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<title>
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Entry
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- #610543 - CHROMOSOME 16p13.3 DELETION SYNDROME, PROXIMAL
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- OMIM
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<span class="h4">#610543</span>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="/phenotypicSeries/PS180849"> <strong>Phenotypic Series</strong> </a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://clinicaltrials.gov/search?cond=CHROMOSOME 16p13.3 DELETION SYNDROME, PROXIMAL" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://decipher.sanger.ac.uk/syndrome/7" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=22128&Typ=Pat" title="Rubinstein-Taybi syndrome due to 16p13.3 microdeletion" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Rubinstein-Taybi syndrome … </a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=151&Typ=Pat" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">Rubinstein-Taybi syndrome </a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=610543[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=353281" title="Rubinstein-Taybi syndrome due to 16p13.3 microdeletion" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Rubinstein-Taybi syndrome …</a></div><div style="margin-left: 0.5em;"><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=783" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">Rubinstein-Taybi syndrome</a></div>
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<div><a href="https://www.possumcore.com/nuxeo/nxdoc/default/ed912871-4baa-40e4-84b0-f8a75804ca2d/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>
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<div><a href="http://www.informatics.jax.org/disease/610543" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:1933" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 353281, 783<br />
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<strong>DO:</strong> 1933<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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610543
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<div>
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CHROMOSOME 16p13.3 DELETION SYNDROME, PROXIMAL
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RUBINSTEIN-TAYBI DELETION SYNDROME<br />
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RSTS DELETION SYNDROME
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Cytogenetic location: <a href="/geneMap/16/4?start=-3&limit=10&highlight=4">16p13.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:1-7800000&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'})">16:1-7,800,000</a> </span>
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<strong>Gene-Phenotype Relationships</strong>
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Inheritance
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Phenotype <br /> mapping key
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<a href="/geneMap/16/4?start=-3&limit=10&highlight=4">
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16p13.3
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<span class="mim-font">
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Chromosome 16p13.3 deletion syndrome
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<a href="/entry/610543"> 610543 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="4 - A contiguous gene duplication or deletion syndrome in which multiple genes are involved">4</abbr>
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<a href="/phenotypicSeries/PS180849" class="btn btn-info" role="button"> Phenotypic Series </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="caret"></span>
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<span class="sr-only">Toggle Dropdown</span>
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/610543" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/610543" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<h5>
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Rubinstein-Taybi syndrome
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- <a href="/phenotypicSeries/PS180849">PS180849</a>
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- 3 Entries
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<strong>Phenotype<br />mapping key</strong>
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<strong>Phenotype<br />MIM number</strong>
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<a href="/geneMap/16/4?start=-3&limit=10&highlight=4"> 16p13.3 </a>
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<span class="mim-font">
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<a href="/entry/610543"> Chromosome 16p13.3 deletion syndrome </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="4 - A contiguous gene duplication or deletion syndrome in which multiple genes are involved"> 4 </abbr>
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<span class="mim-font">
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<a href="/entry/610543"> 610543 </a>
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<a href="/entry/610543"> DEL16p13.3 </a>
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<span class="mim-font">
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<a href="/entry/610543"> 610543 </a>
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<a href="/geneMap/16/150?start=-3&limit=10&highlight=150"> 16p13.3 </a>
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<a href="/entry/180849"> Rubinstein-Taybi syndrome 1 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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<a href="/entry/180849"> 180849 </a>
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<a href="/entry/600140"> CREBBP </a>
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<span class="mim-font">
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<a href="/entry/600140"> 600140 </a>
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<a href="/geneMap/22/315?start=-3&limit=10&highlight=315"> 22q13.2 </a>
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<span class="mim-font">
