA1 represents a very early event in myeloid leukemogenesis in Down syndrome. <a href="#34" class="mim-tip-reference" title="Hitzler, J. K., Cheung, J., Li, Y., Scherer, S. W., Zipursky, A. &lt;strong&gt;GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome.&lt;/strong&gt; Blood 101: 4301-4304, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12586620/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12586620&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2003-01-0013&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12586620">Hitzler et al. (2003)</a> likewise presented evidence that GATA1 mutations are an early event, and that AMKL arises from latent transient leukemia clones following initial apparent remission. All 7 patients reported by <a href="#56" class="mim-tip-reference" title="Mundschau, G., Gurbuxani, S., Gamis, A. S., Greene, M. E., Arceci, R. J., Crispino, J. D. &lt;strong&gt;Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis.&lt;/strong&gt; Blood 101: 4298-4300, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12560215/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12560215&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2002-12-3904&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12560215">Mundschau et al. (2003)</a> and almost all of the patients studied by <a href="#34" class="mim-tip-reference" title="Hitzler, J. K., Cheung, J., Li, Y., Scherer, S. W., Zipursky, A. &lt;strong&gt;GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome.&lt;/strong&gt; Blood 101: 4301-4304, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12586620/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12586620&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1182/blood-2003-01-0013&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12586620">Hitzler et al. (2003)</a> had deletions or insertions in the GATA1 gene rather than nucleotide substitutions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12560215+12586620" 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="#82" class="mim-tip-reference" title="Taketani, T., Taki, T., Takita, J., Ono, R., Horikoshi, Y., Kaneko, Y., Sako, M., Hanada, R., Hongo, T., Hayashi, Y. &lt;strong&gt;Mutation of the AML1/RUNX1 gene in a transient myeloproliferative disorder patient with Down syndrome. (Letter)&lt;/strong&gt; Leukemia 16: 1866-1867, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12200707/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12200707&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.leu.2402612&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12200707">Taketani et al. (2002)</a> screened the RUNX1 gene (<a href="/entry/151385">151385</a>) in 46 Down syndrome patients with hematologic malignancies. They identified a heterozygous missense mutation (H58N; <a href="/entry/151385#0008">151385.0008</a>) in 1 patient diagnosed with TMD 5 days after birth. The patient died suddenly 12 months after birth; it was not known whether she developed acute myeloid leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12200707" 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>Atrioventricular Septal Defects of Down Syndrome</em></strong>
</p>
<p>Given that mutations in the CRELD1 gene (<a href="/entry/607170">607170</a>) appear to be a risk factor for atrioventricular septal defect (AVSD) in the euploid population, and the fact that trisomy 21 is by far the most common finding associated with AVSD, <a href="#49" class="mim-tip-reference" title="Maslen, C., Babcock, D., Robinson, S. W., Bean, L. J. H., Dooley, K. J., Willour, V. L., Sherman, S. L. &lt;strong&gt;CRELD1 mutations contribute to the occurrence of cardiac atrioventricular septal defects in Down syndrome.&lt;/strong&gt; Am. J. Med. Genet. 140A: 2501-2505, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17036335/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17036335&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.31494&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17036335">Maslen et al. (2006)</a> analyzed the CRELD1 gene in 39 individuals with Down syndrome and complete AVSD. They identified heterozygosity for missense mutations in 2 infants (<a href="/entry/607170#0001">607170.0001</a> and <a href="/entry/607170#0005">607170.0005</a>, respectively), and suggested that defects in CRELD1 may contribute to the pathogenesis of AVSD in the context of trisomy 21. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17036335" 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="Ackerman, C., Locke, A. E., Feingold, E., Reshey, B., Espana, K., Thusberg, J., Mooney, S., Bean, L. J. H., Dooley, K. J., Cua, C. L., Reeves, R. H., Sherman, S. L., Maslen, C. L. &lt;strong&gt;An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects.&lt;/strong&gt; Am. J. Hum. Genet. 91: 646-659, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23040494/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23040494&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2012.08.017&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23040494">Ackerman et al. (2012)</a> used a candidate gene approach among individuals with Down syndrome and complete AVSD (141 cases) and Down syndrome with no congenital heart defect (141 controls) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. <a href="#2" class="mim-tip-reference" title="Ackerman, C., Locke, A. E., Feingold, E., Reshey, B., Espana, K., Thusberg, J., Mooney, S., Bean, L. J. H., Dooley, K. J., Cua, C. L., Reeves, R. H., Sherman, S. L., Maslen, C. L. &lt;strong&gt;An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects.&lt;/strong&gt; Am. J. Hum. Genet. 91: 646-659, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23040494/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23040494&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2012.08.017&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23040494">Ackerman et al. (2012)</a> found a significant excess (p less than 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, they found potentially damaging variants in nearly 20% of cases but fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in 6 genes: COL6A1 (<a href="/entry/120220">120220</a>), COL6A2 (<a href="/entry/120240">120240</a>), CRELD1 (mutations in which have already been identified as a cause of AVSD; see <a href="/entry/606217">606217</a>), FBLN2 (<a href="/entry/135821">135821</a>), FRZB (<a href="/entry/605083">605083</a>), and GATA5 (<a href="/entry/611496">611496</a>). Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGFA (<a href="/entry/192240">192240</a>) pathway, suggesting to <a href="#2" class="mim-tip-reference" title="Ackerman, C., Locke, A. E., Feingold, E., Reshey, B., Espana, K., Thusberg, J., Mooney, S., Bean, L. J. H., Dooley, K. J., Cua, C. L., Reeves, R. H., Sherman, S. L., Maslen, C. L. &lt;strong&gt;An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects.&lt;/strong&gt; Am. J. Hum. Genet. 91: 646-659, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23040494/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23040494&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2012.08.017&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23040494">Ackerman et al. (2012)</a> that rare variants in this pathway might contribute to the genetic underpinnings of AVSD in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23040494" 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>Acute Lymphoblastic Leukemia of Down Syndrome</em></strong>
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<p><a href="#11" class="mim-tip-reference" title="Bercovich, D., Ganmore, I., Scott, L. M., Wainreb, G., Birger, Y., Elimelech, A., Shochat, C., Cazzaniga, G., Biandi, A., Basso, G., Cario, G., Schrapper, M., and 17 others. &lt;strong&gt;Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down&#x27;s syndrome.&lt;/strong&gt; Lancet 372: 1484-1492, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18805579/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18805579&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(08)61341-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18805579">Bercovich et al. (2008)</a> identified somatic mutations in the JAK2 gene (<a href="/entry/147796">147796</a>) in 16 (18%) of 88 patients with Down syndrome-associated acute lymphoblastic leukemia. Only 1 of 109 patients with non-Down syndrome-associated leukemia had the mutation, but this child was also found to have an isochromosome 21q. All the JAK2-associated leukemias were of the B-cell precursor type. Children with a JAK2 mutation were younger (mean age 4.5 years) compared to patients without JAK2 mutations (8.6 years) at diagnosis. Five mutant JAK2 alleles were identified, each affecting a highly conserved residue: arg683 (i.e., R683G, R683S, R683K). In vitro functional expression studies in mouse hematopoietic progenitor cells showed that the mutations caused constitutive Jak/Stat activation and cytokine-independent growth, consistent with a gain of function. This growth was sensitive to pharmacologic inhibition with a JAK inhibitor. Modeling studies showed that arg683 is located in an exposed conserved region of the JAK2 pseudokinase domain in a region different from that implicated in myeloproliferative disorders. <a href="#11" class="mim-tip-reference" title="Bercovich, D., Ganmore, I., Scott, L. M., Wainreb, G., Birger, Y., Elimelech, A., Shochat, C., Cazzaniga, G., Biandi, A., Basso, G., Cario, G., Schrapper, M., and 17 others. &lt;strong&gt;Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down&#x27;s syndrome.&lt;/strong&gt; Lancet 372: 1484-1492, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18805579/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18805579&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(08)61341-0&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18805579">Bercovich et al. (2008)</a> concluded that there is a specific association between constitutional trisomy 21 and arg683 JAK2 mutations that predispose to the development of B-cell ALL in patients with Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18805579" 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="#46" class="mim-tip-reference" title="Lyle, R., Bena, F., Gagos, S., Gehrig, C., Lopez, G., Schinzel, A., Lespinasse, J., Bottani, A., Dahoun, S., Taine, L., Doco-Fenzy, M., Cornillet-Lefebvre, P., and 16 others. &lt;strong&gt;Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21.&lt;/strong&gt; Europ. J. Hum. Genet. 17: 454-466, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19002211/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19002211&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19002211[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ejhg.2008.214&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19002211">Lyle et al. (2009)</a> used array comparative genomic hybridization to analyze 30 patients with anomalies of chromosome 21, including 19 with partial trisomy 21 and 11 with partial monosomy 21, all for different segments of the chromosome. They also examined the phenotypes of 5 patients with a Down syndrome-like phenotype with a normal karyotype and 6 with complete trisomy 21. The majority of the phenotypes mapped to distal 21; averaging the phenotype score indicated a region approximately 37 to 44 Mb, which was involved in most Down syndrome phenotypes. These results were not surprising, as this is the most gene-rich region of chromosome 21. Five patients were trisomic for proximal 21 and did not include the so-called Down syndrome critical region (DSCR), thus excluding the possibility there is a single DSCR responsible for all aspects of the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19002211" 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 frequency of trisomy 21 in the population is 1 in 650 to 1,000 live births (<a href="#36" class="mim-tip-reference" title="Hook, E. G. &lt;strong&gt;Epidemiology of Down syndrome. In: Pueschel, S. M.; Rynders, J. E. (eds.): Down Syndrome. Advances in Biomedicine and the Behavioral Sciences.&lt;/strong&gt; Cambridge: Ware Press (pub.) 1982. P. 11 only."None>Hook, 1982</a>).</p>
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<div class="mim-changed mim-change"><p>As a first step in identifying the genes responsible for individual features of Down syndrome and their pathophysiology, <a href="#40" class="mim-tip-reference" title="Korenberg, J. R., Chen, X.-N., Schipper, R., Sun, Z., Gonsky, R., Gerwehr, S., Carpenter, N., Daumer, C., Dignan, P., Disteche, C., Graham, J. M., Jr., Hugdins, L., McGillivray, B., Miyazaki, K., Ogasawara, N., Park, J. P., Pagon, R., Pueschel, S., Sack, G., Say, B., Schuffenhauer, S., Soukup, S., Yamanaka, T. &lt;strong&gt;Down syndrome phenotypes: the consequences of chromosomal imbalance.&lt;/strong&gt; Proc. Nat. Acad. Sci. 91: 4997-5001, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8197171/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8197171&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.91.11.4997&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8197171">Korenberg et al. (1994)</a> established a panel of cell lines derived from 16 individuals with Down syndrome caused by duplication of small regions of chromosome 21. The molecular breakpoints were determined using fluorescence in situ hybridization and Southern blot dosage analysis of 32 markers unique to chromosome 21. Combining this information with detailed clinical evaluations of the subjects, <a href="#40" class="mim-tip-reference" title="Korenberg, J. R., Chen, X.-N., Schipper, R., Sun, Z., Gonsky, R., Gerwehr, S., Carpenter, N., Daumer, C., Dignan, P., Disteche, C., Graham, J. M., Jr., Hugdins, L., McGillivray, B., Miyazaki, K., Ogasawara, N., Park, J. P., Pagon, R., Pueschel, S., Sack, G., Say, B., Schuffenhauer, S., Soukup, S., Yamanaka, T. &lt;strong&gt;Down syndrome phenotypes: the consequences of chromosomal imbalance.&lt;/strong&gt; Proc. Nat. Acad. Sci. 91: 4997-5001, 1994.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/8197171/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;8197171&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.91.11.4997&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="8197171">Korenberg et al. (1994)</a> constructed a 'phenotypic map' that included 25 features and assigned regions of 2 to 20 Mb as likely to contain the genes responsible. This study provided evidence for a significant contribution of genes outside the D21S55 region to the DS phenotypes, including the facies, microcephaly, short stature, hypotonia, abnormal dermatoglyphics, and impaired intellectual development. The results strongly suggest that DS is a contiguous gene syndrome and make it unlikely that a single DS chromosomal region is responsible for most of the DS phenotypic features. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8197171" 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></div>
<p><a href="#14" class="mim-tip-reference" title="Busciglio, J., Pelsman, A., Wong, C., Pigino, G., Yuan, M., Mori, H., Yankner, B. A. &lt;strong&gt;Altered metabolism of the amyloid-beta precursor protein is associated with mitochondrial dysfunction in Down&#x27;s syndrome.&lt;/strong&gt; Neuron 33: 677-688, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11879646/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11879646&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(02)00604-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11879646">Busciglio et al. (2002)</a> found that astrocyte and neuronal cell cultures derived from Down syndrome fetal brains had increased intracellular levels of insoluble beta-amyloid-42 and decreased levels of secreted beta-amyloid. These abnormal patterns of APP (<a href="/entry/104760">104760</a>) processing were recapitulated in normal astrocytes by inhibition of mitochondrial metabolism. In addition, DS astrocytes showed impaired mitochondrial metabolism. <a href="#14" class="mim-tip-reference" title="Busciglio, J., Pelsman, A., Wong, C., Pigino, G., Yuan, M., Mori, H., Yankner, B. A. &lt;strong&gt;Altered metabolism of the amyloid-beta precursor protein is associated with mitochondrial dysfunction in Down&#x27;s syndrome.&lt;/strong&gt; Neuron 33: 677-688, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11879646/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11879646&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/s0896-6273(02)00604-9&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11879646">Busciglio et al. (2002)</a> postulated that mitochondrial dysfunction in Down syndrome may lead to intracellular deposition of beta-amyloid and increased neuronal vulnerability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11879646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<p><a href="#9" class="mim-tip-reference" title="Arron, J. R., Winslow, M. M., Polleri, A., Chang, C.-P., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., Yamasaki, N., Miyakawa, T., Francke, U., Graef, I. A., Crabtree, G. R. &lt;strong&gt;NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.&lt;/strong&gt; Nature 441: 595-600, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16554754/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16554754&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature04678&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16554754">Arron et al. (2006)</a> reported that 2 genes, DSCR1 (RCAN1; <a href="/entry/602917">602917</a>) and DYRK1A (<a href="/entry/600855">600855</a>), that lie within the critical region of human chromosome 21 act synergistically to prevent nuclear occupancy of NFATc transcription factors (see <a href="/entry/600489">600489</a>), which are regulators of vertebrate development. <a href="#9" class="mim-tip-reference" title="Arron, J. R., Winslow, M. M., Polleri, A., Chang, C.-P., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., Yamasaki, N., Miyakawa, T., Francke, U., Graef, I. A., Crabtree, G. R. &lt;strong&gt;NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.&lt;/strong&gt; Nature 441: 595-600, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16554754/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16554754&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature04678&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16554754">Arron et al. (2006)</a> used mathematical modeling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. The authors' observations of calcineurin (see <a href="/entry/114105">114105</a>)- and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down syndrome, and human trisomy 21 are consistent with these predictions. <a href="#9" class="mim-tip-reference" title="Arron, J. R., Winslow, M. M., Polleri, A., Chang, C.-P., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., Yamasaki, N., Miyakawa, T., Francke, U., Graef, I. A., Crabtree, G. R. &lt;strong&gt;NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.&lt;/strong&gt; Nature 441: 595-600, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16554754/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16554754&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature04678&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16554754">Arron et al. (2006)</a> suggested that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down syndrome. <a href="#9" class="mim-tip-reference" title="Arron, J. R., Winslow, M. M., Polleri, A., Chang, C.-P., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., Yamasaki, N., Miyakawa, T., Francke, U., Graef, I. A., Crabtree, G. R. &lt;strong&gt;NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.&lt;/strong&gt; Nature 441: 595-600, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16554754/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16554754&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature04678&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16554754">Arron et al. (2006)</a> concluded that more generally, their observations suggest that the destabilization of regulatory circuits can underlie human disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16554754" 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 resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free calcium ion levels, they are dephosphorylated by the calmodulin (<a href="/entry/114180">114180</a>)-dependent phosphatase calcineurin and translocate to the nucleus. NFAT dephosphorylation by calcineurin is countered by distinct NFAT kinases, among them casein kinase-1 (CK1; <a href="/entry/600505">600505</a>), and glycogen synthase kinase-3 (GSK3; see <a href="/entry/605004">605004</a>). <a href="#31" class="mim-tip-reference" title="Gwack, Y., Sharma, S., Nardone, J., Tanasa, B., Iuga, A., Srikanth, S., Okamura, H., Bolton, D., Feske, S., Hogan, P. G., Rao, A. &lt;strong&gt;A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT.&lt;/strong&gt; Nature 441: 646-650, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16511445/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16511445&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature04631&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16511445">Gwack et al. (2006)</a> used a genomewide RNA interference screen in Drosophila to identify additional regulators of the signaling pathway leading from calcium ion-calcineurin to NFAT. This screen was successful because the pathways regulating NFAT subcellular localization (calcium ion influx, calcium ion-calmodulin-calcineurin signaling, and NFAT kinases) are conserved across species, even though calcium ion-regulated NFAT proteins are not themselves represented in invertebrates. Using the screen, <a href="#31" class="mim-tip-reference" title="Gwack, Y., Sharma, S., Nardone, J., Tanasa, B., Iuga, A., Srikanth, S., Okamura, H., Bolton, D., Feske, S., Hogan, P. G., Rao, A. &lt;strong&gt;A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT.