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Entry
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- *602858 - 7-DEHYDROCHOLESTEROL REDUCTASE; DHCR7
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*602858</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<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="#description">Description</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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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602858">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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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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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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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="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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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="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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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/Location/View?db=core;g=ENSG00000172893;t=ENST00000355527" 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=1717" 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=602858" 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="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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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="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=ENSG00000172893;t=ENST00000355527" 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_001163817,NM_001360,NM_001425107,NM_001425108,NM_001425109,NM_001425110,NM_001425111,NM_001425112,NM_001425113,NM_001425114,NM_001425116,NM_001425117,NM_001425118,NM_001425119,NM_001425120,NM_001425121" 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_001360" 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=602858" 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="panel-title">
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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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</span>
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</span>
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</div>
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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=04174&isoform_id=04174_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/DHCR7" 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/2935281,3171089,4106362,4191398,4581759,6288743,12652617,20138066,119595194,119595195,119595196,119595197,119943112,158260017,189053473,194384088,255308875,608785249,608785533,608785601,957949273,957949276,957949279,957949282,1194445775,1194445777,1194445779,2601493070,2601493076,2601493080,2601493084,2601493086,2601493090,2601493092,2601493108,2601493116,2601493118,2601493120,2601493125,2601493135,2601493137" 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/Q9UBM7" 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>
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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="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=1717" 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=ENSG00000172893;t=ENST00000355527" 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=DHCR7" 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=DHCR7" 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+1717" 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/DHCR7" 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:1717" 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/1717" 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=chr11&hgg_gene=ENST00000355527.8&hgg_start=71427287&hgg_end=71449043&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>
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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="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://search.clinicalgenome.org/kb/gene-dosage/HGNC:2860" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:2860" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/dhcr7" 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=602858[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>
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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">
|
|
<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=602858[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://www.deciphergenomics.org/gene/DHCR7/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000172893" 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.ebi.ac.uk/gwas/search?query=DHCR7" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=DHCR7" 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=DHCR7" 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="http://lovd.i-med.ac.at/home.php?select_db=DHCR7" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=DHCR7&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/PA27321" 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:2860" 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://flybase.org/reports/FBgn0034657.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1298378" 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/DHCR7#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:1298378" 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/1717/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=1717" 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=WBGene00007126;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-030912-9" 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="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:602858" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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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:1717" 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=DHCR7&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> 43929004<br />