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<a href="/entry/613684"> Rubinstein-Taybi syndrome 2 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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<a href="/entry/613684"> 613684 </a>
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<span class="mim-font">
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<a href="/entry/602700"> EP300 </a>
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<span class="mim-font">
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<a href="/entry/602700"> 602700 </a>
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<a href="#mimPhenotypicSeriesFold" data-toggle="collapse">▲ Close</a>
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because the phenotype is a contiguous gene syndrome caused by deletion of chromosome 16p13.3, affecting the CREBBP (<a href="/entry/600140">600140</a>), DNASE1 (<a href="/entry/125505">125505</a>), and TRAP1 (HSP75; <a href="/entry/606219">606219</a>) genes.</p><p>Rubinstein-Taybi syndrome-1 (RSTS1; <a href="/entry/180849">180849</a>) is caused by point mutations or deletions within the CREBBP gene.</p>
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<p><a href="#3" class="mim-tip-reference" title="Bartsch, O., Wagner, A., Hinkel, G. K., Krebs, P., Stumm, M., Schmalenberger, B., Bohm, S., Balci, S., Majewski, F. <strong>FISH studies in 45 patients with Rubinstein-Taybi syndrome: deletions associated with polysplenia, hypoplastic left heart and death in infancy.</strong> Europ. J. Hum. Genet. 7: 748-756, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10573006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10573006</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10573006">Bartsch et al. (1999)</a> reported 2 patients with RSTS caused by large deletions of chromosome 16p13.3 who died in infancy, which is rare in RSTS. One of these patients had accessory spleens, hypoplastic left heart, abnormal pulmonary lobulation, and renal agenesis. The other patient had severe neonatal seizures. The combination of RSTS and hypoplastic left heart had previously been described in only 1 patient (<a href="#12" class="mim-tip-reference" title="Stevens, C. A., Bhakta, M. G. <strong>Cardiac abnormalities in the Rubinstein-Taybi syndrome.</strong> Am. J. Med. Genet. 59: 346-348, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8599359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8599359</a>] [<a href="https://doi.org/10.1002/ajmg.1320590313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8599359">Stevens and Bhakta, 1995</a>). <a href="#3" class="mim-tip-reference" title="Bartsch, O., Wagner, A., Hinkel, G. K., Krebs, P., Stumm, M., Schmalenberger, B., Bohm, S., Balci, S., Majewski, F. <strong>FISH studies in 45 patients with Rubinstein-Taybi syndrome: deletions associated with polysplenia, hypoplastic left heart and death in infancy.</strong> Europ. J. Hum. Genet. 7: 748-756, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10573006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10573006</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10573006">Bartsch et al. (1999)</a> suggested that patients with severe RSTS and large deletions had a distinct contiguous gene syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8599359+10573006" 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="Bartsch, O., Rasi, S., Delicado, A., Dyack, S., Neumann, L. M., Seemanova, E., Volleth, M., Haaf, T., Kalscheuer, V. M. <strong>Evidence for a new contiguous gene syndrome, the chromosome 16p13.3 deletion syndrome alias severe Rubinstein-Taybi syndrome.</strong> Hum. Genet. 120: 179-186, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783566</a>] [<a href="https://doi.org/10.1007/s00439-006-0215-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783566">Bartsch et al. (2006)</a> provided further analysis of the 2 patients with severe RSTS reported by <a href="#3" class="mim-tip-reference" title="Bartsch, O., Wagner, A., Hinkel, G. K., Krebs, P., Stumm, M., Schmalenberger, B., Bohm, S., Balci, S., Majewski, F. <strong>FISH studies in 45 patients with Rubinstein-Taybi syndrome: deletions associated with polysplenia, hypoplastic left heart and death in infancy.</strong> Europ. J. Hum. Genet. 7: 748-756, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10573006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10573006</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200378" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10573006">Bartsch et al. (1999)</a> and a third patient reported by <a href="#1" class="mim-tip-reference" title="Bartsch, O., Locher, K., Meinecke, P., Kress, W., Seemanova, E., Wagner, A., Ostermann, K., Rodel, G. <strong>Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP.</strong> J. Med. Genet. 39: 496-501, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12114483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12114483</a>] [<a href="https://doi.org/10.1136/jmg.39.7.496" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12114483">Bartsch et al. (2002)</a>. All had a severe phenotype with failure to thrive, life-threatening malformations, and/or critical infections, and all died in infancy (5 weeks, 7 months, and 9 months, respectively). <a href="#2" class="mim-tip-reference" title="Bartsch, O., Rasi, S., Delicado, A., Dyack, S., Neumann, L. M., Seemanova, E., Volleth, M., Haaf, T., Kalscheuer, V. M. <strong>Evidence for a new contiguous gene syndrome, the chromosome 16p13.3 deletion syndrome alias severe Rubinstein-Taybi syndrome.</strong> Hum. Genet. 120: 179-186, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783566</a>] [<a href="https://doi.org/10.1007/s00439-006-0215-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783566">Bartsch et al. (2006)</a> noted that <a href="#8" class="mim-tip-reference" title="Kimura, H., Ito, Y., Koda, Y., Hase, Y. <strong>Rubinstein-Taybi syndrome with thymic hypoplasia.</strong> Am. J. Med. Genet. 