&lt;/strong&gt; Nature 441: 646-650, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16511445/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16511445&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature04631&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16511445">Gwack et al. (2006)</a> identified DYRKs (dual-specificity tyrosine phosphorylation-regulated kinases) as novel regulators of NFAT. DYRK1A and DYRK2 (<a href="/entry/603496">603496</a>) counter calcineurin-mediated dephosphorylation of NFAT1 by directly phosphorylating the conserved serine-proline repeat 3 (SP3) motif of the NFAT regulatory domain, thus priming further phosphorylation of the SP2 and serine-rich region 1 (SRR1) motifs by GSK3 and CK1, respectively. Thus, <a href="#31" class="mim-tip-reference" title="Gwack, Y., Sharma, S., Nardone, J., Tanasa, B., Iuga, A., Srikanth, S., Okamura, H., Bolton, D., Feske, S., Hogan, P. G., Rao, A. &lt;strong&gt;A genome-wide Drosophila RNAi screen identifies DYRK-family kinases as regulators of NFAT.&lt;/strong&gt; Nature 441: 646-650, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16511445/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16511445&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature04631&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16511445">Gwack et al. (2006)</a> concluded that genetic screening in Drosophila can be successfully applied to cross evolutionary boundaries and identify new regulators of a transcription factor that is expressed only in vertebrates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16511445" 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>Down syndrome is characterized by extensive phenotypic variability; while cognitive impairment, muscle hypotonia at birth, and dysmorphic features occur to some extent in all affected individuals, most associated traits occur in only a fraction of affected individuals. Since Down syndrome is caused by genomic dosage imbalance, <a href="#69" class="mim-tip-reference" title="Prandini, P., Deutsch, S., Lyle, R., Gagnebin, M., Vivier, C. D., Delorenzi, M., Gehrig, C., Descombes, P., Sherman, S., Bricarelli, F. D., Baldo, C., Novelli, A., Dallapiccola, B., Antonarakis, S. E. &lt;strong&gt;Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance.&lt;/strong&gt; Am. J. Hum. Genet. 81: 252-263, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17668376/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17668376&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17668376[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/519248&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17668376">Prandini et al. (2007)</a> hypothesized that variation in expression of genes on chromosome 21 in individuals with Down syndrome influences the phenotypic variability among affected individuals. They studied gene expression variation in 14 lymphoblastoid and 17 fibroblast cell lines from individuals with Down syndrome and an equal number of controls. Gene expression was assayed on 100 and 106 chromosome 21 genes and 23 and 26 non-chromosome 21 genes in lymphoblastoid and fibroblast cell lines, respectively. Surprisingly, only 39% and 62% of chromosome 21 genes in lymphoblastoid and fibroblast cells, respectively, showed a statistically significant difference between Down syndrome and normal samples, although the average upregulation of chromosome 21 genes was close to the expected 1.5-fold in both cell types. According to the degree of overlapping expression levels, <a href="#69" class="mim-tip-reference" title="Prandini, P., Deutsch, S., Lyle, R., Gagnebin, M., Vivier, C. D., Delorenzi, M., Gehrig, C., Descombes, P., Sherman, S., Bricarelli, F. D., Baldo, C., Novelli, A., Dallapiccola, B., Antonarakis, S. E. &lt;strong&gt;Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance.&lt;/strong&gt; Am. J. Hum. Genet. 81: 252-263, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17668376/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17668376&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17668376[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/519248&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17668376">Prandini et al. (2007)</a> classified all genes into 3 groups: (A) nonoverlapping, (B) partially overlapping, and (C) extensively overlapping expression distributions between normal and Down syndrome samples. The authors hypothesized that, in each cell type, group A genes are the most dosage-sensitive and are most likely involved in the constant Down syndrome traits; group B genes may be involved in variable Down syndrome traits; and group C genes are not dosage-sensitive and are least likely to participate in Down syndrome pathologic phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17668376" 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>Using a transchromosomic mouse model of Down syndrome, <a href="#15" class="mim-tip-reference" title="Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O&#x27;Doherty, A., Lyle, R., Borel, C., Lin-Marq, N., Delom, F., Groet, J., Schnappauf, F., De Vita, S, and 12 others. &lt;strong&gt;DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 83: 388-400, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18771760/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18771760&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18771760[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2008.08.012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18771760">Canzonetta et al. (2008)</a> showed that a 30 to 60% reduced expression of NRSF/REST (<a href="/entry/600571">600571</a>), a key regulator of pluripotency and neuronal differentiation, is an alteration that persists in trisomy 21 from undifferentiated embryonic stem cells to adult brain and is reproducible across several Down syndrome models. Using partially trisomic embryonic stem (ES) cells, <a href="#15" class="mim-tip-reference" title="Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O&#x27;Doherty, A., Lyle, R., Borel, C., Lin-Marq, N., Delom, F., Groet, J., Schnappauf, F., De Vita, S, and 12 others. &lt;strong&gt;DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 83: 388-400, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18771760/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18771760&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18771760[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2008.08.012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18771760">Canzonetta et al. (2008)</a> mapped this effect to a 3-gene segment of human chromosome 21 containing DYRK1A (<a href="/entry/600855">600855</a>). The authors independently identified the same locus as the most significant expression quantitative trait locus (eQTL) controlling REST expression in the human genome. <a href="#15" class="mim-tip-reference" title="Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O&#x27;Doherty, A., Lyle, R., Borel, C., Lin-Marq, N., Delom, F., Groet, J., Schnappauf, F., De Vita, S, and 12 others. &lt;strong&gt;DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 83: 388-400, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18771760/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18771760&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18771760[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2008.08.012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18771760">Canzonetta et al. (2008)</a> found that specifically silencing the third copy of DYRK1A rescued Rest levels, and demonstrated altered Rest expression in response to inhibition of DYRK1A expression or kinase activity, and in a transgenic Dyrk1a mouse. The authors observed that undifferentiated trisomy 21 ES cells showed DYRK1A-dose-sensitive reductions in levels of some pluripotency regulators, including Nanog (<a href="/entry/607937">607937</a>) and Sox2 (<a href="/entry/184429">184429</a>), causing premature expression of transcription factors driving early endodermal and mesodermal differentiation, partially overlapping downstream effects of Rest heterozygosity. The ES cells produced embryoid bodies with elevated levels of the primitive endoderm progenitor marker Gata4 (<a href="/entry/600576">600576</a>) and a strongly reduced neuroectodermal progenitor compartment. <a href="#15" class="mim-tip-reference" title="Canzonetta, C., Mulligan, C., Deutsch, S., Ruf, S., O&#x27;Doherty, A., Lyle, R., Borel, C., Lin-Marq, N., Delom, F., Groet, J., Schnappauf, F., De Vita, S, and 12 others. &lt;strong&gt;DYRK1A-dosage imbalance perturbs NRSF/REST levels, deregulating pluripotency and embryonic stem cell fate in Down syndrome.&lt;/strong&gt; Am. J. Hum. Genet. 83: 388-400, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18771760/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18771760&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18771760[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.ajhg.2008.08.012&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18771760">Canzonetta et al. (2008)</a> concluded that DYRK1A-mediated deregulation of REST is a very early pathologic consequence of trisomy 21 with potential to disturb the development of all embryonic lineages, warranting closer research into its contribution to Down syndrome pathology and rationales for therapeutic approaches. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18771760" 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="#43" class="mim-tip-reference" title="Letourneau, A., Santoni, F. A., Bonilla, X., Sailani, M. R., Gonzalez, D., Kind, J., Chevalier, C., Thurman, R., Sandstrom, R. S., Hibaoui, Y., Garieri, M., Popadin, K., and 16 others. &lt;strong&gt;Domains of genome-wide gene expression dysregulation in Down&#x27;s syndrome.&lt;/strong&gt; Nature 508: 345-350, 2014. Note: Erratum: Nature 531: 400 only, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24740065/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24740065&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature13200&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24740065">Letourneau et al. (2014)</a> studied the transcriptome of fetal fibroblasts from a pair of monozygotic twins discordant for trisomy 21 and showed that the differential expression between the twins was organized in domains along all chromosomes that are either upregulated or downregulated. These gene expression dysregulation domains (GEDDs) can be defined by the expression level of their gene content, and are well conserved in induced pluripotent stem cells derived from the twins' fibroblasts. Comparison of the transcriptome of the Ts65Dn mouse model of Down syndrome and normal littermate mouse fibroblasts also showed GEDDs along the mouse chromosomes that were syntenic in human. The GEDDs correlated with the lamina-associated domains (LADs) and the replication domains of mammalian cells. The overall position of LADs was not altered in trisomic cells; however, the H3K4me3 profile of the trisomic fibroblasts was modified and accurately followed the GEDD pattern. <a href="#43" class="mim-tip-reference" title="Letourneau, A., Santoni, F. A., Bonilla, X., Sailani, M. R., Gonzalez, D., Kind, J., Chevalier, C., Thurman, R., Sandstrom, R. S., Hibaoui, Y., Garieri, M., Popadin, K., and 16 others. &lt;strong&gt;Domains of genome-wide gene expression dysregulation in Down&#x27;s syndrome.&lt;/strong&gt; Nature 508: 345-350, 2014. Note: Erratum: Nature 531: 400 only, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24740065/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24740065&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature13200&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24740065">Letourneau et al. (2014)</a> concluded that the nuclear compartments of trisomic cells undergo modifications of the chromatin environment influencing the overall transcriptome, and that GEDDs may therefore contribute to some trisomy 21 phenotypes. <a href="#43" class="mim-tip-reference" title="Letourneau, A., Santoni, F. A., Bonilla, X., Sailani, M. R., Gonzalez, D., Kind, J., Chevalier, C., Thurman, R., Sandstrom, R. S., Hibaoui, Y., Garieri, M., Popadin, K., and 16 others. &lt;strong&gt;Domains of genome-wide gene expression dysregulation in Down&#x27;s syndrome.&lt;/strong&gt; Nature 508: 345-350, 2014. Note: Erratum: Nature 531: 400 only, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24740065/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24740065&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature13200&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24740065">Letourneau et al. (2014)</a> suggested that this effect may originate from the chromosome 21 protein HMGN1 (<a href="/entry/163920">163920</a>). The correlation of GEDDs with the replication time domains and a prolonged permissive chromatin state in trisomic cells raised the question of an excess of background transcription in trisomic cells. <a href="#43" class="mim-tip-reference" title="Letourneau, A., Santoni, F. A., Bonilla, X., Sailani, M. R., Gonzalez, D., Kind, J., Chevalier, C., Thurman, R., Sandstrom, R. S., Hibaoui, Y., Garieri, M., Popadin, K., and 16 others. &lt;strong&gt;Domains of genome-wide gene expression dysregulation in Down&#x27;s syndrome.&lt;/strong&gt; Nature 508: 345-350, 2014. Note: Erratum: Nature 531: 400 only, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24740065/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24740065&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature13200&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24740065">Letourneau et al. (2014)</a> proposed that the overexpression of 1 or more human chromosome 21 candidate gene(s) modifies the chromatin environment of the nuclear compartments in trisomic cells. These modifications would lead to a general perturbation of the transcriptome that could explain some Down syndrome phenotypes. Alternatively, the GEDDs could be the result of the additional chromosomal material of trisomy 21. The prediction of this latter hypothesis is that other trisomies may have a similar effect on the dysregulation of gene expression, which remained to be studied. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24740065" 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="#28" class="mim-tip-reference" title="Gimenez-Barcons, M., Casteras, A., Armengol, M. P., Porta, E., Correa, P. A., Marin, A., Pujol-Borrell, R., Colobran, R. &lt;strong&gt;Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens.&lt;/strong&gt; J. Immun. 193: 3872-3879, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25217160/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25217160&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.4049/jimmunol.1400223&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25217160">Gimenez-Barcons et al. (2014)</a> noted that Down syndrome is strongly associated with autoimmune disease. The transcription factor AIRE (<a href="/entry/607658">607658</a>), which is encoded on chromosome 21q22.3, regulates promiscuous gene expression (pGE) and thus plays a crucial role in autoimmunity. <a href="#28" class="mim-tip-reference" title="Gimenez-Barcons, M., Casteras, A., Armengol, M. P., Porta, E., Correa, P. A., Marin, A., Pujol-Borrell, R., Colobran, R. &lt;strong&gt;Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens.&lt;/strong&gt; J. Immun. 193: 3872-3879, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25217160/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25217160&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.4049/jimmunol.1400223&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25217160">Gimenez-Barcons et al. (2014)</a> assessed expression of AIRE in thymus samples from 19 patients with Down syndrome and 21 euploid controls. Despite the presence of trisomy 21 and 3 copies of AIRE, AIRE expression was significantly reduced by 2-fold in Down syndrome thymuses compared with controls. Decreased expression of AIRE was associated with reduced pGE because expression of the tissue-restricted antigens CHRNA1 (<a href="/entry/100690">100690</a>), GAD1 (<a href="/entry/605363">605363</a>), PLP1 (<a href="/entry/300401">300401</a>), KLK3 (<a href="/entry/176820">176820</a>), SAG (<a href="/entry/181031">181031</a>), TG (<a href="/entry/188450">188450</a>), and TSHR (<a href="/entry/603372">603372</a>) was reduced. More than half of the Down syndrome patients, and none of the controls, developed thyroid dysfunction over an approximately 20-year period, with 10 patients developing hypothyroidism and 1 developing Graves disease (see <a href="/entry/275000">275000</a>). Patient thymuses contained significantly lower levels of AIRE and TG, an antigen to which tolerance is typically lost in autoimmune thyroiditis, leading to hypothyroidism. <a href="#28" class="mim-tip-reference" title="Gimenez-Barcons, M., Casteras, A., Armengol, M. P., Porta, E., Correa, P. A., Marin, A., Pujol-Borrell, R., Colobran, R. &lt;strong&gt;Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens.&lt;/strong&gt; J. Immun. 193: 3872-3879, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25217160/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25217160&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.4049/jimmunol.1400223&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25217160">Gimenez-Barcons et al. (2014)</a> concluded that AIRE and pGE have fundamental roles in predisposing individuals with Down syndrome to autoimmunity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25217160" 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>Using male mice doubly heterozygous for a 16;17 and a 9;16 translocation in crosses with females with a normal complement of 40 acrocentric chromosomes, <a href="#53" class="mim-tip-reference" title="Miyabara, S., Gropp, A., Winking, H. &lt;strong&gt;Trisomy 16 in the mouse fetus associated with generalized edema and cardiovascular and urinary tract anomalies.&lt;/strong&gt; Teratology 25: 369-380, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7112437/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7112437&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/tera.1420250314&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7112437">Miyabara et al. (1982)</a> generated litters with a high incidence of trisomy 16 in order to investigate the embryonic phenotype. A number of authors, including <a href="#68" class="mim-tip-reference" title="Polani, P. E., Adinolfi, M. &lt;strong&gt;Chromosome 21 of man, 22 of the great apes and 16 of the mouse.&lt;/strong&gt; Dev. Med. Child. Neurol. 22: 223-233, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6445845/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6445845&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1469-8749.1980.tb04331.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6445845">Polani and Adinolfi (1980)</a>, suggested that trisomy 16 in the mouse was likely to be homologous to trisomy 21 in humans since the loci SOD1 (<a href="#25" class="mim-tip-reference" title="Francke, U., Taggart, R. T. &lt;strong&gt;Assignment of the gene for cytoplasmic superoxide dismutase (SOD-1) to a region of chromosome 16 and of Hprt to a region of the X chromosome in the mouse.&lt;/strong&gt; Proc. Nat. Acad. Sci. 76: 5230-5233, 1979.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/291939/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;291939&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.76.10.5230&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="291939">Francke and Taggart, 1979</a>), IFRC (<a href="#17" class="mim-tip-reference" title="Cox, D. R., Epstein, L. B., Epstein, C. J. &lt;strong&gt;Genes coding for sensitivity to interferon (IfRec) and soluble superoxide dismutase (SOD-1) are linked in mouse and man and map to mouse chromosome 16.&lt;/strong&gt; Proc. Nat. Acad. Sci. 77: 2168-2172, 1980.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/6154946/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;6154946&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.77.4.2168&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="6154946">Cox et al., 1980</a>), and PRGS (<a href="#18" class="mim-tip-reference" title="Cox, D. R., Goldblatt, D., Epstein, C. J. &lt;strong&gt;Chromosomal assignment of mouse PRGS: further evidence for homology between mouse chromosome 16 and human chromosome 21. (Abstract)&lt;/strong&gt; Am. J. Hum. Genet. 33: 145A only, 1981."None>Cox et al., 1981</a>) are shared between these chromosomes in the 2 species. The frequency of trisomic embryos declined with advancing gestation; at day 14, 27.3% were recognized to be trisomic whereas only 4.3% of 20-day embryos were shown to be trisomy 16. General hypoplasia and developmental delay were noted together with early edema, all features compatible with the human syndrome. Malformations included a high incidence of hydronephrosis and complex heart anomalies. Like its human counterpart, atrioventricular septal defect in mice was often associated with outflow tract defects including truncus arteriosus, interrupted aortic arch, and double outlet right ventricle. In a subsequent review, <a href="#55" class="mim-tip-reference" title="Miyabara, S. &lt;strong&gt;Cardiovascular malformations of mouse trisomy 16: pathogenetic evaluation as an animal model for human trisomy 21. In: Clarke, E. B.; Takao, A. (eds.): Developmental Cardiology: Morphogenesis and Function.&lt;/strong&gt; Mount Kisco, N. Y.: Futura Publ. Co. (pub.) 1990. Pp. 409-430."None>Miyabara (1990)</a> noted phenotypic overlap with DiGeorge syndrome (<a href="/entry/188400">188400</a>), which may reflect homology with the 22q11 region. The incidence of heart defects was higher in the mouse model than in humans, perhaps a result of earlier examination and the complexity of chromosomal homology. They noted that another influence is the genetic background. Against the NIMR background, <a href="#53" class="mim-tip-reference" title="Miyabara, S., Gropp, A., Winking, H. &lt;strong&gt;Trisomy 16 in the mouse fetus associated with generalized edema and cardiovascular and urinary tract anomalies.&lt;/strong&gt; Teratology 25: 369-380, 1982.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7112437/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7112437&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/tera.1420250314&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7112437">Miyabara et al. (1982)</a> found 56% AVSD cases, whereas against C57BL/6, <a href="#54" class="mim-tip-reference" title="Miyabara, S., Sugihara, H., Yonemitsu, N., Yun, K. &lt;strong&gt;Comparative study of phenotypic expression of mice trisomy 16 by different female strains: attempt at an animal model for human trisomy 21.&lt;/strong&gt; Congenit. Anom. Regist. 24: 283-292, 1984."None>Miyabara et al. (1984)</a> found 95.5% cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6445845+6154946+291939+7112437" 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="#80" class="mim-tip-reference" title="Shinohara, T., Tomizuka, K., Miyabara, S., Takehara, S., Kazuki, Y., Inoue, J., Katoh, M., Nakane, H., Iino, A., Ohguma, A., Ikegami, S., Inokuchi, K., Ishida, I., Reeves, R. H., Oshimura, M. &lt;strong&gt;Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down&#x27;s syndrome.&lt;/strong&gt; Hum. Molec. Genet. 10: 1163-1175, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11371509/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11371509&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/10.11.1163&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11371509">Shinohara et al. (2001)</a> used microcell-mediated chromosome transfer to create chimeric mice containing human chromosome 21. Fluorescence in situ hybridization and PCR-based DNA analysis revealed that chromosome 21 was substantially intact but had sustained a small deletion. The freely segregating chromosome 21 was lost during development in some tissues, resulting in a panel of chimeric mice with varying degrees of mosaicism. The chimeric mice showed a high correlation between retention of chromosome 21 in the brain and impairment in learning or emotional behavior by open-field, contextual fear conditioning, and forced swim tests. A significant number of the chimeric fetuses exhibited both thymic hypoplasia and conotruncal cardiac defects, and most of these animals also exhibited atrioventricular canal malformations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11371509" 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>
