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Entry
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- *602768 - DELTA-LIKE CANONICAL NOTCH LIGAND 3; DLL3
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- OMIM
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<p>
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<span class="h4">*602768</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602768">Table View</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000090932;t=ENST00000356433" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=10683" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=602768" 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'})">UCSC Genome Browser</a></div>
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000090932;t=ENST00000356433" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_016941,NM_203486" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_203486" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=602768" 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'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=04140&isoform_id=04140_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/DLL3" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/7417347,8393264,12229810,12652923,22761305,45243561,119577309,119577310" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/Q9NYJ7" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=10683" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000090932;t=ENST00000356433" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=DLL3" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=DLL3" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+10683" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/DLL3" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:10683" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/10683" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr19&hgg_gene=ENST00000356433.10&hgg_start=39498947&hgg_end=39508469&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://medlineplus.gov/genetics/gene/dll3" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=602768[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>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=602768[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000090932" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.gwascentral.org/search?q=DLL3" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=DLL3" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=DLL3&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA27365" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:2909" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1096877" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/DLL3#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:1096877" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/10683/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=10683" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00000168;class=Gene" 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'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-000125-4" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:10683" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=DLL3&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 61367005<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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602768
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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DELTA-LIKE CANONICAL NOTCH LIGAND 3; DLL3
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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DELTA-LIKE 3<br />
|
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DELTA, DROSOPHILA, HOMOLOG OF
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=DLL3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DLL3</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/19/685?start=-3&limit=10&highlight=685">19q13.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:39498947-39508469&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'})">19:39,498,947-39,508,469</a> </span>
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</em>
|
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
|
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
|
<a href="/geneMap/19/685?start=-3&limit=10&highlight=685">
|
|
19q13.2
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Spondylocostal dysostosis 1, autosomal recessive
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/277300"> 277300 </a>
|
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/602768" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/602768" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="text" class="mim-anchor"></a>
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<h4>
|
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|
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<span class="mim-font">
|
|
<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.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
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</h4>
|
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<div>
|
|
<a id="cloning" class="mim-anchor"></a>
|
|
<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Cloning and Expression</strong>
|
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</span>
|
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</h4>
|
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</div>
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p>Mutation in the mouse delta-like-3 gene (Dll3), which is homologous to the Notch-ligand delta in Drosophila, results in the mouse 'pudgy' phenotype (<a href="#8" class="mim-tip-reference" title="Kusumi, K., Sun, E. S., Kerrebrock, A. W., Bronson, R. T., Chi, D.-C., Bulotsky, M. S., Spencer, J. B., Birren, B. W., Frankel, W. N., Lander, E. S. <strong>The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries.</strong> Nature Genet. 19: 274-278, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662403</a>] [<a href="https://doi.org/10.1038/961" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662403">Kusumi et al., 1998</a>). On the basis of the similarity of human autosomal recessive spondylocostal dysostosis (SCDO1; <a href="/entry/277300">277300</a>) and the mouse 'pudgy' phenotype (see later) and the homologous regions of the 2 chromosomes, <a href="#3" class="mim-tip-reference" title="Bulman, M. P., Kusumi, K., Frayling, T. M., McKeown, C., Garrett, C., Lander, E. S., Krumlauf, R., Hattersley, A. T., Ellard, S., Turnpenny, P. D. <strong>Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.</strong> Nature Genet. 24: 438-441, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742114</a>] [<a href="https://doi.org/10.1038/74307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742114">Bulman et al. (2000)</a> hypothesized that a human Dll3 ortholog would be a candidate for the SCDO1 locus. They cloned the human DLL3 gene and confirmed its localization to 19q13. Several cDNA clones representing exons 2 through 10 of human DLL3 were identified. A comparison of the predicted amino acid sequence showed 79% identity to mouse Dll3 with EGF repeat 5 varying by only 1 residue. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9662403+10742114" 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="#3" class="mim-tip-reference" title="Bulman, M. P., Kusumi, K., Frayling, T. M., McKeown, C., Garrett, C., Lander, E. S., Krumlauf, R., Hattersley, A. T., Ellard, S., Turnpenny, P. D. <strong>Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.</strong> Nature Genet. 24: 438-441, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742114</a>] [<a href="https://doi.org/10.1038/74307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742114">Bulman et al. (2000)</a> demonstrated that the intron/exon junctions within the predicted amino acid sequences were identical between human and mouse Dll3, with the exception of the terminal exon, which corresponds to a fusion of mouse exons 9 and 10. This difference would result in the human protein having 32 additional amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10742114" 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 human DLL3 gene was identified within a critical interval, mapped in 2 consanguineous Arab-Israeli and Pakistani SCDO1 pedigrees, of 7.8 cM at 19q13.1-q13.3 between D19S570 and D19S908 (<a href="#3" class="mim-tip-reference" title="Bulman, M. P., Kusumi, K., Frayling, T. M., McKeown, C., Garrett, C., Lander, E. S., Krumlauf, R., Hattersley, A. T., Ellard, S., Turnpenny, P. D. <strong>Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.</strong> Nature Genet. 24: 438-441, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742114</a>] [<a href="https://doi.org/10.1038/74307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742114">Bulman et al., 2000</a>). The Dll3 gene is located on chromosome 7 of the mouse (<a href="#8" class="mim-tip-reference" title="Kusumi, K., Sun, E. S., Kerrebrock, A. W., Bronson, R. T., Chi, D.-C., Bulotsky, M. S., Spencer, J. B., Birren, B. W., Frankel, W. N., Lander, E. S. <strong>The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries.</strong> Nature Genet. 