46: 293-296, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8488874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8488874</a>] [<a href="https://doi.org/10.1002/ajmg.1320460311" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8488874">Kimura et al. (1993)</a> had described a Japanese boy with RSTS and features of DiGeorge syndrome (<a href="/entry/188400">188400</a>) who died at age 20 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16783566+8488874+12114483+10573006" 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 FISH studies in 3 patients with severe RSTS who died in infancy, <a href="#2" class="mim-tip-reference" title="Bartsch, O., Rasi, S., Delicado, A., Dyack, S., Neumann, L. M., Seemanova, E., Volleth, M., Haaf, T., Kalscheuer, V. M. <strong>Evidence for a new contiguous gene syndrome, the chromosome 16p13.3 deletion syndrome alias severe Rubinstein-Taybi syndrome.</strong> Hum. Genet. 120: 179-186, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783566</a>] [<a href="https://doi.org/10.1007/s00439-006-0215-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783566">Bartsch et al. (2006)</a> identified deletions of chromosome 16p13.3 ranging from 400 kb to over 3 Mb. The deletions in all 3 patients included the entire CREBBP gene as well as 3-prime distal flanking regions containing the DNASE1 and TRAP1 genes. <a href="#2" class="mim-tip-reference" title="Bartsch, O., Rasi, S., Delicado, A., Dyack, S., Neumann, L. M., Seemanova, E., Volleth, M., Haaf, T., Kalscheuer, V. M. <strong>Evidence for a new contiguous gene syndrome, the chromosome 16p13.3 deletion syndrome alias severe Rubinstein-Taybi syndrome.</strong> Hum. Genet. 120: 179-186, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783566</a>] [<a href="https://doi.org/10.1007/s00439-006-0215-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783566">Bartsch et al. (2006)</a> suggested that 'severe RSTS' is distinct from RSTS and represents a contiguous gene syndrome. The authors suggested that the size of the deletion interval should be determined in such patients because of the risk of critical infections and high mortality. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16783566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Stef, M., Simon, D., Mardirossian, B., Delrue, M.-A., Burgelin, I., Hubert, C., Marche, M., Bonnet, F., Gorry, P., Longy, M., Lacombe, D., Coupry, I., Arveiler, B. <strong>Spectrum of CREBBP gene dosage anomalies in Rubinstein-Taybi syndrome patients.</strong> Europ. J. Hum. Genet. 15: 843-847, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17473832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17473832</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17473832">Stef et al. (2007)</a> reported 2 patients with typical RSTS who were found by gene dosage studies to have a large deletion of the chromosome 16p13 region, including the CREBBP and DNASE1 genes. Although the patients had a severe form of RSTS, neither had a particularly severe form of mental retardation, and neither was prone to infection. <a href="#11" class="mim-tip-reference" title="Stef, M., Simon, D., Mardirossian, B., Delrue, M.-A., Burgelin, I., Hubert, C., Marche, M., Bonnet, F., Gorry, P., Longy, M., Lacombe, D., Coupry, I., Arveiler, B. <strong>Spectrum of CREBBP gene dosage anomalies in Rubinstein-Taybi syndrome patients.</strong> Europ. J. Hum. Genet. 15: 843-847, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17473832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17473832</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201847" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17473832">Stef et al. (2007)</a> concluded that the presentation of these 2 patients did not confirm the phenotype described by <a href="#2" class="mim-tip-reference" title="Bartsch, O., Rasi, S., Delicado, A., Dyack, S., Neumann, L. M., Seemanova, E., Volleth, M., Haaf, T., Kalscheuer, V. M. <strong>Evidence for a new contiguous gene syndrome, the chromosome 16p13.3 deletion syndrome alias severe Rubinstein-Taybi syndrome.</strong> Hum. Genet. 120: 179-186, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783566</a>] [<a href="https://doi.org/10.1007/s00439-006-0215-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783566">Bartsch et al. (2006)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16783566+17473832" 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="#4" class="mim-tip-reference" title="Gervasini, C., Castronovo, P., Bentivegna, A., Mottadelli, F., Faravelli, F., Giovannucci-Uzielli, M. L., Pessagno, A., Lucci-Cordisco, E., Pinto, A. M., Salviati, L., Selicorni, A., Tenconi, R., Neri, G., Larizza, L. <strong>High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints.</strong> Genomics 90: 567-573, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17855048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17855048</a>] [<a href="https://doi.org/10.1016/j.ygeno.2007.07.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17855048">Gervasini et al. (2007)</a> used FISH and microsatellite analysis to screen 42 Italian RSTS patients and identified deletions involving the CREBBP gene that ranged in size from 150 kb to 2.6 Mb in 6 patients. Three of the patients were low-level mosaics, with the deletion present in less than 30% of lymphocytes and in less than 20% of epithelial cells analyzed. The authors stated that the clinical presentation was typical in all cases, but more severe in the 3 patients with constitutional deletions, and suggested that there may be underdiagnosis of a few cases of mild RSTS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17855048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Sahoo, T., Theisen, A., Rosenfeld, J. A., Lamb, A. N., Ravnan, J. B., Schultz, R. A., Torchia, B. S., Neill, N., Casci, I., Bejjani, B. A., Shaffer, L. G. <strong>Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems.</strong> Genet. Med. 13: 868-880, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21792059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21792059</a>] [<a href="https://doi.org/10.1097/GIM.0b013e3182217a06" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21792059">Sahoo et al. (2011)</a> analyzed 38,779 individuals referred to the diagnostic laboratory for microarray testing for the presence of copy number variants encompassing 20 putative schizophrenia susceptibility loci. They also analyzed the indications for study for individuals with copy number variants overlapping those found in 6 individuals referred for schizophrenia. After excluding larger gains or losses that encompassed additional genes outside the candidate loci (e.g., whole-arm gains/losses), <a href="#10" class="mim-tip-reference" title="Sahoo, T., Theisen, A., Rosenfeld, J. A., Lamb, A. N., Ravnan, J. B., Schultz, R. A., Torchia, B. S., Neill, N., Casci, I., Bejjani, B. A., Shaffer, L. G. <strong>Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems.</strong> Genet. Med. 13: 868-880, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21792059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21792059</a>] [<a href="https://doi.org/10.1097/GIM.0b013e3182217a06" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21792059">Sahoo et al. (2011)</a> identified 1,113 individuals with copy number variants encompassing schizophrenia susceptibility loci and 37 individuals with copy number variants overlapping those present in the 6 individuals referred for schizophrenia. Of these, 1,035 had a copy number variant of 1 of 6 recurrent loci: 1q21.1 (<a href="/entry/612474">612474</a>, <a href="/entry/612475">612475</a>), 15q11.2 (<a href="/entry/608636">608636</a>), 15q13.3 (<a href="/entry/612001">612001</a>), 16p11.2 (<a href="/entry/611913">611913</a>), 16p13.11 (see also <a href="/entry/613458">613458</a>), and 22q11.2 (<a href="/entry/192430">192430</a>, <a href="/entry/608363">608363</a>). The indications for study for these 1,150 individuals were diverse and included developmental delay, intellectual disability, autism spectrum, and multiple congenital anomalies. <a href="#10" class="mim-tip-reference" title="Sahoo, T., Theisen, A., Rosenfeld, J. A., Lamb, A. N., Ravnan, J. B., Schultz, R. A., Torchia, B. S., Neill, N., Casci, I., Bejjani, B. A., Shaffer, L. G. <strong>Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems.</strong> Genet. Med. 13: 868-880, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21792059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21792059</a>] [<a href="https://doi.org/10.1097/GIM.0b013e3182217a06" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21792059">Sahoo et al. (2011)</a> identified a 16p13.11 microdeletion in 32 individuals; 3 were de novo, 5 maternally inherited, 6 paternally inherited, and 18 of unknown inheritance. The average age at diagnosis was 6.6 years, with an age range of 0.5 to 30 years, and the indications for study included developmental delay, autism spectrum disorder, dysmorphic features, multiple congenital anomalies, epilepsy, and seizure disorder. The microdeletion was seen in 32 of 23,250 cases referred to their laboratory for a frequency of 0.14%, compared with 0 of 5,674 controls (<a href="#6" class="mim-tip-reference" title="Itsara, A., Cooper, G. M., Baker, C., Girirajan, S., Li, J., Absher, D., Krauss, R. M., Myers, R. M., Ridker, P. M., Chasman, D. I., Mefford, H., Ying, P., Nickerson, D. A., Eichler, E. E. <strong>Population analysis of large copy number variants and hotspots of human genetic disease.</strong> Am. J. Hum. Genet. 84: 148-161, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19166990/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19166990</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19166990[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2008.12.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19166990">Itsara et al., 2009</a>), p = 0.0101. The frequency of this microdeletion in a schizophrenia population was reported as 0.12% versus 0.04% in controls (<a href="#5" class="mim-tip-reference" title="Ingason, A., Rujescu, D., Cichon, S., Sigurdsson, E., Sigmundsson, T., Pietilainen, O. P. H., Buizer-Voskamp, J. E., Strengman, E., Francks, C., Muglia, P., Gylfason, A., Gustafsson, O., and 37 others. <strong>Copy number variations of chromosome 16p13.1 region associated with schizophrenia.</strong> Molec. Psychiat. 16: 17-25, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19786961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19786961</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19786961[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/mp.2009.101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19786961">Ingason et al., 2011</a>). This deletion was seen in 0.48% of cases in a neurodevelopmental deficit population and in 0.0% of controls in the study reported by <a href="#13" class="mim-tip-reference" title="Vassos, E., Collier, D. A., Holden, S., Patch, C., Rujescu, D., St Clair, D., Lewis, C. M. <strong>Penetrance for copy number variants associated with schizophrenia.</strong> Hum. Molec. Genet. 19: 3477-3481, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20587603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20587603</a>] [<a href="https://doi.org/10.1093/hmg/ddq259" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20587603">Vassos et al. (2010)</a>. <a href="#10" class="mim-tip-reference" title="Sahoo, T., Theisen, A., Rosenfeld, J. A., Lamb, A. N., Ravnan, J. B., Schultz, R. A., Torchia, B. S., Neill, N., Casci, I., Bejjani, B. A., Shaffer, L. G. <strong>Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems.</strong> Genet. Med. 13: 868-880, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21792059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21792059</a>] [<a href="https://doi.org/10.1097/GIM.0b013e3182217a06" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21792059">Sahoo et al. (2011)</a> concluded that the results from their study, the largest genotype-first analysis of schizophrenia susceptibility loci to that time, suggested that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and implied the existence of shared biologic pathways among multiple neurodevelopmental conditions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19166990+21792059+19786961+20587603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Kaminsky, E. B., Kaul, V., Paschall, J., Church, D. M., Bunke, B., Kunig, D., Moreno-De-Luca, D., Moreno-De-Luca, A., Mulle, J. G., Warren, S. T., Richard, G., Compton, J. G., and 22 others. <strong>An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities.</strong> Genet. Med. 13: 777-784, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21844811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21844811</a>] [<a href="https://doi.org/10.1097/GIM.0b013e31822c79f9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21844811">Kaminsky et al. (2011)</a> presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 16p13.11 deletion was identified in 22 cases and 3 controls for a p value of 0.0063 and an overall frequency of 1 in 716 cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21844811" 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 a combination of FISH and multiple ligation-dependent probe amplification (MLPA) analysis, <a href="#9" class="mim-tip-reference" title="Rusconi, D., Negri, G., Colapietro, P., Picinelli, C., Milani, D., Spena, S., Magnani, C., Silengo, M. C., Sorasio, L., Curtisova, V., Cavaliere, M. L., Prontera, P., and 11 others. <strong>Characterization of 14 novel deletions underlying Rubinstein-Taybi syndrome: an update of the CREBBP deletion repertoire.</strong> Hum. Genet. 134: 613-626, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25805166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25805166</a>] [<a href="https://doi.org/10.1007/s00439-015-1542-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25805166">Rusconi et al. (2015)</a> identified 14 different and novel CREBBP deletions in 14 of 171 patients with a clinical diagnosis of RSTS. The deletions, which accounted for 23% of detected CREBBP mutations in this cohort, ranged in size from 930 bp encompassing single exons to 1.35 Mb encompassing the whole gene and neighboring genes. Genotype/phenotype correlations indicated that patients with larger deletions did not always have a more severe phenotype than those with smaller deletions or point mutations, suggesting that the idea of a contiguous gene deletion syndrome in such patients, as proposed by <a href="#2" class="mim-tip-reference" title="Bartsch, O., Rasi, S., Delicado, A., Dyack, S., Neumann, L. M., Seemanova, E., Volleth, M., Haaf, T., Kalscheuer, V. M. <strong>Evidence for a new contiguous gene syndrome, the chromosome 16p13.3 deletion syndrome alias severe Rubinstein-Taybi syndrome.</strong> Hum. Genet. 120: 179-186, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783566</a>] [<a href="https://doi.org/10.1007/s00439-006-0215-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16783566">Bartsch et al. (2006)</a>, may not be accurate. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25805166+16783566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1136/jmg.39.7.496" target="_blank">Full Text</a>]
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Bartsch, O., Rasi, S., Delicado, A., Dyack, S., Neumann, L. M., Seemanova, E., Volleth, M., Haaf, T., Kalscheuer, V. M.
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<strong>Evidence for a new contiguous gene syndrome, the chromosome 16p13.3 deletion syndrome alias severe Rubinstein-Taybi syndrome.</strong>
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Hum. Genet. 120: 179-186, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16783566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16783566</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16783566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-006-0215-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200378" target="_blank">Full Text</a>]
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Gervasini, C., Castronovo, P., Bentivegna, A., Mottadelli, F., Faravelli, F., Giovannucci-Uzielli, M. L., Pessagno, A., Lucci-Cordisco, E., Pinto, A. M., Salviati, L., Selicorni, A., Tenconi, R., Neri, G., Larizza, L.
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<strong>High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17855048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17855048</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17855048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ygeno.2007.07.012" target="_blank">Full Text</a>]
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Ingason, A., Rujescu, D., Cichon, S., Sigurdsson, E., Sigmundsson, T., Pietilainen, O. P. H., Buizer-Voskamp, J. E., Strengman, E., Francks, C., Muglia, P., Gylfason, A., Gustafsson, O., and 37 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19786961/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19786961</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19786961[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=19786961" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/mp.2009.101" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2008.12.014" target="_blank">Full Text</a>]
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Kaminsky, E. B., Kaul, V., Paschall, J., Church, D. M., Bunke, B., Kunig, D., Moreno-De-Luca, D., Moreno-De-Luca, A., Mulle, J. G., Warren, S. T., Richard, G., Compton, J. G., and 22 others.
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[<a href="https://doi.org/10.1097/GIM.0b013e31822c79f9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320460311" target="_blank">Full Text</a>]
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<a id="Rusconi2015" class="mim-anchor"></a>
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Rusconi, D., Negri, G., Colapietro, P., Picinelli, C., Milani, D., Spena, S., Magnani, C., Silengo, M. C., Sorasio, L., Curtisova, V., Cavaliere, M. L., Prontera, P., and 11 others.
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<strong>Characterization of 14 novel deletions underlying Rubinstein-Taybi syndrome: an update of the CREBBP deletion repertoire.</strong>
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Hum. Genet. 134: 613-626, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25805166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25805166</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25805166" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00439-015-1542-9" target="_blank">Full Text</a>]
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Sahoo, T., Theisen, A., Rosenfeld, J. A., Lamb, A. N., Ravnan, J. B., Schultz, R. A., Torchia, B. S., Neill, N., Casci, I., Bejjani, B. A., Shaffer, L. G.