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<strong>ICD10CM:</strong> E78.72<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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602858
|
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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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7-DEHYDROCHOLESTEROL REDUCTASE; DHCR7
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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>
|
|
<span class="mim-font">
|
|
STEROL DELTA-7-REDUCTASE
|
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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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=DHCR7" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DHCR7</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">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/11/707?start=-3&limit=10&highlight=707">11q13.4</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:71427287-71449043&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'})">11:71,427,287-71,449,043</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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|
|
|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</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>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>The DHCR7 gene encodes delta-7-sterol reductase (<a href="https://enzyme.expasy.org/EC/1.3.1.21" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 1.3.1.21</a>), the penultimate enzyme of mammalian sterol biosynthesis that converts 7-dehydrocholesterol (7-DHC) to cholesterol. This enzyme removes the C(7-8) double bond introduced by the sterol delta8-delta7 isomerases. In addition, its role in drug-induced malformations is known: inhibitors of the last step of cholesterol biosynthesis such as AY9944 and BM15766 severely impair brain development (<a href="#15" class="mim-tip-reference" title="Moebius, F. F., Fitzky, B. U., Lee, J. N., Paik, Y.-K., Glossmann, H. <strong>Molecular cloning and expression of the human delta-7-sterol reductase.</strong> Proc. Nat. Acad. Sci. 95: 1899-1902, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9465114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9465114</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9465114[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.4.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9465114">Moebius et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9465114" 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="#26" class="mim-tip-reference" title="Wassif, C. A., Maslen, C., Kachilele-Linjewile, S., Lin, D., Linck, L. M., Connor, W. E., Steiner, R. D., Porter, F. D. <strong>Mutations in the human sterol delta-7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome.</strong> Am. J. Hum. Genet. 63: 55-62, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634533</a>] [<a href="https://doi.org/10.1086/301936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634533">Wassif et al. (1998)</a> cloned a cDNA encoding human sterol delta-7-reductase (DHCR7) on the basis of its homology with the sterol delta-7-reductase from Arabidopsis thaliana, and they confirmed the enzymatic function of the human gene product by expression in fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9634533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Waterham, H. R., Wijburg, F. A., Hennekam, R. C. M., Vreken, P., Poll-The, B. T., Dorland, L., Duran, M., Jira, P. E., Smeitink, J. A. M., Wevers, R. A., Wanders, R. J. A. <strong>Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene.</strong> Am. J. Hum. Genet. 63: 329-338, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683613</a>] [<a href="https://doi.org/10.1086/301982" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683613">Waterham et al. (1998)</a> identified a partial transcript coding for human 7-dehydrocholesterol reductase by searching the EST database with the amino acid sequence of an A. thaliana enzyme. They isolated the remaining 5-prime sequence by 5-prime RACE. By heterologous expression of the cDNA in Saccharomyces cerevisiae, they confirmed that it coded for 7-dehydrocholesterol reductase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9683613" 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="#15" class="mim-tip-reference" title="Moebius, F. F., Fitzky, B. U., Lee, J. N., Paik, Y.-K., Glossmann, H. <strong>Molecular cloning and expression of the human delta-7-sterol reductase.</strong> Proc. Nat. Acad. Sci. 95: 1899-1902, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9465114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9465114</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9465114[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.4.