19: 274-278, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662403</a>] [<a href="https://doi.org/10.1038/961" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662403">Kusumi et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9662403+10742114" 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="#1" class="mim-tip-reference" title="Bettenhausen, B., Hrabe de Angelis, M., Simon, D., Guenet, J. L., Gossler, A. <strong>Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila delta.</strong> Development 121: 2407-2418, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7671806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7671806</a>] [<a href="https://doi.org/10.1242/dev.121.8.2407" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7671806">Bettenhausen et al. (1995)</a> demonstrated transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila 'delta.' <a href="#4" class="mim-tip-reference" title="Dunwoodie, S. L., Henrique, D., Harrison, S. M., Beddington, R. S. P. <strong>Mouse Dll3: a novel divergent delta gene which may complement the function of other delta homologues during early pattern formation in the mouse embryo.</strong> Development 124: 3065-3076, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9272948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9272948</a>] [<a href="https://doi.org/10.1242/dev.124.16.3065" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9272948">Dunwoodie et al. (1997)</a> presented results suggesting that mouse Dll3 may complement the function of other delta homologs during early pattern formation in the mouse embryo. <a href="#14" class="mim-tip-reference" title="Wong, P. C., Zheng, H., Chen, H., Becher, M. W., Sirinathsinghji, D. J., Trumbauer, M. E., Chen, H. Y., Price, D. L., Van der Ploeg, L. H., Sisodia, S. S. <strong>Presenilin 1 is required for Notch1 and Dll1 expression in the paraxial mesoderm.</strong> Nature 387: 288-292, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9153393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9153393</a>] [<a href="https://doi.org/10.1038/387288a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9153393">Wong et al. (1997)</a> demonstrated that presenilin-1 (PS1; <a href="/entry/104311">104311</a>) is required for Notch1 (<a href="/entry/190198">190198</a>) and Dll1 expression in the paraxial mesoderm. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9153393+9272948+7671806" 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="Pourquie, O., Kusumi, K. <strong>When body segmentation goes wrong.</strong> Clin. Genet. 60: 409-416, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11846732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11846732</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2001.600602.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11846732">Pourquie and Kusumi (2001)</a> discussed errors in body segmentation. They cited work in fish, chick, and mouse embryos indicating that segmentation of the embryonic body relies on a molecular oscillator, called the segmentation clock, that requires Notch signaling for its proper functioning. In humans, the fact that mutations in genes required for oscillation, such as DLL3, result in abnormal segmentation of the vertebral column suggests that the segmentation clock also acts during human embryonic development. Disruption of the Notch pathway occurs in Alagille syndrome (see <a href="/entry/118450">118450</a>), a disorder that has vertebral abnormalities, i.e., 'butterfly vertebrae,' as a feature in about two-thirds of patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11846732" 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="Gridley, T. <strong>Notch signaling and inherited disease syndromes.</strong> Hum. Molec. Genet. 12(R1): R9-R13, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668592</a>] [<a href="https://doi.org/10.1093/hmg/ddg052" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12668592">Gridley (2003)</a> provided a brief review of human disorders due to defects in the Notch signaling pathway: Alagille syndrome, spondylocostal dysostosis, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; <a href="/entry/125310">125310</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12668592" 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="Matsuda, M., Yamanaka, Y., Uemura, M., Osawa, M., Saito, M. K., Nagahashi, A., Nishio, M., Guo, L., Ikegawa, S., Sakurai, S., Kihara, S., Maurissen, T. L., and 10 others. <strong>Recapitulating the human segmentation clock with pluripotent stem cells.</strong> Nature 580: 124-129, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32238941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32238941</a>] [<a href="https://doi.org/10.1038/s41586-020-2144-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32238941">Matsuda et al. (2020)</a> used human induced pluripotent stem cells for in vitro induction of presomitic mesoderm and its derivatives to model human somitogenesis, with a focus on the human segmentation clock. The authors observed oscillatory expression of core segmentation clock genes, including HES7 (<a href="/entry/608059">608059</a>) and DKK1 (<a href="/entry/605189">605189</a>), determined the period of the human segmentation clock to be around 5 hours, and demonstrated the presence of dynamic traveling wave-like gene expression in in vitro-induced human presomitic mesoderm. Identification and comparison of oscillatory genes in human and mouse presomitic mesoderm derived from pluripotent stem cells revealed species-specific and shared molecular components and pathways associated with the putative mouse and human segmentation clocks. Knockout of genes mutated in patients with segmentation defects of vertebrae, including HES7, LFNG (<a href="/entry/602576">602576</a>), DLL3, and MESP2 (<a href="/entry/605195">605195</a>), followed by analysis of patient-like and patient-derived induced pluripotent stem cells revealed gene-specific alterations in oscillation, synchronization, or differentiation properties. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32238941" 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="#3" class="mim-tip-reference" title="Bulman, M. P., Kusumi, K., Frayling, T. M., McKeown, C., Garrett, C., Lander, E. S., Krumlauf, R., Hattersley, A. T., Ellard, S., Turnpenny, P. D. <strong>Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.</strong> Nature Genet. 24: 438-441, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742114</a>] [<a href="https://doi.org/10.1038/74307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742114">Bulman et al. (2000)</a> sequenced the coding region and splice sites of DLL3 in patients with SCDO1 and identified a unique mutation in DLL3 in each of 3 pedigrees. In pedigree 1, there was a 5-bp insertion in exon 5 (<a href="#0001">602768.0001</a>), predicted to truncate the protein in the Delta-Serrate-Lag2 domain before EGF repeat 1. In pedigree 2, there was a 2-bp deletion in the fourth EGF repeat domain that predicted a truncation immediately after EGF repeat 3 (<a href="#0002">602768.0002</a>). In pedigree 3, there was a missense mutation in which aspartic acid replaced glycine in EGF repeat 5 (<a href="#0003">602768.0003</a>). This residue is highly conserved in Delta proteins from Drosophila to humans, and the substitution of a charged polar for a nonpolar residue may disrupt the conformation of the DLL3 protein. Testing of all available family members in each pedigree confirmed that affected SCDO1 individuals were homozygous and obligate carriers heterozygous for the mutation. Clinical examination did not identify any neurologic abnormalities in SCDO1 individuals, and none had mental retardation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10742114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Gassner, M., Grabs, S. G. <strong>Kostovertebrale Dysplasie: ein Rezeptordefekt der Sklerotomentwicklung?</strong> Schweiz. Med. Wschr. 112: 791-797, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7100875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7100875</a>]" pmid="7100875">Gassner and Grabs (1982)</a> reported a cluster of 8 individuals affected by spondylocostal dysostosis in 4 nuclear families indigenous to a village in eastern Switzerland. After the relationship of spondylocostal dysostosis to the DLL3 gene was demonstrated, they tested the presumption that the molecular basis of this cluster was segregation of a single mutation in the DLL3 gene. <a href="#2" class="mim-tip-reference" title="Bonafe, L., Giunta, C., Gassner, M., Steinmann, B., Superti-Furga, A. <strong>A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village.</strong> Clin. Genet. 64: 28-35, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12791036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12791036</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00085.