<div class="mim-changed mim-change"><p><a href="#4" class="mim-tip-reference" title="Altafaj, X., Dierssen, M., Baamonde, C., Marti, E., Visa, J., Guimera, J., Oset, M., Gonzalez, J. R., Florez, J., Fillat, C., Estivill, X. &lt;strong&gt;Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down&#x27;s syndrome.&lt;/strong&gt; Hum. Molec. Genet. 10: 1915-1923, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11555628/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11555628&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/10.18.1915&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11555628">Altafaj et al. (2001)</a> generated transgenic mice overexpressing the full-length cDNA of Dyrk1A (<a href="/entry/600855">600855</a>). Dyrk1A mice exhibited delayed craniocaudal maturation with functional consequences in neuromotor development. Dyrk1A mice also showed altered motor skill acquisition and hyperactivity, which was maintained to adulthood. In the Morris water maze, Dyrk1A mice showed a significant impairment in spatial learning and cognitive flexibility, indicative of hippocampal and prefrontal cortex dysfunction. In the more complex repeated reversal learning paradigm, this defect was specifically related to reference memory, whereas working memory was almost unimpaired. The authors suggested a causative role of DYRK1A in impaired intellectual development and in motor anomalies of DS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11555628" 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></div>
<p>Trisomy 21 results in cerebellar dysmorphism with direct parallels in the Ts65Dn (partial trisomy) mouse. Despite pronounced changes in morphology, cerebellar function is not markedly different. <a href="#76" class="mim-tip-reference" title="Saran, N. G., Pletcher, M. T., Natale, J. E., Cheng, Y., Reeves, R. H. &lt;strong&gt;Global disruption of the cerebellar transcriptome in a Down syndrome mouse model.&lt;/strong&gt; Hum. Molec. Genet. 12: 2013-2019, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12913072/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12913072&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddg217&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12913072">Saran et al. (2003)</a> distinguished trisomic and euploid murine cerebellar transcriptomes by microarray analysis. Changes in expression of individual genes were very subtle, but the differences in respective transcriptome phenotypes extended deeply into the set of nearly 7,000 probes located throughout the genome. Examination of the discriminating genes in 2 independent experiments suggested that the global perturbation may include a significant stochastic component. Thus, dosage imbalance of the 124 genes in Ts65Dn mice altered the expression of thousands of genes to create a variable trisomic transcriptome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12913072" 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="#63" class="mim-tip-reference" title="Olson, L. E., Richtsmeier, J. T., Leszl, J., Reeves, R. H. &lt;strong&gt;A chromosome 21 critical region does not cause specific Down syndrome phenotypes.&lt;/strong&gt; Science 306: 687-690, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15499018/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15499018&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15499018[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1098992&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15499018">Olson et al. (2004)</a> used chromosome engineering to create mice that were trisomic or monosomic for only the mouse chromosome segment orthologous to the Down syndrome critical region and assessed dysmorphologies of the craniofacial skeleton that showed direct parallels with Down syndrome in mice with a larger segmental trisomy. The Down syndrome critical region genes were not sufficient and were largely not necessary to produce the facial phenotype. <a href="#63" class="mim-tip-reference" title="Olson, L. E., Richtsmeier, J. T., Leszl, J., Reeves, R. H. &lt;strong&gt;A chromosome 21 critical region does not cause specific Down syndrome phenotypes.&lt;/strong&gt; Science 306: 687-690, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15499018/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15499018&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=15499018[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1098992&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15499018">Olson et al. (2004)</a> concluded that their results refuted specific predictions of the prevailing hypothesis of gene action in Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15499018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
<p><a href="#61" class="mim-tip-reference" title="O&#x27;Doherty, A., Ruf, S., Mulligan, C., Hildreth, V., Errington, M. L., Cooke, S., Sesay, A., Modino, S., Vanes, L., Hernandez, D., Linehan, J. M., Sharpe, P. T., Brandner, S., Bliss, T. V. P., Henderson, D. J., Nizetic, D., Tybulewicz, V. L. J., Fisher, E. M. C. &lt;strong&gt;An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes.&lt;/strong&gt; Science 309: 2033-2037, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16179473/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16179473&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16179473[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1114535&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16179473">O'Doherty et al. (2005)</a> generated a transspecies aneuploid mouse line that stably transmits a freely segregating, almost complete human chromosome 21. This transchromosomic mouse line, Tc1, is a model of trisomy 21, which manifests as Down syndrome in humans, and has phenotypic alterations in behavior, synaptic plasticity, cerebellar neuronal number, heart development, and mandible size that relate to human Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16179473" 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="#74" class="mim-tip-reference" title="Roper, R. J., Baxter, L. L., Saran, N. G., Klinedinst, D. K., Beachy, P. A., Reeves, R. H. &lt;strong&gt;Defective cerebellar response to mitogenic Hedgehog signaling in Down&#x27;s syndrome mice.&lt;/strong&gt; Proc. Nat. Acad. Sci. 103: 1452-1456, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 103: 5242 only, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16432181/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16432181&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16432181[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0510750103&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16432181">Roper et al. (2006)</a> found that a deficit in cerebellar granule cell neurons in a mouse model of Down syndrome was associated with reduced mitogenic response of granule cell precursors to Hedgehog protein signaling in early postnatal development. Systemic treatment of newborn trisomic mice with a small molecule agonist of the Hedgehog signaling pathway increased mitosis and restored the granule cell precursor population in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16432181" 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 Ts65Dn and Ts1Cje mouse models of Down syndrome, <a href="#75" class="mim-tip-reference" title="Salehi, A., Delcroix, J.-D., Belichenko, P. V., Zhan, K., Wu, C., Valletta, J. S., Takimoto-Kimura, R., Kleschevnikov, A. M., Sambamurti, K., Chung, P. P., Xia, W., Villar, A., Campbell, W. A., Kulnane, L. S., Nixon, R. A., Lamb, B. T., Epstein, C. J., Stokin, G. B., Goldstein, L. S. B., Mobley, W. C. &lt;strong&gt;Increased App expression in a mouse model of Down&#x27;s syndrome disrupts NGF transport and causes cholinergic neuron degeneration.&lt;/strong&gt; Neuron 51: 29-42, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16815330/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16815330&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.neuron.2006.05.022&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16815330">Salehi et al. (2006)</a> found that increased dosage of the App gene markedly decreased retrograde transport of nerve growth factor (NGF; <a href="/entry/162030">162030</a>), thus resulting in degeneration of cholinergic neurons in the basal forebrain. NGF-containing early endosomes were enlarged in cholinergic axons of the Ts65Dn mice and their App content was increased. The findings demonstrated a pathogenic mechanism for Down syndrome whereby disrupted axonal transport in certain neurons results in neuronal degeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16815330" 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="#81" class="mim-tip-reference" title="Sussan, T. E., Yang, A., Li, F., Ostrowski, M. C., Reeves, R. H. &lt;strong&gt;Trisomy represses Apc(Min)-mediated tumours in mouse models of Down&#x27;s syndrome.&lt;/strong&gt; Nature 451: 73-75, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18172498/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18172498&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature06446&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18172498">Sussan et al. (2008)</a> used mouse models of Down syndrome and of cancer in a biologic approach to investigate the relationship between trisomy and the incidence of intestinal tumors. Apc(Min) (<a href="/entry/611731">611731</a>)-mediated tumor number was determined in aneuploid mouse models Ts65Dn, Ts1Rhr, and Ms1Rhr. Trisomy for orthologs of about half of the genes on chromosome 21 (Hsa21) in Ts65Dn mice or just 33 of these genes in Ts1Rhr mice resulted in a significant reduction in the number of intestinal tumors. In Ms1Rhr, segmental monosomy for the same 33 genes that are triplicated in Ts1Rhr resulted in an increased number of tumors. Further studies demonstrated that the Ets2 gene (<a href="/entry/164740">164740</a>) contributed most of the dosage-sensitive effect on intestinal tumor number. The action of Est2 as a repressor when it is overexpressed differs from tumor suppression, which requires normal gene function to prevent cellular transformation. <a href="#81" class="mim-tip-reference" title="Sussan, T. E., Yang, A., Li, F., Ostrowski, M. C., Reeves, R. H. &lt;strong&gt;Trisomy represses Apc(Min)-mediated tumours in mouse models of Down&#x27;s syndrome.&lt;/strong&gt; Nature 451: 73-75, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18172498/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18172498&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature06446&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18172498">Sussan et al. (2008)</a> suggested that upregulation of Ets2 and, potentially, other genes involved in this kind of protective effect may provide a prophylactic effect in all individuals, regardless of ploidy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18172498" 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="#93" class="mim-tip-reference" title="Wilson, M. D., Barbosa-Morais, N. L., Schmidt, D., Conboy, C. M., Vanes, L., Tybulewicz, V. L. J., Fisher, E. M. C., Tavare, S., Odom, D. T. &lt;strong&gt;Species-specific transcription in mice carrying human chromosome 21.&lt;/strong&gt; Science 322: 434-438, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18787134/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18787134&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18787134[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1160930&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18787134">Wilson et al. (2008)</a> used the Tc1 mouse model of Down syndrome to determine whether, on a chromosomal scale, interspecies differences in transcriptional regulation are primarily directed by human genetic sequence or mouse nuclear environment. Virtually all transcription factor-binding locations, landmarks of transcription initiation, and the resulting gene expression observed in human hepatocytes were recapitulated across the entire human chromosome 21 in the mouse hepatocyte nucleus. <a href="#93" class="mim-tip-reference" title="Wilson, M. D., Barbosa-Morais, N. L., Schmidt, D., Conboy, C. M., Vanes, L., Tybulewicz, V. L. J., Fisher, E. M. C., Tavare, S., Odom, D. T. &lt;strong&gt;Species-specific transcription in mice carrying human chromosome 21.&lt;/strong&gt; Science 322: 434-438, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18787134/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18787134&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18787134[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1160930&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18787134">Wilson et al. (2008)</a> concluded that thus, in homologous tissues, genetic sequence is largely responsible for directing transcriptional programs; interspecies differences in epigenetic machinery, cellular environment, and transcription factors themselves play secondary roles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18787134" 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="#89" class="mim-tip-reference" title="Voronov, S. V., Frere, S. G., Giovedi, S., Pollina, E. A., Borel, C., Zhang, H., Schmidt, C., Akeson, E. C., Wenk, M. R., Cimasoni, L., Arancio, O., Davisson, M. T., Antonarakis, S. E., Gardiner, K., De Camilli, P., Di Paolo, G. &lt;strong&gt;Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down&#x27;s syndrome.&lt;/strong&gt; Proc. Nat. Acad. Sci. 105: 9415-9420, 2008.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18591654/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18591654&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18591654[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.0803756105&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18591654">Voronov et al. (2008)</a> found altered phosphatidylinositol-4,5-bisphosphate metabolism in the brains of Ts65Dn mice. The defect could be rescued by restoring Synj1 (<a href="/entry/604297">604297</a>) to disomy in Ts65Dn mice and could also be recapitulated in transgenic mice overexpressing Synj1. The transgenic mice exhibited deficits in performance of the Morris water maze task, suggesting that perturbation of this signaling pathway may contribute to brain dysfunction in patients with Down syndrome. The findings suggested that correct dosage of the Synj1 gene is important for normal brain development and function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18591654" 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="#72" class="mim-tip-reference" title="Reynolds, L. E., Watson, A. R., Baker, M., Jones, T. A., D&#x27;Amico, G., Robinson, S. D., Joffre, C., Garrido-Urbani, S., Rodriguez-Manzaneque, J. C., Martino-Echarri, E., Aurrand-Lions, M., Sheer, D., and 11 others. &lt;strong&gt;Tumour angiogenesis is reduced in the Tc1 mouse model of Down&#x27;s syndrome.&lt;/strong&gt; Nature 465: 813-817, 2010. Note: Erratum: Nature 466: 398 only, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20535211/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20535211&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20535211[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature09106&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20535211">Reynolds et al. (2010)</a> used the Tc1 transchromosomic mouse model of Down syndrome (<a href="#61" class="mim-tip-reference" title="O&#x27;Doherty, A., Ruf, S., Mulligan, C., Hildreth, V., Errington, M. L., Cooke, S., Sesay, A., Modino, S., Vanes, L., Hernandez, D., Linehan, J. M., Sharpe, P. T., Brandner, S., Bliss, T. V. P., Henderson, D. J., Nizetic, D., Tybulewicz, V. L. J., Fisher, E. M. C. &lt;strong&gt;An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes.&lt;/strong&gt; Science 309: 2033-2037, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16179473/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16179473&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16179473[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/science.1114535&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16179473">O'Doherty et al., 2005</a>) to dissect the contribution of extra copies of genes on Hsa21 to tumor angiogenesis. The Tc1 mouse expresses roughly 81% of human chromosome 21 genes but not the human DSCR1 (RCAN1; <a href="/entry/602917">602917</a>) region, implicated as responsible for decreased incidence of solid tumors among patients with Down syndrome. <a href="#72" class="mim-tip-reference" title="Reynolds, L. E., Watson, A. R., Baker, M., Jones, T. A., D&#x27;Amico, G., Robinson, S. D., Joffre, C., Garrido-Urbani, S., Rodriguez-Manzaneque, J. C., Martino-Echarri, E., Aurrand-Lions, M., Sheer, D., and 11 others. &lt;strong&gt;Tumour angiogenesis is reduced in the Tc1 mouse model of Down&#x27;s syndrome.&lt;/strong&gt; Nature 465: 813-817, 2010. Note: Erratum: Nature 466: 398 only, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20535211/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20535211&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20535211[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature09106&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20535211">Reynolds et al. (2010)</a> transplanted B16F0 and Lewis lung carcinoma tumor cells into Tc1 mice and showed that growth of these tumors was substantially reduced compared with wildtype littermate controls. Furthermore, tumor angiogenesis was significantly repressed in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF; <a href="/entry/192240">192240</a>) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative antiangiogenic genes, ADAMTS1 (<a href="/entry/605174">605174</a>) and ERG (<a href="/entry/165080">165080</a>), and novel endothelial cell-specific genes never previously shown to be involved in angiogenesis, JAM-B (<a href="/entry/606870">606870</a>) and PTTG1IP (<a href="/entry/603784">603784</a>), that, when overexpressed, are responsible for inhibiting angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumor angiogenesis, explaining the reduced tumor growth in Down syndrome. Furthermore, <a href="#72" class="mim-tip-reference" title="Reynolds, L. E., Watson, A. R., Baker, M., Jones, T. A., D&#x27;Amico, G., Robinson, S. D., Joffre, C., Garrido-Urbani, S., Rodriguez-Manzaneque, J. C., Martino-Echarri, E., Aurrand-Lions, M., Sheer, D., and 11 others. &lt;strong&gt;Tumour angiogenesis is reduced in the Tc1 mouse model of Down&#x27;s syndrome.&lt;/strong&gt; Nature 465: 813-817, 2010. Note: Erratum: Nature 466: 398 only, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20535211/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20535211&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20535211[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature09106&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20535211">Reynolds et al. (2010)</a> expected that, in addition to the candidate genes that they showed to be involved in the regression of angiogenesis, the Tc1 mouse model of Down syndrome will permit the identification of other endothelium-specific antiangiogenic targets relevant to a broad spectrum of cancer patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20535211+16179473" 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="#65" class="mim-tip-reference" title="Pereira, P. L., Magnol, L., Sahun, I., Brault, V., Duchon, A., Prandini, P., Gruart, A., Bizot, J.-C., Chadefaux-Vekemans, B., Deutsch, S., Trovero, F., Delgado-Garcia, J. M., Antonarakis, S. E., Dierssen, M., Herault, Y. &lt;strong&gt;A new mouse model for the trisomy of the Abcg1-U2af1 region reveals the complexity of the combinatorial genetic code of Down syndrome.&lt;/strong&gt; Hum. Molec. Genet. 