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<strong>Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21792059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21792059</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21792059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1097/GIM.0b013e3182217a06" target="_blank">Full Text</a>]
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Stef, M., Simon, D., Mardirossian, B., Delrue, M.-A., Burgelin, I., Hubert, C., Marche, M., Bonnet, F., Gorry, P., Longy, M., Lacombe, D., Coupry, I., Arveiler, B.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17473832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17473832</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17473832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5201847" target="_blank">Full Text</a>]
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Stevens, C. A., Bhakta, M. G.
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[<a href="https://doi.org/10.1002/ajmg.1320590313" target="_blank">Full Text</a>]
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Vassos, E., Collier, D. A., Holden, S., Patch, C., Rujescu, D., St Clair, D., Lewis, C. M.
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<strong>Penetrance for copy number variants associated with schizophrenia.</strong>
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Hum. Molec. Genet. 19: 3477-3481, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20587603/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20587603</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20587603" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddq259" target="_blank">Full Text</a>]
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Cassandra L. Kniffin - updated : 7/2/2015
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Ada Hamosh - updated : 10/4/2012<br>Ada Hamosh - updated : 12/14/2011<br>Marla J. F. O'Neill - updated : 12/21/2007<br>Cassandra L. Kniffin - updated : 8/13/2007
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Cassandra L. Kniffin : 11/2/2006
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carol : 07/07/2015
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mcolton : 7/6/2015<br>ckniffin : 7/2/2015<br>alopez : 10/4/2012<br>carol : 3/27/2012<br>terry : 1/12/2012<br>alopez : 1/11/2012<br>alopez : 1/3/2012<br>terry : 12/22/2011<br>terry : 12/14/2011<br>carol : 2/3/2011<br>wwang : 12/26/2007<br>terry : 12/21/2007<br>wwang : 8/23/2007<br>ckniffin : 8/13/2007<br>wwang : 11/7/2006<br>wwang : 11/7/2006<br>ckniffin : 11/2/2006
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<span class="mim-font">
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<strong>#</strong> 610543
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CHROMOSOME 16p13.3 DELETION SYNDROME, PROXIMAL
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RUBINSTEIN-TAYBI DELETION SYNDROME<br />
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RSTS DELETION SYNDROME
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<strong>ORPHA:</strong> 353281, 783;
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<strong>DO:</strong> 1933;
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Cytogenetic location: 16p13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:1-7,800,000 </span>
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<strong>Gene-Phenotype Relationships</strong>
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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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16p13.3
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Chromosome 16p13.3 deletion syndrome
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610543
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<p>A number sign (#) is used with this entry because the phenotype is a contiguous gene syndrome caused by deletion of chromosome 16p13.3, affecting the CREBBP (600140), DNASE1 (125505), and TRAP1 (HSP75; 606219) genes.</p><p>Rubinstein-Taybi syndrome-1 (RSTS1; 180849) is caused by point mutations or deletions within the CREBBP gene.</p>
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<strong>Clinical Features</strong>
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<p>Bartsch et al. (1999) reported 2 patients with RSTS caused by large deletions of chromosome 16p13.3 who died in infancy, which is rare in RSTS. One of these patients had accessory spleens, hypoplastic left heart, abnormal pulmonary lobulation, and renal agenesis. The other patient had severe neonatal seizures. The combination of RSTS and hypoplastic left heart had previously been described in only 1 patient (Stevens and Bhakta, 1995). Bartsch et al. (1999) suggested that patients with severe RSTS and large deletions had a distinct contiguous gene syndrome. </p><p>Bartsch et al. (2006) provided further analysis of the 2 patients with severe RSTS reported by Bartsch et al. (1999) and a third patient reported by Bartsch et al. (2002). All had a severe phenotype with failure to thrive, life-threatening malformations, and/or critical infections, and all died in infancy (5 weeks, 7 months, and 9 months, respectively). Bartsch et al. (2006) noted that Kimura et al. (1993) had described a Japanese boy with RSTS and features of DiGeorge syndrome (188400) who died at age 20 months. </p>
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<strong>Molecular Genetics</strong>