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12791036">Bonafe et al. (2003)</a> showed that marker haplotypes around the DLL3 locus contradicted this hypothesis, as 3 different haplotypes were seen in affected individuals and sequence analysis showed that 3 previously unreported DLL3 mutations were segregating: a duplication of 17 bp in exon 8 (1285-1301dup; <a href="#0004">602768.0004</a>), a single-nucleotide deletion in exon 5 (615delC; <a href="#0005">602768.0005</a>), and an R238X (<a href="#0006">602768.0006</a>) nonsense mutation in exon 6. Recessive mutations in the DLL3 gene were present in all affected individuals. Homozygosity for 1285-1301dup, a presumed founder mutation, was found in 2 of 4 families. In the other 2 families, this founder mutation was present in compound heterozygous state with one or the other of the 'new' mutations. Despite the mutation heterogeneity, the phenotype was homogeneous with severe and characteristic vertebral changes, but relatively little associated morbidity and mortality. Affected individuals were recognized at birth by virtue of the shortening of the neck and trunk. However, they did not have respiratory insufficiency after birth, and did not have neurologic signs from compression of the spinal cord or nerves. The vertebral and costal defects were readily recognizable on 'babygrams,' and involved the whole spine and usually multiple ribs. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7100875+12791036" 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="Turnpenny, P. D., Whittock, N., Duncan, J., Dunwoodie, S., Kusumi, K., Ellard, S. <strong>Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis.</strong> J. Med. Genet. 40: 333-339, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12746394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12746394</a>] [<a href="https://doi.org/10.1136/jmg.40.5.333" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12746394">Turnpenny et al. (2003)</a> sequenced the DLL3 gene in a series of spondylocostal dysostosis patients from 14 families and identified 12 mutations, 2 of which occurred twice. The patients represented diverse ethnic backgrounds and 6 came from traditionally consanguineous communities. In all affected individuals, the radiologic phenotype was abnormal segmentation throughout the entire vertebral column with smooth outlines to the vertebral bodies in childhood, for which <a href="#12" class="mim-tip-reference" title="Turnpenny, P. D., Whittock, N., Duncan, J., Dunwoodie, S., Kusumi, K., Ellard, S. <strong>Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis.</strong> J. Med. Genet. 40: 333-339, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12746394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12746394</a>] [<a href="https://doi.org/10.1136/jmg.40.5.333" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12746394">Turnpenny et al. (2003)</a> suggested the term 'pebble beach sign.' This appeared to be a very consistent phenotype-genotype correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12746394" 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="#11" class="mim-tip-reference" title="Shen, J., Bronson, R. T., Chen, D. F., Xia, W., Selkoe, D. J., Tonegawa, S. <strong>Skeletal and CNS defects in presenilin-1-deficient mice.</strong> Cell 89: 629-639, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9160754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9160754</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80244-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9160754">Shen et al. (1997)</a> found skeletal and CNS defects in mice homozygous for disruption of the presenilin-1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9160754" 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>'Pudgy' (pu) homozygous mice exhibit clear patterning defects at the earlier stages of somitogenesis, resulting in adult mice with severe vertebral and rib deformities. By positional cloning and complementation, <a href="#8" class="mim-tip-reference" title="Kusumi, K., Sun, E. S., Kerrebrock, A. W., Bronson, R. T., Chi, D.-C., Bulotsky, M. S., Spencer, J. B., Birren, B. W., Frankel, W. N., Lander, E. S. <strong>The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries.</strong> Nature Genet. 19: 274-278, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662403</a>] [<a href="https://doi.org/10.1038/961" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662403">Kusumi et al. (1998)</a> determined that the pu phenotype is caused by mutation in the delta-like-3 gene (Dll3), which is homologous to the Notch-ligand delta in Drosophila. Histologic and molecular marker analyses showed that the pu mutation disrupts the proper formation of morphologic borders in early somite formation and of rostral-caudal compartment boundaries within somites. Viability analysis also indicated an important role in early development. Overall, the results pointed to a key role for the Notch-signaling pathway in the initiation of patterning of vertebrate paraxial mesoderm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9662403" 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://www.ncbi.nlm.nih.gov/clinvar?term=602768[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786200899 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786200899;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs786200899" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs786200899" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a consanguineous Arab-Israeli family segregating autosomal recessive spondylocostal dysostosis (SCDO1; <a href="/entry/277300">277300</a>), <a href="#3" class="mim-tip-reference" title="Bulman, M. P., Kusumi, K., Frayling, T. M., McKeown, C., Garrett, C., Lander, E. S., Krumlauf, R., Hattersley, A. T., Ellard, S., Turnpenny, P. D. <strong>Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.</strong> Nature Genet. 24: 438-441, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742114</a>] [<a href="https://doi.org/10.1038/74307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742114">Bulman et al. (2000)</a> identified a 5-bp insertion (GCGGT) resulting in a frameshift mutation in exon 5 of the DLL3 gene. This mutation was found in homozygous state in all affected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10742114" 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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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs786200900 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786200900;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs786200900?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs786200900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs786200900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a family from Rawalpindi, Pakistan segregating autosomal recessive spondylocostal dysostosis (SCDO1; <a href="/entry/277300">277300</a>), <a href="#3" class="mim-tip-reference" title="Bulman, M. P., Kusumi, K., Frayling, T. M., McKeown, C., Garrett, C., Lander, E. S., Krumlauf, R., Hattersley, A. T., Ellard, S., Turnpenny, P. D. <strong>Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.</strong> Nature Genet. 24: 438-441, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742114</a>] [<a href="https://doi.org/10.1038/74307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742114">Bulman et al. (2000)</a> identified a 2-bp deletion (AT) resulting in a frameshift in exon 7 of the DLL3 gene. As expected, this mutation was found in homozygous state in all affected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10742114" 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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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894674 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894674;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs104894674?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104894674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs104894674" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a consanguineous Kashmiri family segregating autosomal recessive spondylocostal dysostosis (SCDO1; <a href="/entry/277300">277300</a>), <a href="#3" class="mim-tip-reference" title="Bulman, M. P., Kusumi, K., Frayling, T. M., McKeown, C., Garrett, C., Lander, E. S., Krumlauf, R., Hattersley, A. T., Ellard, S., Turnpenny, P. D. <strong>Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.</strong> Nature Genet. 24: 438-441, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742114</a>] [<a href="https://doi.org/10.1038/74307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742114">Bulman et al. (2000)</a> identified a G-to-A transition at nucleotide 1154 resulting in a gly385-to-asp (G385D) substitution in exon 8 of the DLL3 gene. As expected, all affected individuals were homozygous. Glycine at position 5 is in the fifth epidermal growth factor repeat and is highly conserved in delta proteins from Drosophila to humans. In addition, the substitution replaced a nonpolar residue with a charged polar residue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10742114" 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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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs777791545 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs777791545;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs777791545?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs777791545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs777791545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007233 OR RCV004584594" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007233, RCV004584594" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007233...</a>