18: 4756-4769, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19783846/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19783846&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19783846[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddp438&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19783846">Pereira et al. (2009)</a> showed that trisomy of the 12 genes found in the 0.59 Mb (Abcg1-U2af1) Hsa21 subtelomeric region in mice (Ts1Yah) produced defects in novel object recognition, open-field, and Y-maze tests, similar to other Down syndrome models, but induced an improvement of the hippocampal-dependent spatial memory in the Morris water maze along with enhanced and longer lasting long-term potentiation in vivo in the hippocampus. The authors demonstrated a contribution of the Abcg1-U2af1 genetic region to cognitive defects in working and short-term recognition memory in Down syndrome models. Increase in copy number of the Abcg1-U2af1 interval led to an unexpected gain of cognitive function in spatial learning. Expression analysis pinpointed several genes, such as Ndufv3 (<a href="/entry/602184">602184</a>), Wdr4 (<a href="/entry/605924">605924</a>), Pknox1 (<a href="/entry/602100">602100</a>), and Cbs (<a href="/entry/613381">613381</a>), as candidates whose overexpression in the hippocampus might facilitate learning and memory in Ts1Yah mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19783846" 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>For a model of human monosomy 21, <a href="#95" class="mim-tip-reference" title="Yu, T., Clapcote, S. J., Li, Z., Liu, C., Pao, A., Bechard, A. R., Carattini-Rivera, S., Matsui, S.-I., Roder, J. C., Baldini, A., Mobley, W. C., Bradley, A., Yu, Y. E. &lt;strong&gt;Deficiencies in the region syntenic to human 21q22.3 cause cognitive deficits in mice.&lt;/strong&gt; Mammalian Genome 21: 258-267, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20512340/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20512340&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20512340[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00335-010-9262-x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20512340">Yu et al. (2010)</a> created mutant mice with heterozygous deletions in segments of chromosomes 10 and 17 that are syntenic to regions of human chromosome 21q22.3. The deleted regions of mouse chromosomes 10 and 17 contain 28 and 19 genes, respectively, orthologous to those found on human chromosome 21q22.3. Heterozygous mutant mice showed deficits in spatial learning and memory and context-associated learning. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20512340" 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="#96" class="mim-tip-reference" title="Yu, T., Li, Z., Jia, Z., Clapcote, S. J., Liu, C., Li, S., Asrar, S., Pao, A., Chen, R., Fan, N., Carattini-Rivera, S., Bechard, A. R., Spring, S., Henkelman, R. M., Stoica, G., Matsui, S.-I., Nowak, N. J., Roder, J. C., Chen, C., Bradley, A., Yu, Y. E. &lt;strong&gt;A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions.&lt;/strong&gt; Hum. Molec. Genet. 19: 2780-2791, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20442137/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20442137&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20442137[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddq179&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20442137">Yu et al. (2010)</a> described a mouse model for Down syndrome that carried duplications spanning human chromosome 21 (Hsa21) syntenic regions on 3 mouse chromosomes. The mouse mutant exhibited Down syndrome-related neurologic defects, including impaired cognitive behaviors, reduced hippocampal long-term potentiation, and hydrocephalus. The authors suggested that when all the mouse orthologs of the Hsa21 genes were triplicated, an abnormal cognitively relevant phenotype was the final outcome of their elevated expression and possible functional interactions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20442137" 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="#47" class="mim-tip-reference" title="Martin, K. R., Corlett, A., Dubach, D., Mustafa, T., Coleman, H. A., Parkington, H. C., Merson, T. D., Bourne, J. A., Porta, S., Arbones, M. L., Finkelstein, D. I., Pritchard, M. A. &lt;strong&gt;Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory.&lt;/strong&gt; Hum. Molec. Genet. 21: 3025-3041, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22511596/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22511596&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/dds134&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22511596">Martin et al. (2012)</a> found that modest overexpression of human RCAN1 under the control of its own promoter in transgenic mice did not cause overall brain abnormalities but resulted in significant defects in the hippocampal dentate gyrus region. The volume of the hippocampus was significantly reduced, with a reduced number of neurons and decreased spine density in apical dendrites. Transgenic neural progenitor cells from the dentate gyrus region formed neurospheres in culture, but unlike wildtype neurospheres, they tended to differentiate into astrocytes and oligodendrocytes more readily than neurons. Hippocampal slices from transgenic mice showed defects in long-term potentiation, which were accompanied by reduced phosphorylation of Camk2 (see <a href="/entry/114078">114078</a>) and Erk1 (MAPK3; <a href="/entry/601795">601795</a>)/Erk2 (MAPK1; <a href="/entry/176948">176948</a>), and reduced Ca(2+) transients. Behaviorally, adult transgenic mice showed deficits in learning and memory. <a href="#47" class="mim-tip-reference" title="Martin, K. R., Corlett, A., Dubach, D., Mustafa, T., Coleman, H. A., Parkington, H. C., Merson, T. D., Bourne, J. A., Porta, S., Arbones, M. L., Finkelstein, D. I., Pritchard, M. A. &lt;strong&gt;Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory.&lt;/strong&gt; Hum. Molec. Genet. 21: 3025-3041, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22511596/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22511596&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/dds134&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22511596">Martin et al. (2012)</a> concluded that modest overexpression of RCAN1 in transgenic mice mirrors many of the abnormalities observed in Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22511596" 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="Adorno, M., Sikandar, S., Mitra, S. S., Kuo, A., Nicolas Di Robilant, B., Haro-Acosta, V., Ouadah, Y., Quarta, M., Rodriguez, J., Qian, D., Reddy, V. M., Cheshier, S., Garner, C. C., Clarke, M. F. &lt;strong&gt;Usp16 contributes to somatic stem-cell defects in Down&#x27;s syndrome.&lt;/strong&gt; Nature 501: 380-384, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24025767/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24025767&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24025767[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature12530&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24025767">Adorno et al. (2013)</a> found that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 (<a href="/entry/604735">604735</a>) reduces the self-renewal of hematopoietic stem cells and the expansion of mammary epithelial cells, neuroprogenitors, and fibroblasts. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a (<a href="/entry/600160">600160</a>) and accelerated senescence in Ts65Dn fibroblasts. Usp16 can remove ubiquitination from histone H2A (see <a href="/entry/613499">613499</a>) on lys119, a critical mark for the maintenance of multiple somatic tissues. Downregulation of Usp16, either by mutation of a single normal Usp16 allele or by short interfering RNAs, largely rescues these defects. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down syndrome fibroblasts. <a href="#3" class="mim-tip-reference" title="Adorno, M., Sikandar, S., Mitra, S. S., Kuo, A., Nicolas Di Robilant, B., Haro-Acosta, V., Ouadah, Y., Quarta, M., Rodriguez, J., Qian, D., Reddy, V. M., Cheshier, S., Garner, C. C., Clarke, M. F. &lt;strong&gt;Usp16 contributes to somatic stem-cell defects in Down&#x27;s syndrome.&lt;/strong&gt; Nature 501: 380-384, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24025767/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24025767&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24025767[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature12530&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24025767">Adorno et al. (2013)</a> suggested that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down syndrome and could serve as an attractive target to ameliorate some of the associated pathologies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24025767" 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="#37" class="mim-tip-reference" title="Jiang, J., Jing, Y., Cost, G. J., Chiang, J.-C., Kolpa, H. J., Cotton, A. M., Carone, D. M., Carone, B. R., Shivak, D. A., Guschin, D. Y., Pearl, J. R., Rebar, E. J., Byron, M., Gregory, P. D., Brown, C. J., Urnov, F. D., Hall, L. L., Lawrence, J. B. &lt;strong&gt;Translating dosage compensation to trisomy 21.&lt;/strong&gt; Nature 500: 296-300, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23863942/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23863942&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23863942[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature12394&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23863942">Jiang et al. (2013)</a> tested the concept that a gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, X inactivation-specific transcript (XIST; <a href="/entry/314670">314670</a>). Using genome editing with zinc finger nucleases, <a href="#37" class="mim-tip-reference" title="Jiang, J., Jing, Y., Cost, G. J., Chiang, J.-C., Kolpa, H. J., Cotton, A. M., Carone, D. M., Carone, B. R., Shivak, D. A., Guschin, D. Y., Pearl, J. R., Rebar, E. J., Byron, M., Gregory, P. D., Brown, C. J., Urnov, F. D., Hall, L. L., Lawrence, J. B. &lt;strong&gt;Translating dosage compensation to trisomy 21.&lt;/strong&gt; Nature 500: 296-300, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23863942/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23863942&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23863942[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature12394&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23863942">Jiang et al. (2013)</a> inserted a large inducible XIST transgene into the DYRK1A (<a href="/entry/600855">600855</a>) locus on chromosome 21 in Down syndrome pluripotent stem cells. The XIST noncoding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosomewide transcriptional silencing, and DNA methylation to form a 'chromosome 21 Barr body.' This provided a model to study human chromosome inactivation and created a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. Notably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing 1 chromosome 21. <a href="#37" class="mim-tip-reference" title="Jiang, J., Jing, Y., Cost, G. J., Chiang, J.-C., Kolpa, H. J., Cotton, A. M., Carone, D. M., Carone, B. R., Shivak, D. A., Guschin, D. Y., Pearl, J. R., Rebar, E. J., Byron, M., Gregory, P. D., Brown, C. J., Urnov, F. D., Hall, L. L., Lawrence, J. B. &lt;strong&gt;Translating dosage compensation to trisomy 21.&lt;/strong&gt; Nature 500: 296-300, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23863942/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23863942&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23863942[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/nature12394&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23863942">Jiang et al. (2013)</a> suggested that their successful trisomy silencing in vitro surmounted the major first step towards potential development of chromosome therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23863942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#27" class="mim-tip-reference" title="Garrod, A. E. &lt;strong&gt;On the association of cardiac malformations with other congenital defects.&lt;/strong&gt; St. Bartholemew Hosp. Rep. (London) 30: 53 only, 1894."None>Garrod (1894)</a> first reported the association between Down syndrome and heart malformation. <a href="#1" class="mim-tip-reference" title="Abbott, M. E. &lt;strong&gt;New accessions in cardiac anomalies: pulmonary atresia of inflammatory origin; persistent ostium primum with Mongolian idiocy.&lt;/strong&gt; Int. A. M. Mus. Bull. 10: 111, 1924."None>Abbott (1924)</a> drew attention to the association between AVSD and Down syndrome.</p><p><a href="#59" class="mim-tip-reference" title="Neri, G., Opitz, J. M. &lt;strong&gt;Down syndrome: comments and reflections on the 50th anniversary of Lejeune&#x27;s discovery.&lt;/strong&gt; Am. J. Med. Genet. 149A: 2647-2654, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19921741/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19921741&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.33138&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19921741">Neri and Opitz (2009)</a> provided a detailed review of the history of the scientific developments leading to the molecular characterization of Down syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19921741" 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>Speculation about the historic prevalence of Down syndrome has included references to apparent depictions of the syndrome in 15th (<a href="#90" class="mim-tip-reference" title="Ward, O. C. &lt;strong&gt;Further early historical evidence of Down syndrome. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 126A: 220, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15057991/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15057991&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.20452&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15057991">Ward, 2004</a>) and 16th (<a href="#44" class="mim-tip-reference" title="Levitas, A. S., Reid, C. S. &lt;strong&gt;An angel with Down syndrome in a sixteenth century Flemish Nativity painting.&lt;/strong&gt; Am. J. Med. Genet. 116A: 399-405, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12522800/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12522800&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.10043&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12522800">Levitas and Reid, 2003</a>) century paintings. <a href="#48" class="mim-tip-reference" title="Martinez-Frias, M. L. &lt;strong&gt;The real earliest historical evidence of Down syndrome. (Letter)&lt;/strong&gt; Am. J. Med. Genet. 132A: 231, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15578572/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15578572&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1002/ajmg.a.30455&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15578572">Martinez-Frias (2005)</a> reported what seems likely to be the earliest evidence of the syndrome in a terra-cotta head from approximately 500 AD belonging to the Tolteca culture of Mexico, in which 'it is easy to identify the short palpebral fissures, oblique eyes, midface hypoplasia, and open mouth with macroglossia, findings that clearly define the face of a person with Down syndrome.' <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15578572+12522800+15057991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Bernal, J. E., Briceno, I. &lt;strong&gt;Genetic and other diseases in the pottery of Tumaco-La Tolita culture in Colombia-Ecuador.&lt;/strong&gt; Clin. Genet. 70: 188-191, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16922718/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16922718&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2006.00670.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16922718">Bernal and Briceno (2006)</a> examined pottery artifacts from the Tumaco-La Tolita culture, which existed on the border of present-day Colombia and Ecuador approximately 2,500 years ago, and described several figurines with characteristics suggestive of Down syndrome. <a href="#12" class="mim-tip-reference" title="Bernal, J. E., Briceno, I. &lt;strong&gt;Genetic and other diseases in the pottery of Tumaco-La Tolita culture in Colombia-Ecuador.&lt;/strong&gt; Clin. Genet. 70: 188-191, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16922718/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16922718&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1399-0004.2006.00670.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16922718">Bernal and Briceno (2006)</a> believed these artifacts to be among the earliest artistic representations of disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922718" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="seeAlso" class="mim-anchor"></a>
<h4 href="#mimSeeAlsoFold" id="mimSeeAlsoToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>See Also:</strong>
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<a href="#Hall1962" class="mim-tip-reference" title="Hall, B. &lt;strong&gt;Down&#x27;s syndrome (mongolism) with normal chromosomes.&lt;/strong&gt; Lancet 280: 1026-1027, 1962. Note: Originally Volume II.">Hall (1962)</a>; <a href="#Rex1982" class="mim-tip-reference" title="Rex, A. P., Preus, M. &lt;strong&gt;A diagnostic index for Down syndrome.&lt;/strong&gt; J. Pediat. 100: 903-906, 1982.">Rex and Preus (1982)</a>; <a href="#Tandon1973" class="mim-tip-reference" title="Tandon, R., Edwards, J. E. &lt;strong&gt;Cardiac malformations associated with Down&#x27;s syndrome.&lt;/strong&gt; Circulation 47: 1349-1355, 1973.">Tandon and Edwards (1973)</a>
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<a id="references"class="mim-anchor"></a>
<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
<a id="Abbott1924" class="mim-anchor"></a>
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Abbott, M. E.
<strong>New accessions in cardiac anomalies: pulmonary atresia of inflammatory origin; persistent ostium primum with Mongolian idiocy.</strong>
Int. A. M. Mus. Bull. 10: 111, 1924.
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<a id="2" class="mim-anchor"></a>
<a id="Ackerman2012" class="mim-anchor"></a>
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Ackerman, C., Locke, A. E., Feingold, E., Reshey, B., Espana, K., Thusberg, J., Mooney, S., Bean, L. J. H., Dooley, K. J., Cua, C. L., Reeves, R. H., Sherman, S. L., Maslen, C. L.
<strong>An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects.</strong>
Am. J. Hum. Genet. 91: 646-659, 2012.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23040494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23040494</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23040494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.ajhg.2012.08.017" target="_blank">Full Text</a>]
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<a id="Adorno2013" class="mim-anchor"></a>
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Adorno, M., Sikandar, S., Mitra, S. S., Kuo, A., Nicolas Di Robilant, B., Haro-Acosta, V., Ouadah, Y., Quarta, M., Rodriguez, J., Qian, D., Reddy, V. M., Cheshier, S., Garner, C. C., Clarke, M. F.
<strong>Usp16 contributes to somatic stem-cell defects in Down's syndrome.</strong>
Nature 501: 380-384, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24025767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24025767</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24025767[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=24025767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/nature12530" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
<a id="Altafaj2001" class="mim-anchor"></a>
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Altafaj, X., Dierssen, M., Baamonde, C., Marti, E., Visa, J., Guimera, J., Oset, M., Gonzalez, J. R., Florez, J., Fillat, C., Estivill, X.
<strong>Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome.</strong>
Hum. Molec. Genet. 10: 1915-1923, 2001.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11555628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11555628</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11555628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/10.18.1915" target="_blank">Full Text</a>]
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<a id="Antonarakis1990" class="mim-anchor"></a>
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Antonarakis, S. E., Adelsberger, P. A., Petersen, M. B., Binkert, F., Schinzel, A. A.
<strong>Analysis of DNA polymorphism suggests that most de novo dup(21q) chromosomes in patients with Down syndrome are isochromosomes and not translocations.</strong>
Am. J. Hum. Genet. 47: 968-972, 1990.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1978562/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1978562</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1978562" 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="6" class="mim-anchor"></a>
<a id="Antonarakis1991" class="mim-anchor"></a>
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Antonarakis, S. E., Lewis, J. G., Adelsberger, P. A., Petersen, M. B., Schinzel, A. A., Binkert, F., Schmid, W., Pangalos, C., Raoul, O., Chakravarti, A., Hafez, M., Cohen, M. M., Roulston, D., Schwartz, S., Mikkelsen, M., Tranebjaerg, L., Greenberg, F., Hoar, D. I., Rudd, N. L., Warren, A. C., Metaxotou, C., Bartsocas, C., Down Syndrome Collaborative Group.
<strong>Parental origin of the extra chromosome in trisomy 21 using DNA polymorphism analysis.</strong>
New Eng. J. Med. 324: 872-876, 1991.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1825697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1825697</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1825697" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM199103283241302" target="_blank">Full Text</a>]
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<a id="Antonarakis1992" class="mim-anchor"></a>
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Antonarakis, S. E., Petersen, M. B., McInnis, M. G., Adelsberger, P. A., Schinzel, A. A., Binkert, F., Pangalos, C., Raoul, O., Slaugenhaupt, S. A., Hafez, M., Cohen, M. M., Roulson, D., Schwartz, S., Mikkelsen, M., Tranebjaerg, L., Greenberg, F., Hoar, D. I., Rudd, N. L., Warren, A. C., Metaxotou, C., Bartsocas, C., Chakravarti, A.