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9465114">Moebius et al. (1998)</a> cloned the DHCR7 gene. The deduced protein is membrane-bound with a predicted molecular mass of 55 kD and 6 to 9 putative transmembrane segments. The protein is structurally related to plant and yeast sterol reductases. In adults, the ubiquitously transcribed mRNA is most abundant in adrenal gland, liver, testis, and brain. Although important in vertebrates, the enzyme is absent from yeast. Microsomes from Saccharomyces cerevisiae strains heterologously expressing the human cDNA removed the C(7-8) double bond in 7-dehydrocholesterol. The conversion to cholesterol depends on NADPH and is potently inhibited by AY9944, BM15766, and triparanol. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9465114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using radiation hybrid mapping, <a href="#26" class="mim-tip-reference" title="Wassif, C. A., Maslen, C., Kachilele-Linjewile, S., Lin, D., Linck, L. M., Connor, W. E., Steiner, R. D., Porter, F. D. <strong>Mutations in the human sterol delta-7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome.</strong> Am. J. Hum. Genet. 63: 55-62, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634533</a>] [<a href="https://doi.org/10.1086/301936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634533">Wassif et al. (1998)</a> mapped the DHCR7 gene to chromosome 11q12-q13. By FISH, <a href="#28" class="mim-tip-reference" title="Waterham, H. R., Wijburg, F. A., Hennekam, R. C. M., Vreken, P., Poll-The, B. T., Dorland, L., Duran, M., Jira, P. E., Smeitink, J. A. M., Wevers, R. A., Wanders, R. J. A. <strong>Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene.</strong> Am. J. Hum. Genet. 63: 329-338, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683613</a>] [<a href="https://doi.org/10.1086/301982" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683613">Waterham et al. (1998)</a> assigned the DHCR7 gene to 11q13. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9683613+9634533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Fitzky, B. U., Witsch-Baumgartner, M., Erdel, M., Lee, J. N., Paik, Y.-K., Glossmann, H., Utermann, G., Moebius, F. F. <strong>Mutations in the delta-7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome.</strong> Proc. Nat. Acad. Sci. 95: 8181-8186, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9653161[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.14.8181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9653161">Fitzky et al. (1998)</a> characterized the human and mouse DHCR7 genes and assigned them to syntenic regions on 11q13 and 7F5, respectively, by FISH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9653161" 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="#22" class="mim-tip-reference" title="Porter, J. A., Young, K. E., Beachy, P. A. <strong>Cholesterol modification of hedgehog signaling proteins in animal development.</strong> Science 274: 255-258, 1996. Note: Erratum: Science 274: 1597 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8824192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8824192</a>] [<a href="https://doi.org/10.1126/science.274.5285.255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8824192">Porter et al. (1996)</a> demonstrated that cholesterol is the lipophilic moiety covalently attached to the N-terminal signaling domain of hedgehog proteins (SHH, <a href="/entry/600725">600725</a>; IHH, <a href="/entry/600726">600726</a>) during autoprocessing and that the C-terminal domain acts as an intramolecular cholesterol transferase. They postulated that some of the effects of perturbed cholesterol biosynthesis on animal development may be due to the fact that cholesterol is used to modify embryonic signaling proteins. They postulated that in SLO syndrome, where cholesterol biosynthesis is defective, there may be defective modification of the hedgehog proteins and perhaps other similarly processed proteins. <a href="#22" class="mim-tip-reference" title="Porter, J. A., Young, K. E., Beachy, P. A. <strong>Cholesterol modification of hedgehog signaling proteins in animal development.</strong> Science 274: 255-258, 1996. Note: Erratum: Science 274: 1597 only, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8824192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8824192</a>] [<a href="https://doi.org/10.1126/science.274.5285.255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8824192">Porter et al. (1996)</a> postulated further that the spectrum of developmental malformations seen in SLO syndrome may be due to loss of hedgehog protein function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8824192" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using knockout screens in mouse Pfa1 cells, <a href="#4" class="mim-tip-reference" title="Freitas, F. P., Alborzinia, H., Dos Santos, A. F., Nepachalovich, P., Pedrera, L., Zilka, O., Inague, A., Klein, C., Aroua, N., Kaushal, K., Kast, B., Lorenz, S. M., and 35 others. <strong>7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.