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<p><a href="#2" class="mim-tip-reference" title="Bonafe, L., Giunta, C., Gassner, M., Steinmann, B., Superti-Furga, A. <strong>A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village.</strong> Clin. Genet. 64: 28-35, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12791036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12791036</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00085.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12791036">Bonafe et al. (2003)</a> identified a duplication of 17 bp (nucleotides 1285-1301) in exon 8 of the DLL3 gene as a founder mutation in a village in eastern Switzerland in a founder population. The mutation causes spondylocostal dysostosis (SCDO1; <a href="/entry/277300">277300</a>) when present in homozygous state or present in compound heterozygous state with 615delC (<a href="#0005">602768.0005</a>) or R238X (<a href="#0006">602768.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12791036" 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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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786200902 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786200902;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs786200902" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs786200902" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007234 OR RCV001090646 OR RCV004528088" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007234, RCV001090646, RCV004528088" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007234...</a>
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<p>For discussion of the 1-bp deletion in the DLL3 gene (615delC) that was found in compound heterozygous state in affected individuals from Switzerland with spondylocostal dysostosis (SCDO1; <a href="/entry/277300">277300</a>) by <a href="#2" class="mim-tip-reference" title="Bonafe, L., Giunta, C., Gassner, M., Steinmann, B., Superti-Furga, A. <strong>A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village.</strong> Clin. Genet. 64: 28-35, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12791036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12791036</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00085.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12791036">Bonafe et al. (2003)</a>, see <a href="#0004">602768.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12791036" 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>.0006 SPONDYLOCOSTAL DYSOSTOSIS 1, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894675 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894675;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs104894675?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104894675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs104894675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007235 OR RCV001558657" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007235, RCV001558657" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007235...</a>
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<p>For discussion of the arg238-to-ter (R238X) mutation in the DLL3 gene that was found in compound heterozygous state in affected individuals from Switzerland with spondylocostal dysostosis (SCDO1; <a href="/entry/277300">277300</a>) by <a href="#2" class="mim-tip-reference" title="Bonafe, L., Giunta, C., Gassner, M., Steinmann, B., Superti-Furga, A. <strong>A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village.</strong> Clin. Genet. 64: 28-35, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12791036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12791036</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2003.00085.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12791036">Bonafe et al. (2003)</a>, see <a href="#0004">602768.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12791036" 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>.0007 SPONDYLOCOSTAL DYSOSTOSIS 1, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786200903 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786200903;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs786200903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs786200903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007236" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007236" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007236</a>
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<p>In 2 affected sibs of a family with spondylocostal dysostosis (SCDO1; <a href="/entry/277300">277300</a>), originally reported by <a href="#5" class="mim-tip-reference" title="Floor, E., De Jong, R. O., Fryns, J. P., Smulders, C., Vles, J. S. H. <strong>Spondylocostal dysostosis: an example of autosomal dominant transmission in a large family.</strong> Clin. Genet. 36: 236-241, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2805381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2805381</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1989.tb03196.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2805381">Floor et al. (1989)</a>, <a href="#13" class="mim-tip-reference" title="Whittock, N. V., Ellard, S., Duncan, J., de Die-Smulders, C. E. M., Vles, J. S. H., Turnpenny, P. D. <strong>Pseudodominant inheritance of spondylocostal dysostosis type 1 caused by two familial delta-like 3 mutations.</strong> Clin. Genet. 66: 67-72, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15200511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15200511</a>] [<a href="https://doi.org/10.1111/j.0009-9163.2004.00272.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15200511">Whittock et al. (2004)</a> identified compound heterozygosity for 2 mutations in exon 8 of the DLL3 gene: a 1-bp deletion (1440delG) and a 1511G-A transition. The deletion is predicted to result in a 68-amino acid C-terminal peptide and premature termination at codon 547, with loss of the transmembrane domain; the 1511G-A transition results in a gly504-to-asp substitution (G504D; <a href="#0008">602768.0008</a>) within the predicted transmembrane domain. The family was initially believed to represent autosomal dominant inheritance (see <a href="#5" class="mim-tip-reference" title="Floor, E., De Jong, R. O., Fryns, J. P., Smulders, C., Vles, J. S. H. <strong>Spondylocostal dysostosis: an example of autosomal dominant transmission in a large family.</strong> Clin. Genet. 36: 236-241, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2805381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2805381</a>] [<a href="https://doi.org/10.1111/j.1399-0004.1989.tb03196.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2805381">Floor et al. (1989)</a>), but haplotype analysis by <a href="#13" class="mim-tip-reference" title="Whittock, N. V., Ellard, S., Duncan, J., de Die-Smulders, C. E. M., Vles, J. S. H., Turnpenny, P. D. <strong>Pseudodominant inheritance of spondylocostal dysostosis type 1 caused by two familial delta-like 3 mutations.</strong> Clin. Genet. 66: 67-72, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15200511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15200511</a>] [<a href="https://doi.org/10.1111/j.0009-9163.2004.00272.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15200511">Whittock et al. (2004)</a> suggested linkage to DLL3 in a pseudodominant manner with segregation of 2 distinct disease alleles. Direct sequencing revealed that the affected father was homozygous and all 4 sibs were heterozygous for the 1440delG mutation, whereas the unaffected mother and 2 affected sibs were heterozygous for the G504D substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2805381+15200511" 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>.0008 SPONDYLOCOSTAL DYSOSTOSIS 1, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104894676 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894676;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs104894676?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs104894676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs104894676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007237 OR RCV000996922" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007237, RCV000996922" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007237...</a>
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<p>For discussion of the gly504-to-asp (G504D) mutation in the DLL3 gene that was found in compound heterozygous state in 2 sibs with spondylocostal dysostosis (SCDO1; <a href="/entry/277300">277300</a>) by <a href="#13" class="mim-tip-reference" title="Whittock, N. V., Ellard, S., Duncan, J., de Die-Smulders, C. E. M., Vles, J. S. H., Turnpenny, P. D. <strong>Pseudodominant inheritance of spondylocostal dysostosis type 1 caused by two familial delta-like 3 mutations.</strong> Clin. Genet. 66: 67-72, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15200511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15200511</a>] [<a href="https://doi.org/10.1111/j.0009-9163.2004.00272.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15200511">Whittock et al. (2004)</a>, see <a href="#0007">602768.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15200511" 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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Bettenhausen, B., Hrabe de Angelis, M., Simon, D., Guenet, J. L., Gossler, A.