<strong>The meiotic stage of nondisjunction in trisomy 21: determination using DNA polymorphisms.</strong>
Am. J. Hum. Genet. 50: 544-550, 1992.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1347192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1347192</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1347192" 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="Antonarakis1993" class="mim-anchor"></a>
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Antonarakis, S. E.
<strong>Human chromosome 21: genome mapping and exploration circa 1993.</strong>
Trends Genet. 9: 142-148, 1993.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8516850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8516850</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8516850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/0168-9525(93)90210-9" target="_blank">Full Text</a>]
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<a id="Arron2006" class="mim-anchor"></a>
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Arron, J. R., Winslow, M. M., Polleri, A., Chang, C.-P., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., Yamasaki, N., Miyakawa, T., Francke, U., Graef, I. A., Crabtree, G. R.
<strong>NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.</strong>
Nature 441: 595-600, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16554754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16554754</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16554754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/nature04678" target="_blank">Full Text</a>]
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<a id="Bahn2002" class="mim-anchor"></a>
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<p class="mim-text-font">
Bahn, S., Mimmack, M., Ryan, M., Caldwell, M. A., Jauniaux, E., Starkey, M., Svendsen, C. N., Emson, P.
<strong>Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down's syndrome: a gene expression study.</strong>
Lancet 359: 310-315, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11830198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11830198</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11830198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/S0140-6736(02)07497-4" target="_blank">Full Text</a>]
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<a id="Bercovich2008" class="mim-anchor"></a>
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Bercovich, D., Ganmore, I., Scott, L. M., Wainreb, G., Birger, Y., Elimelech, A., Shochat, C., Cazzaniga, G., Biandi, A., Basso, G., Cario, G., Schrapper, M., and 17 others.
<strong>Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down's syndrome.</strong>
Lancet 372: 1484-1492, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18805579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18805579</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18805579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/S0140-6736(08)61341-0" target="_blank">Full Text</a>]
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<a id="Bernal2006" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Bernal, J. E., Briceno, I.
<strong>Genetic and other diseases in the pottery of Tumaco-La Tolita culture in Colombia-Ecuador.</strong>
Clin. Genet. 70: 188-191, 2006.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16922718/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16922718</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16922718" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1399-0004.2006.00670.x" target="_blank">Full Text</a>]
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<a id="Brown2000" class="mim-anchor"></a>
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<p class="mim-text-font">
Brown, A. S., Feingold, E., Broman, K. W., Sherman, S. L.
<strong>Genome-wide variation in recombination in female meiosis: a risk factor for non-disjunction of chromosome 21.</strong>
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<p class="mim-text-font">
Tsui, N. B. Y., Akolekar, R., Chiu, R. W. K., Chow, K. C. K., Leung, T. Y., Lau, T. K., Nicolaides, K. H., Lo, Y. M. D.
<strong>Synergy of total PLAC4 RNA concentration and measurement of the RNA single-nucleotide polymorphism allelic ratio for the noninvasive prenatal detection of trisomy 21.</strong>
Clin. Chem. 56: 73-81, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19892844/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19892844</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19892844" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1373/clinchem.2009.132662" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="86" class="mim-anchor"></a>
<a id="Tyler2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Tyler, C. V., Jr., Zyzanski, S. J., Runser, L.
<strong>Increased risk of symptomatic gallbladder disease in adults with Down syndrome.</strong>
Am. J. Med. Genet. 130A: 351-353, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15386474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15386474</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15386474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.30243" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="87" class="mim-anchor"></a>
<a id="van Trotsenburg2003" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
van Trotsenburg, A. S. P., Vulsma, T., van Santen, H. M., Cheung, W., de Vijlder, J. J. M.
<strong>Lower neonatal screening thyroxine concentrations in Down syndrome newborns.</strong>
J. Clin. Endocr. Metab. 88: 1512-1515, 2003.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12679431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12679431</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12679431" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1210/jc.2002-021303" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="88" class="mim-anchor"></a>
<a id="Vidal-Taboada1998" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Vidal-Taboada, J. M., Sanz, S., Egeo, A., Scartezzini, P., Oliva, R.
<strong>Identification and characterization of a new gene from human chromosome 21 between markers D21S343 and D21S268 encoding a leucine-rich protein.</strong>
Biochem. Biophys. Res. Commun. 250: 547-554, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9784380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9784380</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9784380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1006/bbrc.1998.9352" target="_blank">Full Text</a>]
</p>
</div>
</li>
<li>
<a id="89" class="mim-anchor"></a>
<a id="Voronov2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Voronov, S. V., Frere, S. G., Giovedi, S., Pollina, E. A., Borel, C., Zhang, H., Schmidt, C., Akeson, E. C., Wenk, M. R., Cimasoni, L., Arancio, O., Davisson, M. T., Antonarakis, S. E., Gardiner, K., De Camilli, P., Di Paolo, G.
<strong>Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome.</strong>
Proc. Nat. Acad. Sci. 105: 9415-9420, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18591654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18591654</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18591654[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=18591654" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.0803756105" target="_blank">Full Text</a>]
</p>
</div>
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<li>
<a id="90" class="mim-anchor"></a>
<a id="Ward2004" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Ward, O. C.
<strong>Further early historical evidence of Down syndrome. (Letter)</strong>
Am. J. Med. Genet. 126A: 220, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15057991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15057991</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15057991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ajmg.a.20452" target="_blank">Full Text</a>]
</p>
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<a id="91" class="mim-anchor"></a>
<a id="Warren1987" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Warren, A. C., Chakravarti, A., Wong, C., Slaugenhaupt, S. A., Halloran, S. L., Watkins, P. C., Metaxotou, C., Antonarakis, S. E.
<strong>Evidence for reduced recombination on the nondisjoined chromosomes 21 in Down syndrome.</strong>
Science 237: 652-654, 1987.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2955519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2955519</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2955519" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.2955519" target="_blank">Full Text</a>]
</p>
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<a id="92" class="mim-anchor"></a>
<a id="Wechsler2002" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wechsler, J., Greene, M., McDevitt, M. A., Anastasi, J., Karp, J. E., Le Beau, M. M., Crispino, J. D.
<strong>Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome.</strong>
Nature Genet. 32: 148-152, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12172547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12172547</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12172547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/ng955" target="_blank">Full Text</a>]
</p>
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<a id="93" class="mim-anchor"></a>
<a id="Wilson2008" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wilson, M. D., Barbosa-Morais, N. L., Schmidt, D., Conboy, C. M., Vanes, L., Tybulewicz, V. L. J., Fisher, E. M. C., Tavare, S., Odom, D. T.
<strong>Species-specific transcription in mice carrying human chromosome 21.</strong>
Science 322: 434-438, 2008.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18787134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18787134</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18787134[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=18787134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1126/science.1160930" target="_blank">Full Text</a>]
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<a id="94" class="mim-anchor"></a>
<a id="Wisniewski1985" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Wisniewski, K. E., Wisniewski, H. M., Wen, G. Y.
<strong>Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome.</strong>
Ann. Neurol. 17: 278-282, 1985.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3158266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3158266</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3158266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1002/ana.410170310" target="_blank">Full Text</a>]
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<a id="95" class="mim-anchor"></a>
<a id="Yu2010" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Yu, T., Clapcote, S. J., Li, Z., Liu, C., Pao, A., Bechard, A. R., Carattini-Rivera, S., Matsui, S.-I., Roder, J. C., Baldini, A., Mobley, W. C., Bradley, A., Yu, Y. E.
<strong>Deficiencies in the region syntenic to human 21q22.3 cause cognitive deficits in mice.</strong>
Mammalian Genome 21: 258-267, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20512340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20512340</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20512340[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=20512340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1007/s00335-010-9262-x" target="_blank">Full Text</a>]
</p>
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<a id="96" class="mim-anchor"></a>
<a id="Yu2010" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Yu, T., Li, Z., Jia, Z., Clapcote, S. J., Liu, C., Li, S., Asrar, S., Pao, A., Chen, R., Fan, N., Carattini-Rivera, S., Bechard, A. R., Spring, S., Henkelman, R. M., Stoica, G., Matsui, S.-I., Nowak, N. J., Roder, J. C., Chen, C., Bradley, A., Yu, Y. E.
<strong>A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions.</strong>
Hum. Molec. Genet. 19: 2780-2791, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20442137/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20442137</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20442137[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=20442137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/ddq179" target="_blank">Full Text</a>]
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<a id="97" class="mim-anchor"></a>
<a id="Zhu2013" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zhu, J. L., Hasle, H., Correa, A., Schendel, D., Friedman, J. M., Olsen, J., Rasmussen, S. A.
<strong>Survival among people with Down syndrome: a nationwide population-based study in Denmark.</strong>
Genet. Med. 15: 64-69, 2013.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22878506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22878506</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22878506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1038/gim.2012.93" target="_blank">Full Text</a>]
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<a id="98" class="mim-anchor"></a>
<a id="Zipursky1987" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Zipursky, A., Peeters, M., Poon, A.
<strong>Megakaryoblastic leukemia and Down syndrome--A review. In: McCoy, E. E.; Epstein, C. J. (eds.): Oncology and Immunology of Down Syndrome.</strong>
New York: Alan R. Liss (pub.) 1987. Pp. 33-56.
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<a id="contributors" class="mim-anchor"></a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Paul J. Converse - updated : 5/28/2015
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<span class="mim-text-font">
Patricia A. Hartz - updated : 3/31/2015<br>Ada Hamosh - updated : 5/8/2014<br>Ada Hamosh - updated : 10/25/2013<br>Ada Hamosh - updated : 10/3/2013<br>George E. Tiller - updated : 8/21/2013<br>Ada Hamosh - updated : 4/17/2013<br>Ada Hamosh - updated : 2/7/2013<br>Patricia A. Hartz - updated : 9/11/2012<br>Cassandra L. Kniffin - updated : 3/6/2012<br>Cassandra L. Kniffin - updated : 7/7/2011<br>Cassandra L. Kniffin - updated : 4/12/2011<br>George E. Tiller - updated : 11/1/2010<br>Ada Hamosh - updated : 8/20/2010<br>Cassandra L. Kniffin - updated : 12/21/2009<br>Cassandra L. Kniffin - updated : 11/13/2009<br>Cassandra L. Kniffin - updated : 9/25/2009<br>Cassandra L. Kniffin - updated : 7/29/2009<br>Cassandra L. Kniffin - updated : 4/21/2009<br>Ada Hamosh - updated : 11/11/2008<br>Ada Hamosh - updated : 11/5/2008<br>Ada Hamosh - updated : 3/7/2008<br>Victor A. McKusick - updated : 8/17/2007<br>Marla J. F. O'Neill - updated : 6/22/2007<br>Marla J. F. O'Neill - updated : 2/5/2007<br>Marla J. F. O'Neill - updated : 11/10/2006<br>Ada Hamosh - updated : 7/24/2006<br>Patricia A. Hartz - updated : 3/24/2006<br>Cassandra L. Kniffin - updated : 12/20/2005<br>Ada Hamosh - updated : 11/2/2005<br>George E. Tiller - updated : 6/7/2005<br>Ada Hamosh - updated : 6/2/2005<br>Victor A. McKusick - updated : 3/21/2005<br>Marla J. F. O'Neill - updated : 1/28/2005<br>Marla J. F. O'Neill - updated : 1/4/2005<br>John A. Phillips, III - updated : 10/2/2003<br>George E. Tiller - updated : 1/30/2002<br>George E. Tiller - updated : 10/16/2001<br>Ada Hamosh - updated : 9/28/2001<br>Ada Hamosh - updated : 9/24/2001<br>Paul J. Converse - updated : 9/27/2000<br>George E. Tiller - updated : 4/27/2000<br>Patti M. Sherman - updated : 4/13/2000<br>Rebekah S. Rasooly - updated : 8/2/1998<br>Orest Hurko - updated : 8/11/1995
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Creation Date:
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<span class="mim-text-font">
Victor A. McKusick : 7/21/1994
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<a id="editHistory" class="mim-anchor"></a>
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carol : 03/07/2025
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carol : 11/01/2023<br>carol : 10/25/2023<br>carol : 10/25/2023<br>carol : 10/24/2023<br>carol : 10/24/2023<br>carol : 10/23/2023<br>carol : 03/16/2022<br>alopez : 07/30/2019<br>alopez : 02/15/2017<br>carol : 09/06/2016<br>carol : 08/04/2016<br>carol : 08/03/2016<br>carol : 12/22/2015<br>mgross : 6/9/2015<br>mcolton : 5/28/2015<br>mgross : 3/31/2015<br>alopez : 5/8/2014<br>alopez : 10/25/2013<br>alopez : 10/3/2013<br>tpirozzi : 8/23/2013<br>tpirozzi : 8/21/2013<br>alopez : 4/17/2013<br>alopez : 2/14/2013<br>alopez : 2/14/2013<br>terry : 2/7/2013<br>terry : 11/13/2012<br>carol : 10/8/2012<br>mgross : 9/13/2012<br>terry : 9/11/2012<br>carol : 3/8/2012<br>ckniffin : 3/6/2012<br>carol : 8/5/2011<br>carol : 8/2/2011<br>wwang : 7/14/2011<br>ckniffin : 7/7/2011<br>wwang : 4/12/2011<br>alopez : 11/3/2010<br>terry : 11/1/2010<br>alopez : 8/30/2010<br>terry : 8/20/2010<br>terry : 5/20/2010<br>terry : 4/30/2010<br>wwang : 1/11/2010<br>ckniffin : 12/21/2009<br>wwang : 12/1/2009<br>ckniffin : 11/13/2009<br>wwang : 10/21/2009<br>ckniffin : 9/25/2009<br>wwang : 8/11/2009<br>ckniffin : 7/29/2009<br>terry : 6/3/2009<br>wwang : 4/30/2009<br>ckniffin : 4/21/2009<br>terry : 2/9/2009<br>alopez : 12/1/2008<br>terry : 11/11/2008<br>terry : 11/5/2008<br>carol : 9/24/2008<br>alopez : 3/21/2008<br>terry : 3/7/2008<br>alopez : 8/27/2007<br>terry : 8/17/2007<br>wwang : 6/26/2007<br>terry : 6/22/2007<br>wwang : 2/5/2007<br>wwang : 11/13/2006<br>terry : 11/10/2006<br>alopez : 7/31/2006<br>alopez : 7/31/2006<br>alopez : 7/31/2006<br>alopez : 7/31/2006<br>terry : 7/24/2006<br>mgross : 3/29/2006<br>terry : 3/24/2006<br>wwang : 12/27/2005<br>ckniffin : 12/20/2005<br>terry : 11/2/2005<br>alopez : 6/7/2005<br>tkritzer : 6/3/2005<br>terry : 6/2/2005<br>terry : 5/17/2005<br>mgross : 3/23/2005<br>mgross : 3/21/2005<br>carol : 2/1/2005<br>terry : 1/28/2005<br>carol : 1/5/2005<br>terry : 1/4/2005<br>carol : 11/19/2004<br>carol : 7/23/2004<br>ckniffin : 11/11/2003<br>alopez : 10/2/2003<br>carol : 7/9/2003<br>ckniffin : 6/23/2003<br>cwells : 2/5/2002<br>cwells : 1/30/2002<br>cwells : 10/30/2001<br>cwells : 10/16/2001<br>alopez : 9/28/2001<br>terry : 9/24/2001<br>mgross : 9/27/2000<br>carol : 5/10/2000<br>alopez : 4/27/2000<br>mcapotos : 4/26/2000<br>psherman : 4/13/2000<br>terry : 5/20/1999<br>alopez : 8/2/1998<br>terry : 11/7/1997<br>alopez : 7/10/1997<br>terry : 7/9/1997<br>mark : 7/8/1997<br>mark : 9/13/1996<br>mimadm : 6/7/1995<br>pfoster : 2/14/1995<br>carol : 9/19/1994<br>davew : 7/21/1994
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<h3>
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<strong>#</strong> 190685
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DOWN SYNDROME
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<em>Alternative titles; symbols</em>
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TRISOMY 21
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Other entities represented in this entry:
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DOWN SYNDROME CHROMOSOME REGION, INCLUDED; DCR, INCLUDED
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DOWN SYNDROME CRITICAL REGION, INCLUDED; DSCR, INCLUDED
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<strong>SNOMEDCT:</strong> 737542000; &nbsp;
<strong>ICD10CM:</strong> Q90, Q90.9; &nbsp;
<strong>ICD9CM:</strong> 758.0; &nbsp;
<strong>ORPHA:</strong> 870; &nbsp;
<strong>DO:</strong> 14250; &nbsp;
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Cytogenetic location: 21q22.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 21:41,200,001-46,709,983 </span>
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<strong>Gene-Phenotype 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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21q22.3
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Down syndrome
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190685
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Isolated cases