</strong> Nature 626: 401-410, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38297129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38297129</a>] [<a href="https://doi.org/10.1038/s41586-023-06878-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38297129">Freitas et al. (2024)</a> identified Dhcr7 as a proferroptotic gene. DHCR7 knockout in the human ferroptosis fibrosarcoma cell line HT1080 led to accumulation of 7-DHC and resistance to ferroptosis, whereas reexpression of DHCR7 abolished 7-DHC concentrations and resensitized cells to ferroptosis. The accumulated 7-DHC in response to DHCR7 knockout functioned as an antiferroptotic metabolite that blocked peroxidation of phospholipids, resulting in truncated phospholipids that prevented execution of ferroptosis to protect cells. In addition, 7-DHC accumulation increased cell fitness and appeared to have in impact on lymphoma growth in a mouse model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38297129" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By knockdown screens in HEK293T cells, <a href="#12" class="mim-tip-reference" title="Li, Y., Ran, Q., Duan, Q., Jin, J., Wang, Y., Yu, L., Wang, C., Zhu, Z., Chen, X., Weng, L., Li, Z., Wang, J., and 13 others. <strong>7-Dehydrocholesterol dictates ferroptosis sensitivity.</strong> Nature 626: 411-418, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38297130/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38297130</a>] [<a href="https://doi.org/10.1038/s41586-023-06983-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38297130">Li et al. (2024)</a> independently identified DHCR7 as a proferroptotic gene. DHCR7 knockout strongly suppressed ferroptosis, whereas reexpression of DHCR7 reversed ferroptosis resistance in DHCR7-knockout cells. Loss of DHCR7 resulted in accumulation of 7-DHC, which protected the cells from ferroptosis by inhibiting peroxidation of phospholipids. 7-DHC was also involved in regulation of tumor ferroptosis and protection of kidneys from ischemia-reperfusion injury in a mouse model. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38297130" 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>Children with the Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>) have elevated serum 7-DHC levels and low serum cholesterol levels. In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol delta-7-reductase. Liver microsomes from an SLOS homozygote were shown by <a href="#25" class="mim-tip-reference" title="Shefer, S., Salen, G., Batta, A. K., Honda, A., Tint, G. S., Irons, M., Elias, E. R., Chen, T. C., Holick, M. F. <strong>Markedly inhibited 7-dehydrocholesterol-delta(7)-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes.</strong> J. Clin. Invest. 96: 1779-1785, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7560069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7560069</a>] [<a href="https://doi.org/10.1172/JCI118223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7560069">Shefer et al. (1995)</a> to have reduced activity of this enzyme. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7560069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 unrelated patients with SLOS, <a href="#26" class="mim-tip-reference" title="Wassif, C. A., Maslen, C., Kachilele-Linjewile, S., Lin, D., Linck, L. M., Connor, W. E., Steiner, R. D., Porter, F. D. <strong>Mutations in the human sterol delta-7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome.</strong> Am. J. Hum. Genet. 63: 55-62, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634533</a>] [<a href="https://doi.org/10.1086/301936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634533">Wassif et al. (1998)</a> identified 4 different mutations in the DHCR7 gene (<a href="#0001">602858.0001</a>-<a href="#0004">602858.0004</a>). <a href="#3" class="mim-tip-reference" title="Fitzky, B. U., Witsch-Baumgartner, M., Erdel, M., Lee, J. N., Paik, Y.-K., Glossmann, H., Utermann, G., Moebius, F. F. <strong>Mutations in the delta-7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome.</strong> Proc. Nat. Acad. Sci. 95: 8181-8186, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9653161[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.14.8181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9653161">Fitzky et al. (1998)</a> identified mutations in the DHCR7 gene (see, e.g., <a href="#0009">602858.0009</a> and <a href="#0011">602858.0011</a>) in patients with SLOS. <a href="#28" class="mim-tip-reference" title="Waterham, H. R., Wijburg, F. A., Hennekam, R. C. M., Vreken, P., Poll-The, B. T., Dorland, L., Duran, M., Jira, P. E., Smeitink, J. A. M., Wevers, R. A., Wanders, R. J. A. <strong>Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene.</strong> Am. J. Hum. Genet. 63: 329-338, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683613</a>] [<a href="https://doi.org/10.1086/301982" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683613">Waterham et al. (1998)</a> identified homozygous and compound heterozygous mutations in the DHCR7 gene, including the intron 8 splice-site mutation (<a href="#0001">602858.0001</a>), in patients with SLOS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9683613+9653161+9634533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="De Brasi, D., Esposito, T., Rossi, M., Parenti, G., Sperandeo, M. P., Zuppaldi, A., Bardaro, T., Ambruzzi, M. A., Zelante, L., Ciccodicola, A., Sebastio, G., D'Urso, M., Andria, G. <strong>Smith-Lemli-Opitz syndrome: evidence of T93M as a common mutation of delta-7-sterol reductase in Italy and report of three novel mutations.</strong> Europ. J. Hum. Genet. 