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<strong>Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila delta.</strong>
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Development 121: 2407-2418, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7671806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7671806</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7671806" 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/10.1242/dev.121.8.2407" target="_blank">Full Text</a>]
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Bonafe, L., Giunta, C., Gassner, M., Steinmann, B., Superti-Furga, A.
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<strong>A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village.</strong>
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Clin. Genet. 64: 28-35, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12791036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12791036</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12791036" 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/10.1034/j.1399-0004.2003.00085.x" target="_blank">Full Text</a>]
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<p class="mim-text-font">
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Bulman, M. P., Kusumi, K., Frayling, T. M., McKeown, C., Garrett, C., Lander, E. S., Krumlauf, R., Hattersley, A. T., Ellard, S., Turnpenny, P. D.
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<strong>Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.</strong>
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Nature Genet. 24: 438-441, 2000.
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[<a href="https://doi.org/10.1038/74307" target="_blank">Full Text</a>]
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<a id="Dunwoodie1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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<strong>Mouse Dll3: a novel divergent delta gene which may complement the function of other delta homologues during early pattern formation in the mouse embryo.</strong>
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[<a href="https://doi.org/10.1242/dev.124.16.3065" target="_blank">Full Text</a>]
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<div class="">
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<p class="mim-text-font">
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<strong>Spondylocostal dysostosis: an example of autosomal dominant transmission in a large family.</strong>
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[<a href="https://doi.org/10.1111/j.1399-0004.1989.tb03196.x" target="_blank">Full Text</a>]
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<a id="Gassner1982" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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<strong>Kostovertebrale Dysplasie: ein Rezeptordefekt der Sklerotomentwicklung?</strong>
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<a id="Gridley2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gridley, T.
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<strong>Notch signaling and inherited disease syndromes.</strong>
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Hum. Molec. Genet. 12(R1): R9-R13, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668592</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12668592" 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/ddg052" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Kusumi1998" class="mim-anchor"></a>
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Kusumi, K., Sun, E. S., Kerrebrock, A. W., Bronson, R. T., Chi, D.-C., Bulotsky, M. S., Spencer, J. B., Birren, B. W., Frankel, W. N., Lander, E. S.
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<strong>The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries.</strong>
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Nature Genet. 19: 274-278, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662403</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9662403" 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/10.1038/961" target="_blank">Full Text</a>]
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<a id="Matsuda2020" class="mim-anchor"></a>
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Matsuda, M., Yamanaka, Y., Uemura, M., Osawa, M., Saito, M. K., Nagahashi, A., Nishio, M., Guo, L., Ikegawa, S., Sakurai, S., Kihara, S., Maurissen, T. L., and 10 others.
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<strong>Recapitulating the human segmentation clock with pluripotent stem cells.</strong>
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Nature 580: 124-129, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32238941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32238941</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32238941" 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/s41586-020-2144-9" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="Pourquie2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pourquie, O., Kusumi, K.
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<strong>When body segmentation goes wrong.</strong>
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Clin. Genet. 60: 409-416, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11846732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11846732</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11846732" 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/10.1034/j.1399-0004.2001.600602.x" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
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<a id="Shen1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shen, J., Bronson, R. T., Chen, D. F., Xia, W., Selkoe, D. J., Tonegawa, S.
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<strong>Skeletal and CNS defects in presenilin-1-deficient mice.</strong>
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Cell 89: 629-639, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9160754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9160754</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9160754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)80244-5" target="_blank">Full Text</a>]
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<a id="12" class="mim-anchor"></a>
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<a id="Turnpenny2003" class="mim-anchor"></a>
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<div class="">
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Turnpenny, P. D., Whittock, N., Duncan, J., Dunwoodie, S., Kusumi, K., Ellard, S.
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<strong>Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis.</strong>
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J. Med. Genet. 40: 333-339, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12746394/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12746394</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12746394" 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/10.1136/jmg.40.5.333" target="_blank">Full Text</a>]
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<a id="Whittock2004" class="mim-anchor"></a>
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Whittock, N. V., Ellard, S., Duncan, J., de Die-Smulders, C. E. M., Vles, J. S. H., Turnpenny, P. D.
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<strong>Pseudodominant inheritance of spondylocostal dysostosis type 1 caused by two familial delta-like 3 mutations.</strong>
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Clin. Genet. 66: 67-72, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15200511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15200511</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15200511" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.0009-9163.2004.00272.x" target="_blank">Full Text</a>]
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<a id="Wong1997" class="mim-anchor"></a>
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Wong, P. C., Zheng, H., Chen, H., Becher, M. W., Sirinathsinghji, D. J., Trumbauer, M. E., Chen, H. Y., Price, D. L., Van der Ploeg, L. H., Sisodia, S. S.