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4
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because Down syndrome is caused by a chromosomal aberration, trisomy 21, and many genes are involved in the phenotype.</p>
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<strong>Description</strong>
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<p>Down syndrome, the most frequent form of impaired intellectual development caused by a microscopically demonstrable chromosomal aberration, is characterized by well-defined and distinctive phenotypic features and natural history. It is caused by triplicate state (trisomy) of all or a critical portion of chromosome 21.</p>
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<strong>Clinical Features</strong>
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<p>Down syndrome (Down, 1866), a particular combination of phenotypic features that includes impaired intellectual development and characteristic facies, is caused by trisomy 21 (Lejeune et al., 1959), one of the most common chromosomal abnormalities in liveborn children. </p><p>It has long been recognized that the risk of having a child with trisomy 21 increases with maternal age (Penrose, 1933). For example, the risk of having a liveborn with Down syndrome at maternal age 30 is 1 in 1,000 and at maternal age 40 is 9 in 1,000 (Hook, 1982; Hook et al., 1983). </p><p>Individuals with Down syndrome often have specific major congenital malformations such as those of the heart (30-40% in some studies), particularly atrioventricular septal defect (AVSD), and of the gastrointestinal tract, such as duodenal stenosis or atresia, imperforate anus, and Hirschsprung disease (142623). Some of these clinical features have been incorporated into the preliminary phenotypic maps of chromosome 21 developed by Korenberg (1993), Korenberg et al. (1992), and Delabar et al. (1993). </p><p>Leukemia (both ALL and AML) and leukemoid reactions show increased incidence in Down syndrome (Fong and Brodeur, 1987; Robison, 1992). Estimates of the relative risk have ranged from 10 to 20 times higher than the normal population; in particular, acute megakaryocytic leukemia occurs 200 to 400 times more frequently in the Down syndrome than in the chromosomally normal population (Zipursky et al., 1987). Transient leukemoid reactions have been reported repeatedly in the neonatal period (Niikawa et al., 1991). </p><p>Ninety percent of all Down syndrome patients have a significant hearing loss, usually of the conductive type (Mazzoni et al., 1994). </p><p>For additional defects and phenotypic characteristics, see Epstein (1989).</p><p>Patients with Down syndrome develop the neuropathologic hallmarks of Alzheimer disease at a much earlier age than individuals with Alzheimer disease without trisomy 21 (Wisniewski et al., 1985). Characteristic senile plaques and neurofibrillary tangles are present in the brain of all individuals with Down syndrome over the age of 40 years (Wisniewski et al., 1985). The triplication of the amyloid precursor protein gene (APP; 104760) may be the cause of this phenomenon. Several mutations in the APP gene have been described in families with early-onset Alzheimer disease without trisomy 21 (e.g., Goate et al., 1991). </p><p>Castilla et al. (1998) performed an epidemiologic analysis of the association of polydactyly with other congenital anomalies in 5,927 consecutively born polydactyly cases. Trisomy 13, Meckel syndrome (249000), and Down syndrome explained 255 of the 338 syndromic polydactyly cases. Down syndrome was strongly associated with first-digit duplication, and negatively associated with postaxial polydactyly. </p><p>In a retrospective study of high-altitude pulmonary edema performed at Children's Hospital in Denver, Durmowicz (2001) identified 6 of 52 patients as having Down syndrome. Five of the 6 children had preexisting illnesses including chronic pulmonary hypertension, existing cardiac defects with left-to-right shunt, or previous defects of left-to-right shunt that had been repaired. One child had Eisenmenger syndrome. Durmowicz (2001) suggested caution in traveling to even moderate altitudes with children with Down syndrome. </p><p>To determine whether newborns with DS have decreased blood T4 (thyroxine; tetraiodothyronine) concentrations at the time of the neonatal screening, van Trotsenburg et al. (2003) conducted an observational study in a large and representative cohort of Dutch children with DS born in 1996 and 1997. Results of congenital hypothyroidism (CH) screening measuring T4, TSH (see 188540), and T4-binding globulin (314200) concentrations were analyzed in comparison with clinical information obtained by interviewing the parents and data from the general newborn population and a large control group. The mean T4 concentration of the 284 studied children with DS was significantly decreased. The individual T4 concentrations were normally (Gaussian) distributed but shifted to lower concentrations. Mean TSH and T4-binding globulin concentrations were significantly increased and normal, respectively. The decreased T4 concentration, left-shifted normal distribution, and mildly elevated TSH concentrations pointed to a mild hypothyroid state in newborns with DS and supported the existence of a DS-specific thyroid (regulation) disorder. </p><p>In a case-control study, Tyler et al. (2004) found that the rate of symptomatic gallbladder disease was 25% among 28 index cases of adults with Down syndrome compared to 4.5% among sex-matched controls (p = 0.002). The adjusted relative risk for gallbladder disease among individuals with Down syndrome was 3.52. </p><p>Henry et al. (2007) examined complete blood counts obtained in the first week of life from 158 consecutive neonates with Down syndrome and found that neutrophilia, thrombocytopenia, and polycythemia were the most common hematologic abnormalities, occurring in 80%, 66%, and 33% of patients, respectively. </p><p><strong><em>Survival</em></strong></p><p>
Zhu et al. (2013) studied survival among individuals with Down syndrome from the Danish population using a national cohort of 3,530 persons with Down syndrome identified from the Danish Cytogenetic Register and a reference cohort of persons without Down syndrome randomly selected from the general population followed from 1 April 1968 to 15 January 2009 by linkages to the Register of Causes of Death and the Civil Registration System. Overall, persons with Down syndrome had higher mortality than the reference cohort but to a lesser degree for persons with mosaic trisomy 21 than for persons with standard trisomy 21 or with Robertsonian translocations (hazard ratio 4.98 (95% CI 3.52-7.08), 8.94 (8.32-9.60) and 10.23 (7.50-13.97), respectively). Among persons with Down syndrome born after April 1968, more recent birth cohorts had lower mortality rates than older birth cohorts, which was largely due to declining mortality among persons with Down syndrome who also had congenital heart defects. </p>
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<strong>Diagnosis</strong>
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<p>During the second trimester of pregnancy, serum alpha-feto protein (AFP; 104150) is commonly used for evaluating the risk of Down syndrome. Decreased levels of AFP are indicative of Down syndrome. However, Petit et al. (2009) noted that a congenital deficiency of AFP may result in decreased AFP in the maternal serum and amniotic fluid. They reported a male fetus with congenital absence of AFP, due to a truncating mutation (104150.0003), who showed normal growth and development. </p><p>Tsui et al. (2010) showed that analysis of PLAC4 (613770) can aid in the noninvasive prenatal detection of trisomy 21 using maternal plasma samples. PLAC4 is transcribed from chromosome 21 in the placenta and is specific for the fetus in maternal plasma. One analytic method, termed the RNA-SNP approach, measures the ratio of alleles for a SNP in placenta-derived mRNA molecules in maternal plasma. The RNA-SNP approach detected the deviated RNA-SNP allelic ratio in PLAC4 mRNA caused by an imbalance in chromosome 21 dosage. In a study of 153 pregnant women, the diagnostic sensitivity and specificity using this method was 100% and 89.7%, respectively. In fetuses homozygous for the SNP, a second analytic approach was used, which quantifies circulating PLAC4 mRNA concentrations. Trisomy 21 pregnancies showed significantly increased plasma PLAC mRNA compared to unaffected pregnancies. The sensitivity and specificity of this method were 91.7% and 81.0% using real-time PCR, and 83.3% and 83.5% using digital PCR. The overall findings suggested that the synergistic use of these 2 methods will increase the yield of correct diagnosis of trisomy 21 using noninvasive methods. </p>
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<strong>Cytogenetics</strong>
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<p>Most individuals (95%) with trisomy 21 have 3 free copies of chromosome 21; in about 5% of patients, 1 copy is translocated to another acrocentric chromosome, most often chromosome 14 or 21 (Thuline and Pueschel, 1982; Hook, 1982). In 2 to 4% of cases with free trisomy 21 there is recognizable mosaicism for a trisomic and a normal cell line (Mikkelsen, 1977). </p><p><strong><em>Origin of Free Trisomy 21</em></strong></p><p>
The availability of highly informative DNA markers has allowed the parental origin of the extra chromosome 21 and the meiotic/mitotic origin to be determined. More than 400 families have been studied (Antonarakis et al. (1991, 1992); Antonarakis, 1993; Sherman et al. (1991, 1992)) and the results are as follows: (1) Errors in meiosis that lead to trisomy 21 are overwhelmingly of maternal origin; only about 5% occur during spermatogenesis. (2) Most errors in maternal meiosis occur in meiosis I and the mean maternal age associated with these is 32 years (the mean maternal age of the general population is approximately 27 years). Thus, meiosis I errors account for 76 to 80% of maternal meiotic errors and 67 to 73% of all instances of free trisomy 21. (3) Maternal meiosis II errors constitute 20 to 24% of maternal errors and 18 to 20% of all cases of free trisomy 21. The mean maternal age is also advanced and is 31.4 in one study and 34.1 in another. (4) In rare families in which there is paternal nondisjunction, most of the errors occur in meiosis II. The mean maternal and paternal ages are similar to the mean reproductive age in western societies. (5) In 5% of trisomic individuals the supernumerary chromosome 21 appears to result from an error in mitosis. In these cases there is no advanced maternal age and there is no preference for which chromosome 21 is duplicated in the mitotic error. </p><p>Warren et al. (1987) and Sherman et al. (1991) have described an association between trisomy 21 and reduced recombination in meioses. A significant proportion (at least 30%) of maternal meiosis I nondisjunctions of chromosome 21 is associated with failure to recombine. It is not known whether the paucity of recombination is related to maternal age; moreover, the mechanism of recombination failure (asynapsis vs abnormalities during or after synapsis) is as yet unclear. </p><p>There is a well-established association between altered recombination patterns and nondisjunction of human chromosomes. Brown et al. (2000) investigated the possibility of reduced recombination in the total genome of an egg with a nondisjoined chromosome 21 and no detectable recombination. By genotyping 15 patients (at 366 autosomal markers) with trisomy 21, as well as their parents and maternal grandparents, the authors found a statistically significant genomewide reduction (p less than 0.05) in the mean recombination rate in these eggs with nondisjoined chromosomes 21. This reduction was felt to be consistent with normal variation in recombination observed among eggs. The authors hypothesized that when the number of genomewide recombination events is less than some threshold, specific chromosomes may be at an increased risk for nondisjunction. </p><p><strong><em>Origin of Translocation Trisomy 21</em></strong></p><p>
All de novo t(14;21) trisomies studied have originated in maternal germ cells (Petersen et al., 1991; Shaffer et al., 1992). The mean maternal age was 29.2 years. In de novo t(21;21) Down syndrome the situation is different (Grasso et al., 1989; Antonarakis et al., 1990; Shaffer et al., 1992). In most cases (14 out of 17) the t(21;21) is an isochromosome (dup21q) rather than the result of a Robertsonian translocation caused by a fusion between 2 heterologous chromatids. About half were of paternal and half of maternal origin. In the 3 de novo t(21;21) true Robertsonian trisomy 21 cases, the extra chromosome 21 was maternal. </p>
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<strong>Mapping</strong>
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<p><strong><em>Down Syndrome Critical Region</em></strong></p><p>
Mapping of the chromosomal region that, if triplicated, results in the phenotypic characteristics of Down syndrome has been facilitated by the use of DNA samples from individuals who have partial trisomy 21 with or without features of the Down syndrome phenotype (Rahmani et al., 1989; McCormick et al., 1989; Korenberg et al., 1990; Delabar et al., 1993; Korenberg, 1993). Although detailed analysis of these DNAs is still under way, an area of approximately 5 Mb between loci D21S58 and D21S42 has been identified that is associated with impaired intellectual development and most of the facial features of the syndrome. In particular, a subregion that includes D21S55 and MX1 (interferon-induced protein p78; 147150), the latter being located in band 21q22.3, has been associated with impaired intellectual development and several morphologic features, including oblique eye fissure, epicanthus, flat nasal bridge, protruding tongue, short broad hands, clinodactyly of the fifth finger, gap between first and second toes, hypotonia, short stature, Brushfield spots, and characteristic dermatoglyphics (Delabar et al., 1993). Additional phenotypic characteristics may map outside the minimum critical region (symbolized DCR). Material from other rare patients who have features of Down syndrome but no visible chromosomal abnormality may help to narrow down the critical region. In several such studies, however, no triplicated region has been identified (McCormick et al., 1989; Delabar et al., 1993). It is possible that these patients do not have any chromosome 21 abnormality and their phenotype is a phenocopy of Down syndrome. </p><p>Korenberg et al. (1990) defined the critical region for AVSD as involving D21S39, D21S42, and D21S43. Their subsequent publications further refined the minimum region for the major phenotypic features, although it remains unclear whether the region essential for AVSD is the same, since many clinical reports give insufficient information about the nature of the heart defect (Korenberg et al., 1992). Korenberg et al. (1992) correlated the human and mouse chromosome maps and suggested that the area of greatest interest extends from D21S55 to MX1. </p><p>By analysis of a 3-generation Japanese family containing 4 Down syndrome individuals with partial trisomy 21 (Korenberg et al., 1990), Ohira et al. (1996) defined a 1.6-Mb region between LA68 and ERG (165080) in 21q22 as the Down syndrome critical region. They constructed a contig map covering more than 95% of this 1.6-Mb region. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Genes Within the Down Syndrome Critical Region</em></strong></p><p>
Fuentes et al. (1995) cloned a gene (RCAN1; 602917), which they designated DSCR1, from the Down syndrome critical region that is highly expressed in brain and heart, and suggested it as a candidate for involvement in the pathogenesis of DS, in particular impaired intellectual development and/or cardiac defects. </p><p>Nakamura et al. (1997) identified DSCR4 (604829) as 2 ESTs that map to the 1.6-Mb Down syndrome critical region. DSCR4 is predominantly expressed in placenta. </p><p>Vidal-Taboada et al. (1998) identified DSCR2 (605296) within the Down syndrome critical region 2 between DNA marker D21S55 and MX1. </p><p>Nakamura et al. (1997) identified DSCR3 (605298) within the Down syndrome critical region. </p><p>Using indexing-based differential display PCR on neuronal precursor cells to study gene expression in Down syndrome, Bahn et al. (2002) found that genes regulated by the REST (600571) transcription factor were selectively repressed. One of these genes, SCG10 (600621), which encodes a neuron-specific growth-associated protein, was almost undetectable. The REST factor itself was also downregulated by 49% compared to controls. In cell culture, the Down syndrome cells showed a reduction of neurogenesis, as well as decreased neurite length and abnormal changes in neuron morphology. The authors noted that REST-regulated genes play an important part in brain development, plasticity, and synapse formation, and they suggested a link between dysregulation of REST and some of the neurologic deficits seen in Down syndrome. </p><p>Eggermann et al. (2010) reported a patient with a paternally inherited 0.46-Mb duplication of chromosome 21q22, including the KCNE1 (176261) and RCAN1 genes, who did not have typical facial or cardiac features of Down syndrome. The patient had a clinical phenotype resembling Silver-Russell syndrome (SRS; 180860), which is characterized by poor growth, but typical epigenetic changes associated with SRS were excluded. The duplication was inherited from the unaffected father. Eggermann et al. (2010) concluded that the RCAN1 gene is not sufficient for generating the phenotypic features associated with Down syndrome. </p><p><strong><em>Acute Megakaryoblastic Leukemia of Down Syndrome</em></strong></p><p>
Children with Down syndrome have a 10- to 20-fold elevated risk of developing leukemia, particularly acute megakaryoblastic leukemia (AMKL). Wechsler et al. (2002) showed that leukemic cells from individuals with Down syndrome-related AMKL had mutations in the GATA1 gene (305371). </p><p>Look (2002) reviewed the mechanism by which GATA1 mutations might interact with trisomy 21 to result in AMKL. He pointed out that several lines of evidence indicated that at least 2 classes of mutations are needed to transform a normal hematopoietic stem cell into a clonal acute myeloid leukemia. One class imparts a myeloproliferative or survival advantage, as illustrated by activating mutations in FLT3 (136351), encoding a receptor tyrosine kinase, or the increased dosage of genes in chromosome 21 in persons with Down syndrome. To generate overt leukemia, a second class of genetic alterations must produce lineage-specific blocks in differentiation. The mutations responsible for this step have been demonstrated mainly in genes encoding chimeric transcription factors produced by chromosomal translocation. GATA1 is a transcription factor that plays a pivotal role in myeloid lineage commitment. </p><p><strong><em>Transient Myeloproliferative Disorder of Down Syndrome</em></strong></p><p>