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<p>Using FISH studies in 3 patients with severe RSTS who died in infancy, Bartsch et al. (2006) identified deletions of chromosome 16p13.3 ranging from 400 kb to over 3 Mb. The deletions in all 3 patients included the entire CREBBP gene as well as 3-prime distal flanking regions containing the DNASE1 and TRAP1 genes. Bartsch et al. (2006) suggested that 'severe RSTS' is distinct from RSTS and represents a contiguous gene syndrome. The authors suggested that the size of the deletion interval should be determined in such patients because of the risk of critical infections and high mortality. </p><p>Stef et al. (2007) reported 2 patients with typical RSTS who were found by gene dosage studies to have a large deletion of the chromosome 16p13 region, including the CREBBP and DNASE1 genes. Although the patients had a severe form of RSTS, neither had a particularly severe form of mental retardation, and neither was prone to infection. Stef et al. (2007) concluded that the presentation of these 2 patients did not confirm the phenotype described by Bartsch et al. (2006). </p><p>Gervasini et al. (2007) used FISH and microsatellite analysis to screen 42 Italian RSTS patients and identified deletions involving the CREBBP gene that ranged in size from 150 kb to 2.6 Mb in 6 patients. Three of the patients were low-level mosaics, with the deletion present in less than 30% of lymphocytes and in less than 20% of epithelial cells analyzed. The authors stated that the clinical presentation was typical in all cases, but more severe in the 3 patients with constitutional deletions, and suggested that there may be underdiagnosis of a few cases of mild RSTS. </p><p>Sahoo et al. (2011) analyzed 38,779 individuals referred to the diagnostic laboratory for microarray testing for the presence of copy number variants encompassing 20 putative schizophrenia susceptibility loci. They also analyzed the indications for study for individuals with copy number variants overlapping those found in 6 individuals referred for schizophrenia. After excluding larger gains or losses that encompassed additional genes outside the candidate loci (e.g., whole-arm gains/losses), Sahoo et al. (2011) identified 1,113 individuals with copy number variants encompassing schizophrenia susceptibility loci and 37 individuals with copy number variants overlapping those present in the 6 individuals referred for schizophrenia. Of these, 1,035 had a copy number variant of 1 of 6 recurrent loci: 1q21.1 (612474, 612475), 15q11.2 (608636), 15q13.3 (612001), 16p11.2 (611913), 16p13.11 (see also 613458), and 22q11.2 (192430, 608363). The indications for study for these 1,150 individuals were diverse and included developmental delay, intellectual disability, autism spectrum, and multiple congenital anomalies. Sahoo et al. (2011) identified a 16p13.11 microdeletion in 32 individuals; 3 were de novo, 5 maternally inherited, 6 paternally inherited, and 18 of unknown inheritance. The average age at diagnosis was 6.6 years, with an age range of 0.5 to 30 years, and the indications for study included developmental delay, autism spectrum disorder, dysmorphic features, multiple congenital anomalies, epilepsy, and seizure disorder. The microdeletion was seen in 32 of 23,250 cases referred to their laboratory for a frequency of 0.14%, compared with 0 of 5,674 controls (Itsara et al., 2009), p = 0.0101. The frequency of this microdeletion in a schizophrenia population was reported as 0.12% versus 0.04% in controls (Ingason et al., 2011). This deletion was seen in 0.48% of cases in a neurodevelopmental deficit population and in 0.0% of controls in the study reported by Vassos et al. (2010). Sahoo et al. (2011) concluded that the results from their study, the largest genotype-first analysis of schizophrenia susceptibility loci to that time, suggested that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and implied the existence of shared biologic pathways among multiple neurodevelopmental conditions. </p><p>Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 16p13.11 deletion was identified in 22 cases and 3 controls for a p value of 0.0063 and an overall frequency of 1 in 716 cases. </p>
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<strong>Genotype/Phenotype Correlations</strong>
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<p>Using a combination of FISH and multiple ligation-dependent probe amplification (MLPA) analysis, Rusconi et al. (2015) identified 14 different and novel CREBBP deletions in 14 of 171 patients with a clinical diagnosis of RSTS. The deletions, which accounted for 23% of detected CREBBP mutations in this cohort, ranged in size from 930 bp encompassing single exons to 1.35 Mb encompassing the whole gene and neighboring genes. Genotype/phenotype correlations indicated that patients with larger deletions did not always have a more severe phenotype than those with smaller deletions or point mutations, suggesting that the idea of a contiguous gene deletion syndrome in such patients, as proposed by Bartsch et al. (2006), may not be accurate. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</h4>
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<ol>
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<p class="mim-text-font">
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Bartsch, O., Locher, K., Meinecke, P., Kress, W., Seemanova, E., Wagner, A., Ostermann, K., Rodel, G.
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<strong>Molecular studies in 10 cases of Rubinstein-Taybi syndrome, including a mild variant showing a missense mutation in codon 1175 of CREBBP.</strong>
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J. Med. Genet. 39: 496-501, 2002.
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[PubMed: 12114483]
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[Full Text: https://doi.org/10.1136/jmg.39.7.496]
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<p class="mim-text-font">
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Bartsch, O., Rasi, S., Delicado, A., Dyack, S., Neumann, L. M., Seemanova, E., Volleth, M., Haaf, T., Kalscheuer, V. M.
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<strong>Evidence for a new contiguous gene syndrome, the chromosome 16p13.3 deletion syndrome alias severe Rubinstein-Taybi syndrome.</strong>
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Hum. Genet. 120: 179-186, 2006.