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<strong>Presenilin 1 is required for Notch1 and Dll1 expression in the paraxial mesoderm.</strong>
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Nature 387: 288-292, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9153393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9153393</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9153393" 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/10.1038/387288a0" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 11/12/2020
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 8/4/2005<br>George E. Tiller - updated : 3/2/2005<br>Victor A. McKusick - updated : 11/6/2003<br>Victor A. McKusick - updated : 7/18/2003<br>Victor A. McKusick - updated : 2/12/2002<br>Ada Hamosh - updated : 3/29/2000
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 7/1/1998
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mgross : 11/12/2020
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<span class="mim-text-font">
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carol : 08/07/2019<br>carol : 08/17/2015<br>mcolton : 8/12/2015<br>carol : 10/19/2009<br>carol : 8/16/2006<br>wwang : 8/5/2005<br>terry : 8/4/2005<br>alopez : 3/2/2005<br>tkritzer : 11/11/2003<br>tkritzer : 11/7/2003<br>terry : 11/6/2003<br>cwells : 7/31/2003<br>terry : 7/18/2003<br>alopez : 2/14/2002<br>alopez : 2/14/2002<br>terry : 2/12/2002<br>alopez : 5/3/2000<br>alopez : 3/30/2000<br>carol : 3/29/2000<br>dholmes : 7/22/1998<br>alopez : 7/2/1998<br>alopez : 7/2/1998<br>alopez : 7/1/1998
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<strong>*</strong> 602768
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<h3>
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DELTA-LIKE CANONICAL NOTCH LIGAND 3; DLL3
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<em>Alternative titles; symbols</em>
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DELTA-LIKE 3<br />
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DELTA, DROSOPHILA, HOMOLOG OF
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: DLL3</em></strong>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 61367005;
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</span>
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</p>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 19q13.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:39,498,947-39,508,469 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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19q13.2
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</span>
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</td>
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<td>
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<span class="mim-font">
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Spondylocostal dysostosis 1, autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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277300
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Mutation in the mouse delta-like-3 gene (Dll3), which is homologous to the Notch-ligand delta in Drosophila, results in the mouse 'pudgy' phenotype (Kusumi et al., 1998). On the basis of the similarity of human autosomal recessive spondylocostal dysostosis (SCDO1; 277300) and the mouse 'pudgy' phenotype (see later) and the homologous regions of the 2 chromosomes, Bulman et al. (2000) hypothesized that a human Dll3 ortholog would be a candidate for the SCDO1 locus. They cloned the human DLL3 gene and confirmed its localization to 19q13. Several cDNA clones representing exons 2 through 10 of human DLL3 were identified. A comparison of the predicted amino acid sequence showed 79% identity to mouse Dll3 with EGF repeat 5 varying by only 1 residue. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Bulman et al. (2000) demonstrated that the intron/exon junctions within the predicted amino acid sequences were identical between human and mouse Dll3, with the exception of the terminal exon, which corresponds to a fusion of mouse exons 9 and 10. This difference would result in the human protein having 32 additional amino acids. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The human DLL3 gene was identified within a critical interval, mapped in 2 consanguineous Arab-Israeli and Pakistani SCDO1 pedigrees, of 7.8 cM at 19q13.1-q13.3 between D19S570 and D19S908 (Bulman et al., 2000). The Dll3 gene is located on chromosome 7 of the mouse (Kusumi et al., 1998). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Bettenhausen et al. (1995) demonstrated transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila 'delta.' Dunwoodie et al. (1997) presented results suggesting that mouse Dll3 may complement the function of other delta homologs during early pattern formation in the mouse embryo. Wong et al. (1997) demonstrated that presenilin-1 (PS1; 104311) is required for Notch1 (190198) and Dll1 expression in the paraxial mesoderm. </p><p>Pourquie and Kusumi (2001) discussed errors in body segmentation. They cited work in fish, chick, and mouse embryos indicating that segmentation of the embryonic body relies on a molecular oscillator, called the segmentation clock, that requires Notch signaling for its proper functioning. In humans, the fact that mutations in genes required for oscillation, such as DLL3, result in abnormal segmentation of the vertebral column suggests that the segmentation clock also acts during human embryonic development. Disruption of the Notch pathway occurs in Alagille syndrome (see 118450), a disorder that has vertebral abnormalities, i.e., 'butterfly vertebrae,' as a feature in about two-thirds of patients. </p><p>Gridley (2003) provided a brief review of human disorders due to defects in the Notch signaling pathway: Alagille syndrome, spondylocostal dysostosis, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; 125310). </p><p>Matsuda et al. (2020) used human induced pluripotent stem cells for in vitro induction of presomitic mesoderm and its derivatives to model human somitogenesis, with a focus on the human segmentation clock. The authors observed oscillatory expression of core segmentation clock genes, including HES7 (608059) and DKK1 (605189), determined the period of the human segmentation clock to be around 5 hours, and demonstrated the presence of dynamic traveling wave-like gene expression in in vitro-induced human presomitic mesoderm. Identification and comparison of oscillatory genes in human and mouse presomitic mesoderm derived from pluripotent stem cells revealed species-specific and shared molecular components and pathways associated with the putative mouse and human segmentation clocks. Knockout of genes mutated in patients with segmentation defects of vertebrae, including HES7, LFNG (602576), DLL3, and MESP2 (605195), followed by analysis of patient-like and patient-derived induced pluripotent stem cells revealed gene-specific alterations in oscillation, synchronization, or differentiation properties. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Bulman et al. (2000) sequenced the coding region and splice sites of DLL3 in patients with SCDO1 and identified a unique mutation in DLL3 in each of 3 pedigrees. In pedigree 1, there was a 5-bp insertion in exon 5 (602768.0001), predicted to truncate the protein in the Delta-Serrate-Lag2 domain before EGF repeat 1. In pedigree 2, there was a 2-bp deletion in the fourth EGF repeat domain that predicted a truncation immediately after EGF repeat 3 (602768.0002). In pedigree 3, there was a missense mutation in which aspartic acid replaced glycine in EGF repeat 5 (602768.0003). This residue is highly conserved in Delta proteins from Drosophila to humans, and the substitution of a charged polar for a nonpolar residue may disrupt the conformation of the DLL3 protein. Testing of all available family members in each pedigree confirmed that affected SCDO1 individuals were homozygous and obligate carriers heterozygous for the mutation. Clinical examination did not identify any neurologic abnormalities in SCDO1 individuals, and none had mental retardation. </p><p>Gassner and Grabs (1982) reported a cluster of 8 individuals affected by spondylocostal dysostosis in 4 nuclear families indigenous to a village in eastern Switzerland. After the relationship of spondylocostal dysostosis to the DLL3 gene was demonstrated, they tested the presumption that the molecular basis of this cluster was segregation of a single mutation in the DLL3 gene. Bonafe et al. (2003) showed that marker haplotypes around the DLL3 locus contradicted this hypothesis, as 3 different haplotypes were seen in affected individuals and sequence analysis showed that 3 previously unreported DLL3 mutations were segregating: a duplication of 17 bp in exon 8 (1285-1301dup; 602768.0004), a single-nucleotide deletion in exon 5 (615delC; 602768.0005), and an R238X (602768.0006) nonsense mutation in exon 6. Recessive mutations in the DLL3 gene were present in all affected individuals. Homozygosity for 1285-1301dup, a presumed founder mutation, was found in 2 of 4 families. In the other 2 families, this founder mutation was present in compound heterozygous state with one or the other of the 'new' mutations. Despite the mutation heterogeneity, the phenotype was homogeneous with severe and characteristic vertebral changes, but relatively little associated morbidity and mortality. Affected individuals were recognized at birth by virtue of the shortening of the neck and trunk. However, they did not have respiratory insufficiency after birth, and did not have neurologic signs from compression of the spinal cord or nerves. The vertebral and costal defects were readily recognizable on 'babygrams,' and involved the whole spine and usually multiple ribs. </p><p>Turnpenny et al. (2003) sequenced the DLL3 gene in a series of spondylocostal dysostosis patients from 14 families and identified 12 mutations, 2 of which occurred twice. The patients represented diverse ethnic backgrounds and 6 came from traditionally consanguineous communities. In all affected individuals, the radiologic phenotype was abnormal segmentation throughout the entire vertebral column with smooth outlines to the vertebral bodies in childhood, for which Turnpenny et al. (2003) suggested the term 'pebble beach sign.' This appeared to be a very consistent phenotype-genotype correlation. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Shen et al. (1997) found skeletal and CNS defects in mice homozygous for disruption of the presenilin-1 gene. </p><p>'Pudgy' (pu) homozygous mice exhibit clear patterning defects at the earlier stages of somitogenesis, resulting in adult mice with severe vertebral and rib deformities. By positional cloning and complementation, Kusumi et al. (1998) determined that the pu phenotype is caused by mutation in the delta-like-3 gene (Dll3), which is homologous to the Notch-ligand delta in Drosophila. Histologic and molecular marker analyses showed that the pu mutation disrupts the proper formation of morphologic borders in early somite formation and of rostral-caudal compartment boundaries within somites. Viability analysis also indicated an important role in early development. Overall, the results pointed to a key role for the Notch-signaling pathway in the initiation of patterning of vertebrate paraxial mesoderm. </p>
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</span>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
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</span>
|
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<strong>8 Selected Examples):</strong>
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</span>
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</h4>
|
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<div>
|
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<p />
|
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 SPONDYLOCOSTAL DYSOSTOSIS 1, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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DLL3, 5-BP INS, NT593
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<br />
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SNP: rs786200899,
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ClinVar: RCV000007230, RCV000990213, RCV001531895
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a consanguineous Arab-Israeli family segregating autosomal recessive spondylocostal dysostosis (SCDO1; 277300), Bulman et al. (2000) identified a 5-bp insertion (GCGGT) resulting in a frameshift mutation in exon 5 of the DLL3 gene. This mutation was found in homozygous state in all affected individuals. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 SPONDYLOCOSTAL DYSOSTOSIS 1, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DLL3, 2-BP DEL, 945AT
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<br />
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SNP: rs786200900,
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gnomAD: rs786200900,
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ClinVar: RCV000007231, RCV003555952
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family from Rawalpindi, Pakistan segregating autosomal recessive spondylocostal dysostosis (SCDO1; 277300), Bulman et al. (2000) identified a 2-bp deletion (AT) resulting in a frameshift in exon 7 of the DLL3 gene. As expected, this mutation was found in homozygous state in all affected individuals. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 SPONDYLOCOSTAL DYSOSTOSIS 1, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DLL3, GLY385ASP
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<br />
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SNP: rs104894674,
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gnomAD: rs104894674,
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ClinVar: RCV000007232, RCV004724730
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a consanguineous Kashmiri family segregating autosomal recessive spondylocostal dysostosis (SCDO1; 277300), Bulman et al. (2000) identified a G-to-A transition at nucleotide 1154 resulting in a gly385-to-asp (G385D) substitution in exon 8 of the DLL3 gene. As expected, all affected individuals were homozygous. Glycine at position 5 is in the fifth epidermal growth factor repeat and is highly conserved in delta proteins from Drosophila to humans. In addition, the substitution replaced a nonpolar residue with a charged polar residue. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 SPONDYLOCOSTAL DYSOSTOSIS 1, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DLL3, 17-BP DEL, NT1285
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<br />
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SNP: rs777791545,
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gnomAD: rs777791545,
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ClinVar: RCV000007233, RCV004584594
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>Bonafe et al. (2003) identified a duplication of 17 bp (nucleotides 1285-1301) in exon 8 of the DLL3 gene as a founder mutation in a village in eastern Switzerland in a founder population. The mutation causes spondylocostal dysostosis (SCDO1; 277300) when present in homozygous state or present in compound heterozygous state with 615delC (602768.0005) or R238X (602768.0006). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0005 SPONDYLOCOSTAL DYSOSTOSIS 1, AUTOSOMAL RECESSIVE</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DLL3, 1-BP DEL, 615C
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<br />
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SNP: rs786200902,
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ClinVar: RCV000007234, RCV001090646, RCV004528088
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>For discussion of the 1-bp deletion in the DLL3 gene (615delC) that was found in compound heterozygous state in affected individuals from Switzerland with spondylocostal dysostosis (SCDO1; 277300) by Bonafe et al. (2003), see 602768.0004. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0006 SPONDYLOCOSTAL DYSOSTOSIS 1, AUTOSOMAL RECESSIVE</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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DLL3, ARG238TER
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<br />
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SNP: rs104894675,
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gnomAD: rs104894675,
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ClinVar: RCV000007235, RCV001558657
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>For discussion of the arg238-to-ter (R238X) mutation in the DLL3 gene that was found in compound heterozygous state in affected individuals from Switzerland with spondylocostal dysostosis (SCDO1; 277300) by Bonafe et al. (2003), see 602768.0004. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 SPONDYLOCOSTAL DYSOSTOSIS 1, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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DLL3, 1-BP DEL, 1440G
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<br />
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SNP: rs786200903,
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ClinVar: RCV000007236
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</span>
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</div>
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<p>In 2 affected sibs of a family with spondylocostal dysostosis (SCDO1; 277300), originally reported by Floor et al. (1989), Whittock et al. (2004) identified compound heterozygosity for 2 mutations in exon 8 of the DLL3 gene: a 1-bp deletion (1440delG) and a 1511G-A transition. The deletion is predicted to result in a 68-amino acid C-terminal peptide and premature termination at codon 547, with loss of the transmembrane domain; the 1511G-A transition results in a gly504-to-asp substitution (G504D; 602768.0008) within the predicted transmembrane domain. The family was initially believed to represent autosomal dominant inheritance (see Floor et al. (1989)), but haplotype analysis by Whittock et al. (2004) suggested linkage to DLL3 in a pseudodominant manner with segregation of 2 distinct disease alleles. Direct sequencing revealed that the affected father was homozygous and all 4 sibs were heterozygous for the 1440delG mutation, whereas the unaffected mother and 2 affected sibs were heterozygous for the G504D substitution. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 SPONDYLOCOSTAL DYSOSTOSIS 1, AUTOSOMAL RECESSIVE</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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DLL3, GLY504ASP
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<br />
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SNP: rs104894676,
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gnomAD: rs104894676,
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ClinVar: RCV000007237, RCV000996922
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the gly504-to-asp (G504D) mutation in the DLL3 gene that was found in compound heterozygous state in 2 sibs with spondylocostal dysostosis (SCDO1; 277300) by Whittock et al. (2004), see 602768.0007. </p>
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</span>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Bettenhausen, B., Hrabe de Angelis, M., Simon, D., Guenet, J. L., Gossler, A.