As many as 10% of infants with Down syndrome present with transient myeloproliferative disorder (TMD; 159595) at or shortly after birth. TMD is characterized by an abundance of blasts within peripheral blood and liver, and undergoes spontaneous remission in a majority of cases. TMD may be a precursor to AMKL, with an estimated 30% of TMD patients developing AMKL within 3 years. Mutations in GATA1 are associated with AMKL of Down syndrome. To determine whether the acquisition of GATA1 mutations is a late event restricted to acute leukemia, Mundschau et al. (2003) analyzed GATA1 in DNA from TMD patients. They found that GATA1 was mutated in the TMD blasts from every infant examined. These results demonstrated that GATA1 is likely to play a critical role in the etiology of TMD, and mutagenesis of GATA1 represents a very early event in myeloid leukemogenesis in Down syndrome. Hitzler et al. (2003) likewise presented evidence that GATA1 mutations are an early event, and that AMKL arises from latent transient leukemia clones following initial apparent remission. All 7 patients reported by Mundschau et al. (2003) and almost all of the patients studied by Hitzler et al. (2003) had deletions or insertions in the GATA1 gene rather than nucleotide substitutions. </p><p>Taketani et al. (2002) screened the RUNX1 gene (151385) in 46 Down syndrome patients with hematologic malignancies. They identified a heterozygous missense mutation (H58N; 151385.0008) in 1 patient diagnosed with TMD 5 days after birth. The patient died suddenly 12 months after birth; it was not known whether she developed acute myeloid leukemia. </p><p><strong><em>Atrioventricular Septal Defects of Down Syndrome</em></strong></p><p>
Given that mutations in the CRELD1 gene (607170) appear to be a risk factor for atrioventricular septal defect (AVSD) in the euploid population, and the fact that trisomy 21 is by far the most common finding associated with AVSD, Maslen et al. (2006) analyzed the CRELD1 gene in 39 individuals with Down syndrome and complete AVSD. They identified heterozygosity for missense mutations in 2 infants (607170.0001 and 607170.0005, respectively), and suggested that defects in CRELD1 may contribute to the pathogenesis of AVSD in the context of trisomy 21. </p><p>Ackerman et al. (2012) used a candidate gene approach among individuals with Down syndrome and complete AVSD (141 cases) and Down syndrome with no congenital heart defect (141 controls) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. Ackerman et al. (2012) found a significant excess (p less than 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, they found potentially damaging variants in nearly 20% of cases but fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in 6 genes: COL6A1 (120220), COL6A2 (120240), CRELD1 (mutations in which have already been identified as a cause of AVSD; see 606217), FBLN2 (135821), FRZB (605083), and GATA5 (611496). Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGFA (192240) pathway, suggesting to Ackerman et al. (2012) that rare variants in this pathway might contribute to the genetic underpinnings of AVSD in humans. </p><p><strong><em>Acute Lymphoblastic Leukemia of Down Syndrome</em></strong></p><p>
Bercovich et al. (2008) identified somatic mutations in the JAK2 gene (147796) in 16 (18%) of 88 patients with Down syndrome-associated acute lymphoblastic leukemia. Only 1 of 109 patients with non-Down syndrome-associated leukemia had the mutation, but this child was also found to have an isochromosome 21q. All the JAK2-associated leukemias were of the B-cell precursor type. Children with a JAK2 mutation were younger (mean age 4.5 years) compared to patients without JAK2 mutations (8.6 years) at diagnosis. Five mutant JAK2 alleles were identified, each affecting a highly conserved residue: arg683 (i.e., R683G, R683S, R683K). In vitro functional expression studies in mouse hematopoietic progenitor cells showed that the mutations caused constitutive Jak/Stat activation and cytokine-independent growth, consistent with a gain of function. This growth was sensitive to pharmacologic inhibition with a JAK inhibitor. Modeling studies showed that arg683 is located in an exposed conserved region of the JAK2 pseudokinase domain in a region different from that implicated in myeloproliferative disorders. Bercovich et al. (2008) concluded that there is a specific association between constitutional trisomy 21 and arg683 JAK2 mutations that predispose to the development of B-cell ALL in patients with Down syndrome. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Lyle et al. (2009) used array comparative genomic hybridization to analyze 30 patients with anomalies of chromosome 21, including 19 with partial trisomy 21 and 11 with partial monosomy 21, all for different segments of the chromosome. They also examined the phenotypes of 5 patients with a Down syndrome-like phenotype with a normal karyotype and 6 with complete trisomy 21. The majority of the phenotypes mapped to distal 21; averaging the phenotype score indicated a region approximately 37 to 44 Mb, which was involved in most Down syndrome phenotypes. These results were not surprising, as this is the most gene-rich region of chromosome 21. Five patients were trisomic for proximal 21 and did not include the so-called Down syndrome critical region (DSCR), thus excluding the possibility there is a single DSCR responsible for all aspects of the phenotype. </p>
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<strong>Population Genetics</strong>
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<p>The frequency of trisomy 21 in the population is 1 in 650 to 1,000 live births (Hook, 1982).</p>
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<strong>Pathogenesis</strong>
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<p>As a first step in identifying the genes responsible for individual features of Down syndrome and their pathophysiology, Korenberg et al. (1994) established a panel of cell lines derived from 16 individuals with Down syndrome caused by duplication of small regions of chromosome 21. The molecular breakpoints were determined using fluorescence in situ hybridization and Southern blot dosage analysis of 32 markers unique to chromosome 21. Combining this information with detailed clinical evaluations of the subjects, Korenberg et al. (1994) constructed a 'phenotypic map' that included 25 features and assigned regions of 2 to 20 Mb as likely to contain the genes responsible. This study provided evidence for a significant contribution of genes outside the D21S55 region to the DS phenotypes, including the facies, microcephaly, short stature, hypotonia, abnormal dermatoglyphics, and impaired intellectual development. The results strongly suggest that DS is a contiguous gene syndrome and make it unlikely that a single DS chromosomal region is responsible for most of the DS phenotypic features. </p><p>Busciglio et al. (2002) found that astrocyte and neuronal cell cultures derived from Down syndrome fetal brains had increased intracellular levels of insoluble beta-amyloid-42 and decreased levels of secreted beta-amyloid. These abnormal patterns of APP (104760) processing were recapitulated in normal astrocytes by inhibition of mitochondrial metabolism. In addition, DS astrocytes showed impaired mitochondrial metabolism. Busciglio et al. (2002) postulated that mitochondrial dysfunction in Down syndrome may lead to intracellular deposition of beta-amyloid and increased neuronal vulnerability. </p><p>Arron et al. (2006) reported that 2 genes, DSCR1 (RCAN1; 602917) and DYRK1A (600855), that lie within the critical region of human chromosome 21 act synergistically to prevent nuclear occupancy of NFATc transcription factors (see 600489), which are regulators of vertebrate development. Arron et al. (2006) used mathematical modeling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. The authors' observations of calcineurin (see 114105)- and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down syndrome, and human trisomy 21 are consistent with these predictions. Arron et al. (2006) suggested that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down syndrome. Arron et al. (2006) concluded that more generally, their observations suggest that the destabilization of regulatory circuits can underlie human disease. </p><p>In resting cells, NFAT proteins are heavily phosphorylated and reside in the cytoplasm; in cells exposed to stimuli that raise intracellular free calcium ion levels, they are dephosphorylated by the calmodulin (114180)-dependent phosphatase calcineurin and translocate to the nucleus. NFAT dephosphorylation by calcineurin is countered by distinct NFAT kinases, among them casein kinase-1 (CK1; 600505), and glycogen synthase kinase-3 (GSK3; see 605004). Gwack et al. (2006) used a genomewide RNA interference screen in Drosophila to identify additional regulators of the signaling pathway leading from calcium ion-calcineurin to NFAT. This screen was successful because the pathways regulating NFAT subcellular localization (calcium ion influx, calcium ion-calmodulin-calcineurin signaling, and NFAT kinases) are conserved across species, even though calcium ion-regulated NFAT proteins are not themselves represented in invertebrates. Using the screen, Gwack et al. (2006) identified DYRKs (dual-specificity tyrosine phosphorylation-regulated kinases) as novel regulators of NFAT. DYRK1A and DYRK2 (603496) counter calcineurin-mediated dephosphorylation of NFAT1 by directly phosphorylating the conserved serine-proline repeat 3 (SP3) motif of the NFAT regulatory domain, thus priming further phosphorylation of the SP2 and serine-rich region 1 (SRR1) motifs by GSK3 and CK1, respectively. Thus, Gwack et al. (2006) concluded that genetic screening in Drosophila can be successfully applied to cross evolutionary boundaries and identify new regulators of a transcription factor that is expressed only in vertebrates. </p><p>Down syndrome is characterized by extensive phenotypic variability; while cognitive impairment, muscle hypotonia at birth, and dysmorphic features occur to some extent in all affected individuals, most associated traits occur in only a fraction of affected individuals. Since Down syndrome is caused by genomic dosage imbalance, Prandini et al. (2007) hypothesized that variation in expression of genes on chromosome 21 in individuals with Down syndrome influences the phenotypic variability among affected individuals. They studied gene expression variation in 14 lymphoblastoid and 17 fibroblast cell lines from individuals with Down syndrome and an equal number of controls. Gene expression was assayed on 100 and 106 chromosome 21 genes and 23 and 26 non-chromosome 21 genes in lymphoblastoid and fibroblast cell lines, respectively. Surprisingly, only 39% and 62% of chromosome 21 genes in lymphoblastoid and fibroblast cells, respectively, showed a statistically significant difference between Down syndrome and normal samples, although the average upregulation of chromosome 21 genes was close to the expected 1.5-fold in both cell types. According to the degree of overlapping expression levels, Prandini et al. (2007) classified all genes into 3 groups: (A) nonoverlapping, (B) partially overlapping, and (C) extensively overlapping expression distributions between normal and Down syndrome samples. The authors hypothesized that, in each cell type, group A genes are the most dosage-sensitive and are most likely involved in the constant Down syndrome traits; group B genes may be involved in variable Down syndrome traits; and group C genes are not dosage-sensitive and are least likely to participate in Down syndrome pathologic phenotypes. </p><p>Using a transchromosomic mouse model of Down syndrome, Canzonetta et al. (2008) showed that a 30 to 60% reduced expression of NRSF/REST (600571), a key regulator of pluripotency and neuronal differentiation, is an alteration that persists in trisomy 21 from undifferentiated embryonic stem cells to adult brain and is reproducible across several Down syndrome models. Using partially trisomic embryonic stem (ES) cells, Canzonetta et al. (2008) mapped this effect to a 3-gene segment of human chromosome 21 containing DYRK1A (600855). The authors independently identified the same locus as the most significant expression quantitative trait locus (eQTL) controlling REST expression in the human genome. Canzonetta et al. (2008) found that specifically silencing the third copy of DYRK1A rescued Rest levels, and demonstrated altered Rest expression in response to inhibition of DYRK1A expression or kinase activity, and in a transgenic Dyrk1a mouse. The authors observed that undifferentiated trisomy 21 ES cells showed DYRK1A-dose-sensitive reductions in levels of some pluripotency regulators, including Nanog (607937) and Sox2 (184429), causing premature expression of transcription factors driving early endodermal and mesodermal differentiation, partially overlapping downstream effects of Rest heterozygosity. The ES cells produced embryoid bodies with elevated levels of the primitive endoderm progenitor marker Gata4 (600576) and a strongly reduced neuroectodermal progenitor compartment. Canzonetta et al. (2008) concluded that DYRK1A-mediated deregulation of REST is a very early pathologic consequence of trisomy 21 with potential to disturb the development of all embryonic lineages, warranting closer research into its contribution to Down syndrome pathology and rationales for therapeutic approaches. </p><p>Letourneau et al. (2014) studied the transcriptome of fetal fibroblasts from a pair of monozygotic twins discordant for trisomy 21 and showed that the differential expression between the twins was organized in domains along all chromosomes that are either upregulated or downregulated. These gene expression dysregulation domains (GEDDs) can be defined by the expression level of their gene content, and are well conserved in induced pluripotent stem cells derived from the twins' fibroblasts. Comparison of the transcriptome of the Ts65Dn mouse model of Down syndrome and normal littermate mouse fibroblasts also showed GEDDs along the mouse chromosomes that were syntenic in human. The GEDDs correlated with the lamina-associated domains (LADs) and the replication domains of mammalian cells. The overall position of LADs was not altered in trisomic cells; however, the H3K4me3 profile of the trisomic fibroblasts was modified and accurately followed the GEDD pattern. Letourneau et al. (2014) concluded that the nuclear compartments of trisomic cells undergo modifications of the chromatin environment influencing the overall transcriptome, and that GEDDs may therefore contribute to some trisomy 21 phenotypes. Letourneau et al. (2014) suggested that this effect may originate from the chromosome 21 protein HMGN1 (163920). The correlation of GEDDs with the replication time domains and a prolonged permissive chromatin state in trisomic cells raised the question of an excess of background transcription in trisomic cells. Letourneau et al. (2014) proposed that the overexpression of 1 or more human chromosome 21 candidate gene(s) modifies the chromatin environment of the nuclear compartments in trisomic cells. These modifications would lead to a general perturbation of the transcriptome that could explain some Down syndrome phenotypes. Alternatively, the GEDDs could be the result of the additional chromosomal material of trisomy 21. The prediction of this latter hypothesis is that other trisomies may have a similar effect on the dysregulation of gene expression, which remained to be studied. </p><p>Gimenez-Barcons et al. (2014) noted that Down syndrome is strongly associated with autoimmune disease. The transcription factor AIRE (607658), which is encoded on chromosome 21q22.3, regulates promiscuous gene expression (pGE) and thus plays a crucial role in autoimmunity. Gimenez-Barcons et al. (2014) assessed expression of AIRE in thymus samples from 19 patients with Down syndrome and 21 euploid controls. Despite the presence of trisomy 21 and 3 copies of AIRE, AIRE expression was significantly reduced by 2-fold in Down syndrome thymuses compared with controls. Decreased expression of AIRE was associated with reduced pGE because expression of the tissue-restricted antigens CHRNA1 (100690), GAD1 (605363), PLP1 (300401), KLK3 (176820), SAG (181031), TG (188450), and TSHR (603372) was reduced. More than half of the Down syndrome patients, and none of the controls, developed thyroid dysfunction over an approximately 20-year period, with 10 patients developing hypothyroidism and 1 developing Graves disease (see 275000). Patient thymuses contained significantly lower levels of AIRE and TG, an antigen to which tolerance is typically lost in autoimmune thyroiditis, leading to hypothyroidism. Gimenez-Barcons et al. (2014) concluded that AIRE and pGE have fundamental roles in predisposing individuals with Down syndrome to autoimmunity. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Using male mice doubly heterozygous for a 16;17 and a 9;16 translocation in crosses with females with a normal complement of 40 acrocentric chromosomes, Miyabara et al. (1982) generated litters with a high incidence of trisomy 16 in order to investigate the embryonic phenotype. A number of authors, including Polani and Adinolfi (1980), suggested that trisomy 16 in the mouse was likely to be homologous to trisomy 21 in humans since the loci SOD1 (Francke and Taggart, 1979), IFRC (Cox et al., 1980), and PRGS (Cox et al., 1981) are shared between these chromosomes in the 2 species. The frequency of trisomic embryos declined with advancing gestation; at day 14, 27.3% were recognized to be trisomic whereas only 4.3% of 20-day embryos were shown to be trisomy 16. General hypoplasia and developmental delay were noted together with early edema, all features compatible with the human syndrome. Malformations included a high incidence of hydronephrosis and complex heart anomalies. Like its human counterpart, atrioventricular septal defect in mice was often associated with outflow tract defects including truncus arteriosus, interrupted aortic arch, and double outlet right ventricle. In a subsequent review, Miyabara (1990) noted phenotypic overlap with DiGeorge syndrome (188400), which may reflect homology with the 22q11 region. The incidence of heart defects was higher in the mouse model than in humans, perhaps a result of earlier examination and the complexity of chromosomal homology. They noted that another influence is the genetic background. Against the NIMR background, Miyabara et al. (1982) found 56% AVSD cases, whereas against C57BL/6, Miyabara et al. (1984) found 95.5% cases. </p><p>Shinohara et al. (2001) used microcell-mediated chromosome transfer to create chimeric mice containing human chromosome 21. Fluorescence in situ hybridization and PCR-based DNA analysis revealed that chromosome 21 was substantially intact but had sustained a small deletion. The freely segregating chromosome 21 was lost during development in some tissues, resulting in a panel of chimeric mice with varying degrees of mosaicism. The chimeric mice showed a high correlation between retention of chromosome 21 in the brain and impairment in learning or emotional behavior by open-field, contextual fear conditioning, and forced swim tests. A significant number of the chimeric fetuses exhibited both thymic hypoplasia and conotruncal cardiac defects, and most of these animals also exhibited atrioventricular canal malformations. </p><p>Altafaj et al. (2001) generated transgenic mice overexpressing the full-length cDNA of Dyrk1A (600855). Dyrk1A mice exhibited delayed craniocaudal maturation with functional consequences in neuromotor development. Dyrk1A mice also showed altered motor skill acquisition and hyperactivity, which was maintained to adulthood. In the Morris water maze, Dyrk1A mice showed a significant impairment in spatial learning and cognitive flexibility, indicative of hippocampal and prefrontal cortex dysfunction. In the more complex repeated reversal learning paradigm, this defect was specifically related to reference memory, whereas working memory was almost unimpaired. The authors suggested a causative role of DYRK1A in impaired intellectual development and in motor anomalies of DS. </p><p>Trisomy 21 results in cerebellar dysmorphism with direct parallels in the Ts65Dn (partial trisomy) mouse. Despite pronounced changes in morphology, cerebellar function is not markedly different. Saran et al. (2003) distinguished trisomic and euploid murine cerebellar transcriptomes by microarray analysis. Changes in expression of individual genes were very subtle, but the differences in respective transcriptome phenotypes extended deeply into the set of nearly 7,000 probes located throughout the genome. Examination of the discriminating genes in 2 independent experiments suggested that the global perturbation may include a significant stochastic component. Thus, dosage imbalance of the 124 genes in Ts65Dn mice altered the expression of thousands of genes to create a variable trisomic transcriptome. </p><p>Olson et al. (2004) used chromosome engineering to create mice that were trisomic or monosomic for only the mouse chromosome segment orthologous to the Down syndrome critical region and assessed dysmorphologies of the craniofacial skeleton that showed direct parallels with Down syndrome in mice with a larger segmental trisomy. The Down syndrome critical region genes were not sufficient and were largely not necessary to produce the facial phenotype. Olson et al. (2004) concluded that their results refuted specific predictions of the prevailing hypothesis of gene action in Down syndrome. </p><p>O'Doherty et al. (2005) generated a transspecies aneuploid mouse line that stably transmits a freely segregating, almost complete human chromosome 21. This transchromosomic mouse line, Tc1, is a model of trisomy 21, which manifests as Down syndrome in humans, and has phenotypic alterations in behavior, synaptic plasticity, cerebellar neuronal number, heart development, and mandible size that relate to human Down syndrome. </p><p>Roper et al. (2006) found that a deficit in cerebellar granule cell neurons in a mouse model of Down syndrome was associated with reduced mitogenic response of granule cell precursors to Hedgehog protein signaling in early postnatal development. Systemic treatment of newborn trisomic mice with a small molecule agonist of the Hedgehog signaling pathway increased mitosis and restored the granule cell precursor population in vivo. </p><p>In Ts65Dn and Ts1Cje mouse models of Down syndrome, Salehi et al. (2006) found that increased dosage of the App gene markedly decreased retrograde transport of nerve growth factor (NGF; 162030), thus resulting in degeneration of cholinergic neurons in the basal forebrain. NGF-containing early endosomes were enlarged in cholinergic axons of the Ts65Dn mice and their App content was increased. The findings demonstrated a pathogenic mechanism for Down syndrome whereby disrupted axonal transport in certain neurons results in neuronal degeneration. </p><p>Sussan et al. (2008) used mouse models of Down syndrome and of cancer in a biologic approach to investigate the relationship between trisomy and the incidence of intestinal tumors. Apc(Min) (611731)-mediated tumor number was determined in aneuploid mouse models Ts65Dn, Ts1Rhr, and Ms1Rhr. Trisomy for orthologs of about half of the genes on chromosome 21 (Hsa21) in Ts65Dn mice or just 33 of these genes in Ts1Rhr mice resulted in a significant reduction in the number of intestinal tumors. In Ms1Rhr, segmental monosomy for the same 33 genes that are triplicated in Ts1Rhr resulted in an increased number of tumors. Further studies demonstrated that the Ets2 gene (164740) contributed most of the dosage-sensitive effect on intestinal tumor number. The action of Est2 as a repressor when it is overexpressed differs from tumor suppression, which requires normal gene function to prevent cellular transformation. Sussan et al. (2008) suggested that upregulation of Ets2 and, potentially, other genes involved in this kind of protective effect may provide a prophylactic effect in all individuals, regardless of ploidy. </p><p>Wilson et al. (2008) used the Tc1 mouse model of Down syndrome to determine whether, on a chromosomal scale, interspecies differences in transcriptional regulation are primarily directed by human genetic sequence or mouse nuclear environment. Virtually all transcription factor-binding locations, landmarks of transcription initiation, and the resulting gene expression observed in human hepatocytes were recapitulated across the entire human chromosome 21 in the mouse hepatocyte nucleus. Wilson et al. (2008) concluded that thus, in homologous tissues, genetic sequence is largely responsible for directing transcriptional programs; interspecies differences in epigenetic machinery, cellular environment, and transcription factors themselves play secondary roles. </p><p>Voronov et al. (2008) found altered phosphatidylinositol-4,5-bisphosphate metabolism in the brains of Ts65Dn mice. The defect could be rescued by restoring Synj1 (604297) to disomy in Ts65Dn mice and could also be recapitulated in transgenic mice overexpressing Synj1. The transgenic mice exhibited deficits in performance of the Morris water maze task, suggesting that perturbation of this signaling pathway may contribute to brain dysfunction in patients with Down syndrome. The findings suggested that correct dosage of the Synj1 gene is important for normal brain development and function. </p><p>Reynolds et al. (2010) used the Tc1 transchromosomic mouse model of Down syndrome (O'Doherty et al., 2005) to dissect the contribution of extra copies of genes on Hsa21 to tumor angiogenesis. The Tc1 mouse expresses roughly 81% of human chromosome 21 genes but not the human DSCR1 (RCAN1; 602917) region, implicated as responsible for decreased incidence of solid tumors among patients with Down syndrome. Reynolds et al. (2010) transplanted B16F0 and Lewis lung carcinoma tumor cells into Tc1 mice and showed that growth of these tumors was substantially reduced compared with wildtype littermate controls. Furthermore, tumor angiogenesis was significantly repressed in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF; 192240) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative antiangiogenic genes, ADAMTS1 (605174) and ERG (165080), and novel endothelial cell-specific genes never previously shown to be involved in angiogenesis, JAM-B (606870) and PTTG1IP (603784), that, when overexpressed, are responsible for inhibiting angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumor angiogenesis, explaining the reduced tumor growth in Down syndrome. Furthermore, Reynolds et al. (2010) expected that, in addition to the candidate genes that they showed to be involved in the regression of angiogenesis, the Tc1 mouse model of Down syndrome will permit the identification of other endothelium-specific antiangiogenic targets relevant to a broad spectrum of cancer patients. </p><p>Pereira et al. (2009) showed that trisomy of the 12 genes found in the 0.59 Mb (Abcg1-U2af1) Hsa21 subtelomeric region in mice (Ts1Yah) produced defects in novel object recognition, open-field, and Y-maze tests, similar to other Down syndrome models, but induced an improvement of the hippocampal-dependent spatial memory in the Morris water maze along with enhanced and longer lasting long-term potentiation in vivo in the hippocampus. The authors demonstrated a contribution of the Abcg1-U2af1 genetic region to cognitive defects in working and short-term recognition memory in Down syndrome models. Increase in copy number of the Abcg1-U2af1 interval led to an unexpected gain of cognitive function in spatial learning. Expression analysis pinpointed several genes, such as Ndufv3 (602184), Wdr4 (605924), Pknox1 (602100), and Cbs (613381), as candidates whose overexpression in the hippocampus might facilitate learning and memory in Ts1Yah mice. </p><p>For a model of human monosomy 21, Yu et al. (2010) created mutant mice with heterozygous deletions in segments of chromosomes 10 and 17 that are syntenic to regions of human chromosome 21q22.3. The deleted regions of mouse chromosomes 10 and 17 contain 28 and 19 genes, respectively, orthologous to those found on human chromosome 21q22.3. Heterozygous mutant mice showed deficits in spatial learning and memory and context-associated learning. </p><p>Yu et al. (2010) described a mouse model for Down syndrome that carried duplications spanning human chromosome 21 (Hsa21) syntenic regions on 3 mouse chromosomes. The mouse mutant exhibited Down syndrome-related neurologic defects, including impaired cognitive behaviors, reduced hippocampal long-term potentiation, and hydrocephalus. The authors suggested that when all the mouse orthologs of the Hsa21 genes were triplicated, an abnormal cognitively relevant phenotype was the final outcome of their elevated expression and possible functional interactions. </p><p>Martin et al. (2012) found that modest overexpression of human RCAN1 under the control of its own promoter in transgenic mice did not cause overall brain abnormalities but resulted in significant defects in the hippocampal dentate gyrus region. The volume of the hippocampus was significantly reduced, with a reduced number of neurons and decreased spine density in apical dendrites. Transgenic neural progenitor cells from the dentate gyrus region formed neurospheres in culture, but unlike wildtype neurospheres, they tended to differentiate into astrocytes and oligodendrocytes more readily than neurons. Hippocampal slices from transgenic mice showed defects in long-term potentiation, which were accompanied by reduced phosphorylation of Camk2 (see 114078) and Erk1 (MAPK3; 601795)/Erk2 (MAPK1; 176948), and reduced Ca(2+) transients. Behaviorally, adult transgenic mice showed deficits in learning and memory. Martin et al. (2012) concluded that modest overexpression of RCAN1 in transgenic mice mirrors many of the abnormalities observed in Down syndrome. </p><p>Adorno et al. (2013) found that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 (604735) reduces the self-renewal of hematopoietic stem cells and the expansion of mammary epithelial cells, neuroprogenitors, and fibroblasts. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a (600160) and accelerated senescence in Ts65Dn fibroblasts. Usp16 can remove ubiquitination from histone H2A (see 613499) on lys119, a critical mark for the maintenance of multiple somatic tissues. Downregulation of Usp16, either by mutation of a single normal Usp16 allele or by short interfering RNAs, largely rescues these defects. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down syndrome fibroblasts. Adorno et al. (2013) suggested that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down syndrome and could serve as an attractive target to ameliorate some of the associated pathologies. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Other Features</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Jiang et al. (2013) tested the concept that a gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, X inactivation-specific transcript (XIST; 314670). Using genome editing with zinc finger nucleases, Jiang et al. (2013) inserted a large inducible XIST transgene into the DYRK1A (600855) locus on chromosome 21 in Down syndrome pluripotent stem cells. The XIST noncoding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosomewide transcriptional silencing, and DNA methylation to form a 'chromosome 21 Barr body.' This provided a model to study human chromosome inactivation and created a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. Notably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing 1 chromosome 21. Jiang et al. (2013) suggested that their successful trisomy silencing in vitro surmounted the major first step towards potential development of chromosome therapy. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>History</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Garrod (1894) first reported the association between Down syndrome and heart malformation. Abbott (1924) drew attention to the association between AVSD and Down syndrome.</p><p>Neri and Opitz (2009) provided a detailed review of the history of the scientific developments leading to the molecular characterization of Down syndrome. </p><p>Speculation about the historic prevalence of Down syndrome has included references to apparent depictions of the syndrome in 15th (Ward, 2004) and 16th (Levitas and Reid, 2003) century paintings. Martinez-Frias (2005) reported what seems likely to be the earliest evidence of the syndrome in a terra-cotta head from approximately 500 AD belonging to the Tolteca culture of Mexico, in which 'it is easy to identify the short palpebral fissures, oblique eyes, midface hypoplasia, and open mouth with macroglossia, findings that clearly define the face of a person with Down syndrome.' </p><p>Bernal and Briceno (2006) examined pottery artifacts from the Tumaco-La Tolita culture, which existed on the border of present-day Colombia and Ecuador approximately 2,500 years ago, and described several figurines with characteristics suggestive of Down syndrome. Bernal and Briceno (2006) believed these artifacts to be among the earliest artistic representations of disease. </p>
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>See Also:</strong>
</span>
</h4>
<span class="mim-text-font">
Hall (1962); Rex and Preus (1982); Tandon and Edwards (1973)
</span>
<div>
<br />
</div>
</div>
<div>
<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Abbott, M. E.
<strong>New accessions in cardiac anomalies: pulmonary atresia of inflammatory origin; persistent ostium primum with Mongolian idiocy.</strong>
Int. A. M. Mus. Bull. 10: 111, 1924.
</p>
</li>
<li>
<p class="mim-text-font">
Ackerman, C., Locke, A. E., Feingold, E., Reshey, B., Espana, K., Thusberg, J., Mooney, S., Bean, L. J. H., Dooley, K. J., Cua, C. L., Reeves, R. H., Sherman, S. L., Maslen, C. L.
<strong>An excess of deleterious variants in VEGF-A pathway genes in Down-syndrome-associated atrioventricular septal defects.</strong>
Am. J. Hum. Genet. 91: 646-659, 2012.
[PubMed: 23040494]
[Full Text: https://doi.org/10.1016/j.ajhg.2012.08.017]
</p>
</li>
<li>
<p class="mim-text-font">
Adorno, M., Sikandar, S., Mitra, S. S., Kuo, A., Nicolas Di Robilant, B., Haro-Acosta, V., Ouadah, Y., Quarta, M., Rodriguez, J., Qian, D., Reddy, V. M., Cheshier, S., Garner, C. C., Clarke, M. F.
<strong>Usp16 contributes to somatic stem-cell defects in Down&#x27;s syndrome.</strong>
Nature 501: 380-384, 2013.
[PubMed: 24025767]
[Full Text: https://doi.org/10.1038/nature12530]
</p>
</li>
<li>
<p class="mim-text-font">
Altafaj, X., Dierssen, M., Baamonde, C., Marti, E., Visa, J., Guimera, J., Oset, M., Gonzalez, J. R., Florez, J., Fillat, C., Estivill, X.
<strong>Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down&#x27;s syndrome.</strong>
Hum. Molec. Genet. 10: 1915-1923, 2001.
[PubMed: 11555628]
[Full Text: https://doi.org/10.1093/hmg/10.18.1915]
</p>
</li>
<li>
<p class="mim-text-font">
Antonarakis, S. E., Adelsberger, P. A., Petersen, M. B., Binkert, F., Schinzel, A. A.
<strong>Analysis of DNA polymorphism suggests that most de novo dup(21q) chromosomes in patients with Down syndrome are isochromosomes and not translocations.</strong>
Am. J. Hum. Genet. 47: 968-972, 1990.
[PubMed: 1978562]
</p>
</li>
<li>
<p class="mim-text-font">
Antonarakis, S. E., Lewis, J. G., Adelsberger, P. A., Petersen, M. B., Schinzel, A. A., Binkert, F., Schmid, W., Pangalos, C., Raoul, O., Chakravarti, A., Hafez, M., Cohen, M. M., Roulston, D., Schwartz, S., Mikkelsen, M., Tranebjaerg, L., Greenberg, F., Hoar, D. I., Rudd, N. L., Warren, A. C., Metaxotou, C., Bartsocas, C., Down Syndrome Collaborative Group.
<strong>Parental origin of the extra chromosome in trisomy 21 using DNA polymorphism analysis.</strong>
New Eng. J. Med. 324: 872-876, 1991.
[PubMed: 1825697]
[Full Text: https://doi.org/10.1056/NEJM199103283241302]
</p>
</li>
<li>
<p class="mim-text-font">
Antonarakis, S. E., Petersen, M. B., McInnis, M. G., Adelsberger, P. A., Schinzel, A. A., Binkert, F., Pangalos, C., Raoul, O., Slaugenhaupt, S. A., Hafez, M., Cohen, M. M., Roulson, D., Schwartz, S., Mikkelsen, M., Tranebjaerg, L., Greenberg, F., Hoar, D. I., Rudd, N. L., Warren, A. C., Metaxotou, C., Bartsocas, C., Chakravarti, A.
<strong>The meiotic stage of nondisjunction in trisomy 21: determination using DNA polymorphisms.</strong>
Am. J. Hum. Genet. 50: 544-550, 1992.
[PubMed: 1347192]
</p>
</li>
<li>
<p class="mim-text-font">
Antonarakis, S. E.
<strong>Human chromosome 21: genome mapping and exploration circa 1993.</strong>
Trends Genet. 9: 142-148, 1993.
[PubMed: 8516850]
[Full Text: https://doi.org/10.1016/0168-9525(93)90210-9]
</p>
</li>
<li>
<p class="mim-text-font">
Arron, J. R., Winslow, M. M., Polleri, A., Chang, C.-P., Wu, H., Gao, X., Neilson, J. R., Chen, L., Heit, J. J., Kim, S. K., Yamasaki, N., Miyakawa, T., Francke, U., Graef, I. A., Crabtree, G. R.
<strong>NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21.</strong>
Nature 441: 595-600, 2006.
[PubMed: 16554754]
[Full Text: https://doi.org/10.1038/nature04678]
</p>
</li>
<li>
<p class="mim-text-font">
Bahn, S., Mimmack, M., Ryan, M., Caldwell, M. A., Jauniaux, E., Starkey, M., Svendsen, C. N., Emson, P.
<strong>Neuronal target genes of the neuron-restrictive silencer factor in neurospheres derived from fetuses with Down&#x27;s syndrome: a gene expression study.</strong>
Lancet 359: 310-315, 2002.
[PubMed: 11830198]
[Full Text: https://doi.org/10.1016/S0140-6736(02)07497-4]
</p>
</li>
<li>
<p class="mim-text-font">
Bercovich, D., Ganmore, I., Scott, L. M., Wainreb, G., Birger, Y., Elimelech, A., Shochat, C., Cazzaniga, G., Biandi, A., Basso, G., Cario, G., Schrapper, M., and 17 others.
<strong>Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down&#x27;s syndrome.</strong>
Lancet 372: 1484-1492, 2008.
[PubMed: 18805579]
[Full Text: https://doi.org/10.1016/S0140-6736(08)61341-0]
</p>
</li>
<li>
<p class="mim-text-font">
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Paul J. Converse - updated : 5/28/2015<br>Patricia A. Hartz - updated : 3/31/2015<br>Ada Hamosh - updated : 5/8/2014<br>Ada Hamosh - updated : 10/25/2013<br>Ada Hamosh - updated : 10/3/2013<br>George E. Tiller - updated : 8/21/2013<br>Ada Hamosh - updated : 4/17/2013<br>Ada Hamosh - updated : 2/7/2013<br>Patricia A. Hartz - updated : 9/11/2012<br>Cassandra L. Kniffin - updated : 3/6/2012<br>Cassandra L. Kniffin - updated : 7/7/2011<br>Cassandra L. Kniffin - updated : 4/12/2011<br>George E. Tiller - updated : 11/1/2010<br>Ada Hamosh - updated : 8/20/2010<br>Cassandra L. Kniffin - updated : 12/21/2009<br>Cassandra L. Kniffin - updated : 11/13/2009<br>Cassandra L. Kniffin - updated : 9/25/2009<br>Cassandra L. Kniffin - updated : 7/29/2009<br>Cassandra L. Kniffin - updated : 4/21/2009<br>Ada Hamosh - updated : 11/11/2008<br>Ada Hamosh - updated : 11/5/2008<br>Ada Hamosh - updated : 3/7/2008<br>Victor A. McKusick - updated : 8/17/2007<br>Marla J. F. O&#x27;Neill - updated : 6/22/2007<br>Marla J. F. O&#x27;Neill - updated : 2/5/2007<br>Marla J. F. O&#x27;Neill - updated : 11/10/2006<br>Ada Hamosh - updated : 7/24/2006<br>Patricia A. Hartz - updated : 3/24/2006<br>Cassandra L. Kniffin - updated : 12/20/2005<br>Ada Hamosh - updated : 11/2/2005<br>George E. Tiller - updated : 6/7/2005<br>Ada Hamosh - updated : 6/2/2005<br>Victor A. McKusick - updated : 3/21/2005<br>Marla J. F. O&#x27;Neill - updated : 1/28/2005<br>Marla J. F. O&#x27;Neill - updated : 1/4/2005<br>John A. Phillips, III - updated : 10/2/2003<br>George E. Tiller - updated : 1/30/2002<br>George E. Tiller - updated : 10/16/2001<br>Ada Hamosh - updated : 9/28/2001<br>Ada Hamosh - updated : 9/24/2001<br>Paul J. Converse - updated : 9/27/2000<br>George E. Tiller - updated : 4/27/2000<br>Patti M. Sherman - updated : 4/13/2000<br>Rebekah S. Rasooly - updated : 8/2/1998<br>Orest Hurko - updated : 8/11/1995
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