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[PubMed: 16783566]
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[Full Text: https://doi.org/10.1007/s00439-006-0215-0]
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</li>
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<li>
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<p class="mim-text-font">
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Bartsch, O., Wagner, A., Hinkel, G. K., Krebs, P., Stumm, M., Schmalenberger, B., Bohm, S., Balci, S., Majewski, F.
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<strong>FISH studies in 45 patients with Rubinstein-Taybi syndrome: deletions associated with polysplenia, hypoplastic left heart and death in infancy.</strong>
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Europ. J. Hum. Genet. 7: 748-756, 1999.
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[PubMed: 10573006]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5200378]
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</li>
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<li>
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<p class="mim-text-font">
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Gervasini, C., Castronovo, P., Bentivegna, A., Mottadelli, F., Faravelli, F., Giovannucci-Uzielli, M. L., Pessagno, A., Lucci-Cordisco, E., Pinto, A. M., Salviati, L., Selicorni, A., Tenconi, R., Neri, G., Larizza, L.
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<strong>High frequency of mosaic CREBBP deletions in Rubinstein-Taybi syndrome patients and mapping of somatic and germ-line breakpoints.</strong>
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Genomics 90: 567-573, 2007.
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[PubMed: 17855048]
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[Full Text: https://doi.org/10.1016/j.ygeno.2007.07.012]
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<li>
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<p class="mim-text-font">
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Ingason, A., Rujescu, D., Cichon, S., Sigurdsson, E., Sigmundsson, T., Pietilainen, O. P. H., Buizer-Voskamp, J. E., Strengman, E., Francks, C., Muglia, P., Gylfason, A., Gustafsson, O., and 37 others.
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<strong>Copy number variations of chromosome 16p13.1 region associated with schizophrenia.</strong>
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Molec. Psychiat. 16: 17-25, 2011.
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[PubMed: 19786961]
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[Full Text: https://doi.org/10.1038/mp.2009.101]
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<li>
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<p class="mim-text-font">
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Itsara, A., Cooper, G. M., Baker, C., Girirajan, S., Li, J., Absher, D., Krauss, R. M., Myers, R. M., Ridker, P. M., Chasman, D. I., Mefford, H., Ying, P., Nickerson, D. A., Eichler, E. E.
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<strong>Population analysis of large copy number variants and hotspots of human genetic disease.</strong>
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Am. J. Hum. Genet. 84: 148-161, 2009.
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[PubMed: 19166990]
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[Full Text: https://doi.org/10.1016/j.ajhg.2008.12.014]
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</li>
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<li>
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<p class="mim-text-font">
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Kaminsky, E. B., Kaul, V., Paschall, J., Church, D. M., Bunke, B., Kunig, D., Moreno-De-Luca, D., Moreno-De-Luca, A., Mulle, J. G., Warren, S. T., Richard, G., Compton, J. G., and 22 others.
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<strong>An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities.</strong>
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Genet. Med. 13: 777-784, 2011.
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[PubMed: 21844811]
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[Full Text: https://doi.org/10.1097/GIM.0b013e31822c79f9]
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</p>
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<li>
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<p class="mim-text-font">
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Kimura, H., Ito, Y., Koda, Y., Hase, Y.
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<strong>Rubinstein-Taybi syndrome with thymic hypoplasia.</strong>
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Am. J. Med. Genet. 46: 293-296, 1993.
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[PubMed: 8488874]
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[Full Text: https://doi.org/10.1002/ajmg.1320460311]
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Rusconi, D., Negri, G., Colapietro, P., Picinelli, C., Milani, D., Spena, S., Magnani, C., Silengo, M. C., Sorasio, L., Curtisova, V., Cavaliere, M. L., Prontera, P., and 11 others.
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Sahoo, T., Theisen, A., Rosenfeld, J. A., Lamb, A. N., Ravnan, J. B., Schultz, R. A., Torchia, B. S., Neill, N., Casci, I., Bejjani, B. A., Shaffer, L. G.
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Stef, M., Simon, D., Mardirossian, B., Delrue, M.-A., Burgelin, I., Hubert, C., Marche, M., Bonnet, F., Gorry, P., Longy, M., Lacombe, D., Coupry, I., Arveiler, B.
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<strong>Spectrum of CREBBP gene dosage anomalies in Rubinstein-Taybi syndrome patients.</strong>
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<strong>Cardiac abnormalities in the Rubinstein-Taybi syndrome.</strong>
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Vassos, E., Collier, D. A., Holden, S., Patch, C., Rujescu, D., St Clair, D., Lewis, C. M.
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<strong>Penetrance for copy number variants associated with schizophrenia.</strong>
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Cassandra L. Kniffin - updated : 7/2/2015<br>Ada Hamosh - updated : 10/4/2012<br>Ada Hamosh - updated : 12/14/2011<br>Marla J. F. O'Neill - updated : 12/21/2007<br>Cassandra L. Kniffin - updated : 8/13/2007
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Cassandra L. Kniffin : 11/2/2006
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