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<strong>Transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila delta.</strong>
|
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Development 121: 2407-2418, 1995.
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[PubMed: 7671806]
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[Full Text: https://doi.org/10.1242/dev.121.8.2407]
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</li>
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<li>
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<p class="mim-text-font">
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Bonafe, L., Giunta, C., Gassner, M., Steinmann, B., Superti-Furga, A.
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<strong>A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village.</strong>
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Clin. Genet. 64: 28-35, 2003.
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[PubMed: 12791036]
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[Full Text: https://doi.org/10.1034/j.1399-0004.2003.00085.x]
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<p class="mim-text-font">
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Bulman, M. P., Kusumi, K., Frayling, T. M., McKeown, C., Garrett, C., Lander, E. S., Krumlauf, R., Hattersley, A. T., Ellard, S., Turnpenny, P. D.
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<strong>Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis.</strong>
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Nature Genet. 24: 438-441, 2000.
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<p class="mim-text-font">
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Dunwoodie, S. L., Henrique, D., Harrison, S. M., Beddington, R. S. P.
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<strong>Mouse Dll3: a novel divergent delta gene which may complement the function of other delta homologues during early pattern formation in the mouse embryo.</strong>
|
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Development 124: 3065-3076, 1997.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Floor, E., De Jong, R. O., Fryns, J. P., Smulders, C., Vles, J. S. H.
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<strong>Spondylocostal dysostosis: an example of autosomal dominant transmission in a large family.</strong>
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Clin. Genet. 36: 236-241, 1989.
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[Full Text: https://doi.org/10.1111/j.1399-0004.1989.tb03196.x]
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<p class="mim-text-font">
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Gassner, M., Grabs, S. G.
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<strong>Kostovertebrale Dysplasie: ein Rezeptordefekt der Sklerotomentwicklung?</strong>
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Schweiz. Med. Wschr. 112: 791-797, 1982.
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[PubMed: 7100875]
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<li>
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<p class="mim-text-font">
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Gridley, T.
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<strong>Notch signaling and inherited disease syndromes.</strong>
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Hum. Molec. Genet. 12(R1): R9-R13, 2003.
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[PubMed: 12668592]
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[Full Text: https://doi.org/10.1093/hmg/ddg052]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kusumi, K., Sun, E. S., Kerrebrock, A. W., Bronson, R. T., Chi, D.-C., Bulotsky, M. S., Spencer, J. B., Birren, B. W., Frankel, W. N., Lander, E. S.
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<strong>The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries.</strong>
|
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Nature Genet. 19: 274-278, 1998.
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[PubMed: 9662403]
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[Full Text: https://doi.org/10.1038/961]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Matsuda, M., Yamanaka, Y., Uemura, M., Osawa, M., Saito, M. K., Nagahashi, A., Nishio, M., Guo, L., Ikegawa, S., Sakurai, S., Kihara, S., Maurissen, T. L., and 10 others.
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<strong>Recapitulating the human segmentation clock with pluripotent stem cells.</strong>
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Nature 580: 124-129, 2020.
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[PubMed: 32238941]
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[Full Text: https://doi.org/10.1038/s41586-020-2144-9]
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</p>
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<li>
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<p class="mim-text-font">
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Pourquie, O., Kusumi, K.
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<strong>When body segmentation goes wrong.</strong>
|
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Clin. Genet. 60: 409-416, 2001.
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[PubMed: 11846732]
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[Full Text: https://doi.org/10.1034/j.1399-0004.2001.600602.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Shen, J., Bronson, R. T., Chen, D. F., Xia, W., Selkoe, D. J., Tonegawa, S.
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<strong>Skeletal and CNS defects in presenilin-1-deficient mice.</strong>
|
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Cell 89: 629-639, 1997.
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[PubMed: 9160754]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)80244-5]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Turnpenny, P. D., Whittock, N., Duncan, J., Dunwoodie, S., Kusumi, K., Ellard, S.
|
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<strong>Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis.</strong>
|
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J. Med. Genet. 40: 333-339, 2003.
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[PubMed: 12746394]
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[Full Text: https://doi.org/10.1136/jmg.40.5.333]
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</p>
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<li>
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<p class="mim-text-font">
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Whittock, N. V., Ellard, S., Duncan, J., de Die-Smulders, C. E. M., Vles, J. S. H., Turnpenny, P. D.
|
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<strong>Pseudodominant inheritance of spondylocostal dysostosis type 1 caused by two familial delta-like 3 mutations.</strong>
|
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Clin. Genet. 66: 67-72, 2004.
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[PubMed: 15200511]
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[Full Text: https://doi.org/10.1111/j.0009-9163.2004.00272.x]
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</p>
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<li>
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<p class="mim-text-font">
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Wong, P. C., Zheng, H., Chen, H., Becher, M. W., Sirinathsinghji, D. J., Trumbauer, M. E., Chen, H. Y., Price, D. L., Van der Ploeg, L. H., Sisodia, S. S.
|
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<strong>Presenilin 1 is required for Notch1 and Dll1 expression in the paraxial mesoderm.</strong>
|
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Nature 387: 288-292, 1997.
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[PubMed: 9153393]
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[Full Text: https://doi.org/10.1038/387288a0]
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</p>
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</li>
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</ol>
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<br />
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Contributors:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 11/12/2020<br>Marla J. F. O'Neill - updated : 8/4/2005<br>George E. Tiller - updated : 3/2/2005<br>Victor A. McKusick - updated : 11/6/2003<br>Victor A. McKusick - updated : 7/18/2003<br>Victor A. McKusick - updated : 2/12/2002<br>Ada Hamosh - updated : 3/29/2000
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<span class="mim-text-font">
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Victor A. McKusick : 7/1/1998
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mgross : 11/12/2020<br>carol : 08/07/2019<br>carol : 08/17/2015<br>mcolton : 8/12/2015<br>carol : 10/19/2009<br>carol : 8/16/2006<br>wwang : 8/5/2005<br>terry : 8/4/2005<br>alopez : 3/2/2005<br>tkritzer : 11/11/2003<br>tkritzer : 11/7/2003<br>terry : 11/6/2003<br>cwells : 7/31/2003<br>terry : 7/18/2003<br>alopez : 2/14/2002<br>alopez : 2/14/2002<br>terry : 2/12/2002<br>alopez : 5/3/2000<br>alopez : 3/30/2000<br>carol : 3/29/2000<br>dholmes : 7/22/1998<br>alopez : 7/2/1998<br>alopez : 7/2/1998<br>alopez : 7/1/1998
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