7: 937-940, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10602371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10602371</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10602371">De Brasi et al. (1999)</a> stated that 19 mutations in the DHCR7 gene had been described; among these, mutations impairing the activity of the C terminus appeared to be the most severe. They performed mutation analysis of the DHCR7 gene in 9 Italian SLOS patients and identified 3 novel mutations. They found that the T93M mutation (<a href="#0009">602858.0009</a>) was the most frequent (7 of 18 alleles) in their survey. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10602371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 84 patients with clinically and biochemically characterized SLOS, <a href="#30" class="mim-tip-reference" title="Witsch-Baumgartner, M., Fitzky, B. U., Ogorelkova, M., Kraft, H. G., Moebius, F. F., Glossmann, H., Seedorf, U., Gillessen-Kaesbach, G., Hoffmann, G. F., Clayton, P., Kelley, R. I., Utermann, G. <strong>Mutational spectrum in the delta-7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome.</strong> Am. J. Hum. Genet. 66: 402-412, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677299[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677299">Witsch-Baumgartner et al. (2000)</a> identified 40 different mutations in the DHCR7 gene. All but 1 of their patients were white, the exception having mostly American Cherokee heritage. On the basis of mutation type and expression studies, the authors grouped the mutations into 4 classes: nonsense and splice site mutations resulting in putative null alleles, missense mutations in the transmembrane domains, mutations in the fourth cytoplasmic loop, and mutations in the C-terminal endoplasmic reticulum (ER) domain. All but 1 of the tested missense mutations reduced protein stability. The mildest clinical phenotypes were associated with transmembrane and C-terminal ER domain mutations, and the most severe types were associated with null alleles and mutations in the fourth cytoplasmic loop. Most homozygotes for null alleles had severe SLOS; 1 patient had a moderate phenotype. Homozygosity for null mutations in the DHCR7 gene appeared compatible with life, suggesting that cholesterol may be synthesized in the absence of this enzyme or that exogenous sources of cholesterol can be used. Given that only a few null mutations exist, the authors were surprised to find that 2 of them, IVS8-1G-C (<a href="#0001">602858.0001</a>) and trp151 to ter (<a href="#0011">602858.0011</a>), accounted for more than one-third of all mutant alleles. In a note added in proof, <a href="#30" class="mim-tip-reference" title="Witsch-Baumgartner, M., Fitzky, B. U., Ogorelkova, M., Kraft, H. G., Moebius, F. F., Glossmann, H., Seedorf, U., Gillessen-Kaesbach, G., Hoffmann, G. F., Clayton, P., Kelley, R. I., Utermann, G. <strong>Mutational spectrum in the delta-7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome.</strong> Am. J. Hum. Genet. 66: 402-412, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677299[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677299">Witsch-Baumgartner et al. (2000)</a> stated that 7 additional DHCR7 mutations had been detected in 12 patients with SLOS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10677299" 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="#34" class="mim-tip-reference" title="Yu, H., Tint, G. S., Salen, G., Patel, S. B. <strong>Detection of a common mutation in the RSH or Smith-Lemli-Opitz syndrome by a PCR-RFLP assay: IVS8-1G-C is found in over sixty percent of US propositi.</strong> Am. J. Med. Genet. 90: 347-350, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10710236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10710236</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000214)90:4<347::aid-ajmg16>3.0.co;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10710236">Yu et al. (2000)</a> reported a simple PCR-based restriction endonuclease digestion assay for rapid detection of the IVS8-1G-C mutation. This mutation results in abnormal splicing of exon 9 with a 134-bp insertion of intron 8 sequences, a resultant frameshift, and a premature translation stop (<a href="#0001">602858.0001</a>). The authors identified this mutation in 21 of 33 SLOS propositi (21 of 66 alleles). Since none of their patients was homozygous for this mutation, the authors hypothesized that homozygosity for the mutation may often be prenatally lethal. They also screened unrelated normal individuals for the prevalence of this mutation, including 90 American Caucasians, 120 Finnish Caucasians, 121 Sierra Leone Africans, 95 Han Chinese, and 103 Japanese. One IVS8-1G-C mutation was identified in the American Caucasian population; none was observed in the other populations. <a href="#34" class="mim-tip-reference" title="Yu, H., Tint, G. S., Salen, G., Patel, S. B. <strong>Detection of a common mutation in the RSH or Smith-Lemli-Opitz syndrome by a PCR-RFLP assay: IVS8-1G-C is found in over sixty percent of US propositi.</strong> Am. J. Med. Genet. 90: 347-350, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10710236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10710236</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000214)90:4<347::aid-ajmg16>3.0.co;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10710236">Yu et al. (2000)</a> concluded that the IVS8-1G-C transversion is a very common mutation in SLOS patients from the U.S. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10710236" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Yu, H., Lee, M.-H., Starck, L., Elias, E. R., Irons, M., Salen, G., Patel, S. B., Tint, G. S. <strong>Spectrum of delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome.</strong> Hum. Molec. Genet. 9: 1385-1391, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1903 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814720</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814720">Yu et al. (2000)</a> screened an additional 32 patients with SLOS, 28 from the U.S.A. and 4 from Sweden. Twenty missense mutations, 1 nonsense mutation (<a href="#0012">602858.0012</a>), and 1 splice-site mutation involving the exon 9 acceptor site (IVS8-1G-C; <a href="#0001">602858.0001</a>) were detected. All probands were heterozygous for mutations. Three mutations accounted for 54% of those observed in their cohort, the splice acceptor site mutation IVS8-1G-C (22/64 alleles, 34%), T93M (<a href="#0009">602858.0009</a>) (8/64, 12.5%), and V326L (<a href="#0011">602858.0011</a>) (5/64, 7.8%). Severity of SLOS was negatively correlated with both plasma cholesterol and relative plasma cholesterol, but not with 7-dehydrocholesterol, the immediate precursor, confirming previous observations. However, no correlation was observed between mutations and phenotype, suggesting that the degree of severity may be affected by other factors. The authors estimated that 33 to 42% of the variation in the SLOS severity score is accounted for by variation in plasma cholesterol, suggesting that factors other than plasma cholesterol are additionally involved in determining severity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10814720" 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="Krakowiak, P. A., Nwokoro, N. A., Wassif, C. A., Battaile, K. P., Nowaczyk, M. J. M., Connor, W. E., Maslen, C., Steiner, R. D., Porter, F. D. <strong>Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping.</strong> Am. J. Med. Genet. 94: 214-227, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10995508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10995508</a>]" pmid="10995508">Krakowiak et al. (2000)</a> reported clinical and molecular data concerning 16 patients with SLOS of varying phenotypic severity. In each they identified mutations in both alleles. They found 6 previously undescribed mutations. They also reported rapid PCR-based assays developed to detect 4 of the recurring mutations and 6 others. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10995508" 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="#29" class="mim-tip-reference" title="Witsch-Baumgartner, M., Ciara, E., Loffler, J., Menzel, H. J., Seedorf, U., Burn, J., Gillessen-Kaesbach, G., Hoffmann, G. F., Fitzky, B. U., Mundy, H., Clayton, P., Kelley, R. I., Krajewska-Walasek, M., Utermann, G. <strong>Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations.</strong> Europ. J. Hum. Genet. 9: 45-50, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175299</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175299">Witsch-Baumgartner et al. (2001)</a> reported mutation analysis of the DHCR7 gene in 59 SLOS patients, 28 of whom had previously been reported (<a href="#30" class="mim-tip-reference" title="Witsch-Baumgartner, M., Fitzky, B. U., Ogorelkova, M., Kraft, H. G., Moebius, F. F., Glossmann, H., Seedorf, U., Gillessen-Kaesbach, G., Hoffmann, G. F., Clayton, P., Kelley, R. I., Utermann, G. <strong>Mutational spectrum in the delta-7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome.</strong> Am. J. Hum. Genet. 66: 402-412, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677299[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677299">Witsch-Baumgartner et al., 2000</a>). Fifteen patients were from Poland, 22 from Germany/Austria, and 22 from Great Britain. Mutations were detected on 114 of 118 SLOS chromosomes (96.6%). Altogether, 35 different mutations were identified, but in all 3 populations 3 mutations accounted for more than 50% of SLOS alleles. The mutation spectra were, however, significantly different across these populations. W151X (<a href="#0010">602858.0010</a>) was the most frequent mutation in the Polish population (33.3%), had an intermediate frequency in German/Austrian patients (18.2%), and was rare in British patients (2.3%). The V326L mutation (<a href="#0011">602858.0011</a>) showed the same east-west gradient. In contrast, IVS8-1G-C (<a href="#0001">602858.0001</a>) was most frequent in Britain (34.1%), intermediate in Germany/Austria (20.5%), and rare in Poland (3.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene gave evidence for both recurrent mutations and founder effects; all IVS8-1G-C and V326L alleles shared the same haplotype, whereas the W151X allele occurred on different haplotypes. <a href="#29" class="mim-tip-reference" title="Witsch-Baumgartner, M., Ciara, E., Loffler, J., Menzel, H. J., Seedorf, U., Burn, J., Gillessen-Kaesbach, G., Hoffmann, G. F., Fitzky, B. U., Mundy, H., Clayton, P., Kelley, R. I., Krajewska-Walasek, M., Utermann, G. <strong>Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations.</strong> Europ. J. Hum. Genet. 9: 45-50, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175299</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175299">Witsch-Baumgartner et al. (2001)</a> concluded that the distribution pattern of DHCR7 mutations in Europe may reflect ancient and modern migrations in Europe. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10677299+11175299" 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>Among 37 ethnic Polish patients with SLOS, <a href="#1" class="mim-tip-reference" title="Ciara, E., Nowaczyk, M. J. M., Witsch-Baumgartner, M., Malunowicz, E., Popowska, E., Jezela-Stanek, A., Piotrowicz, M., Waye, J. S., Utermann, G., Krajewska-Walasek, M. <strong>DHCR7 mutations and genotype-phenotype correlation in 37 Polish patients with Smith-Lemli-Opitz syndrome.</strong> Clin. Genet. 66: 517-524, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15521979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15521979</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00350.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15521979">Ciara et al. (2004)</a> found that 2 mutations, W151X (<a href="#0010">602858.0010</a>), present in 22 of 68 alleles (32%), and V326L (<a href="#0011">602858.0011</a>), present in 19 of 68 alleles (28%), accounted for 60% of all mutations observed in this group. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15521979" 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="#24" class="mim-tip-reference" title="Scalco, F. B., Correa-Cerro, L. S., Wassif, C. A., Porter, F. D., Moretti-Ferreira, D. <strong>DHCR7 mutations in Brazilian Smith-Lemli-Opitz syndrome patients. (Letter)</strong> Am. J. Med. Genet. 136A: 278-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15952211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15952211</a>] [<a href="https://doi.org/10.1002/ajmg.a.30810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15952211">Scalco et al. (2005)</a> reported on DHCR7 mutation analysis of 14 Brazilian SLOS patients. The most frequent mutations in this population were the IVS8-1G-C (<a href="#0001">602858.0001</a>) and T93M (<a href="#0009">602858.0009</a>) mutations. A mutation disrupting the normal initiation codon (M1V; <a href="#0020">602858.0020</a>) was identified in a mildly affected child. <a href="#11" class="mim-tip-reference" title="Langius, F. A. A., Waterham, H. R., Romeijn, G. J., Oostheim, W., de Barse, M. M. J., Dorland, L., Duran, M., Beemer, F. A., Wanders, R. J. A., Poll-The, B. T. <strong>Identification of 3 patients with a very mild form of Smith-Lemli-Opitz syndrome.</strong> Am. J. Med. Genet. 122A: 24-29, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12949967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12949967</a>] [<a href="https://doi.org/10.1002/ajmg.a.20207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12949967">Langius et al. (2003)</a> had reported a mutation in the initiator methionine (M1L; <a href="#0017">602858.0017</a>) in 3 patients who were also mildly affected. <a href="#26" class="mim-tip-reference" title="Wassif, C. A., Maslen, C., Kachilele-Linjewile, S., Lin, D., Linck, L. M., Connor, W. E., Steiner, R. D., Porter, F. D. <strong>Mutations in the human sterol delta-7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome.</strong> Am. J. Hum. Genet. 63: 55-62, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634533</a>] [<a href="https://doi.org/10.1086/301936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634533">Wassif et al. (1998)</a> had previously shown that initiation of translation at met59 gives rise to a functional protein. Both <a href="#11" class="mim-tip-reference" title="Langius, F. A. A., Waterham, H. R., Romeijn, G. J., Oostheim, W., de Barse, M. M. J., Dorland, L., Duran, M., Beemer, F. A., Wanders, R. J. A., Poll-The, B. T. <strong>Identification of 3 patients with a very mild form of Smith-Lemli-Opitz syndrome.</strong> Am. J. Med. Genet. 122A: 24-29, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12949967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12949967</a>] [<a href="https://doi.org/10.1002/ajmg.a.20207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12949967">Langius et al. (2003)</a> and <a href="#24" class="mim-tip-reference" title="Scalco, F. B., Correa-Cerro, L. S., Wassif, C. A., Porter, F. D., Moretti-Ferreira, D. <strong>DHCR7 mutations in Brazilian Smith-Lemli-Opitz syndrome patients. (Letter)</strong> Am. J. Med. Genet. 136A: 278-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15952211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15952211</a>] [<a href="https://doi.org/10.1002/ajmg.a.30810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15952211">Scalco et al. (2005)</a> suspected that protein initiation at met59 allows for synthesis of a functional DHCR7 enzyme, accounting for the mild nature of the disorder in these mutations of the initiator methionine. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12949967+15952211+9634533" 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="#19" class="mim-tip-reference" title="Nowaczyk, M. J. M., Waye, J. S., Douketis, J. D. <strong>DHCR7 mutation carrier rates and prevalence of the RSH/Smith-Lemli-Opitz syndrome: where are the patients?</strong> Am. J. Med. Genet. 140A: 2057-2062, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16906538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16906538</a>] [<a href="https://doi.org/10.1002/ajmg.a.31413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16906538">Nowaczyk et al. (2006)</a> pointed out that the carrier rate for the most frequently occurring DHCR7 mutation causing SLOS, IVS8-1G-C (<a href="#0001">602858.0001</a>), is approximately 1 in 100 for the Caucasian population of North America and possibly as high as 1 in 50 to 1 in 30 in central European populations. Based on the frequencies and the proportion of this mutation observed in various patient populations, the expected incidence of SLOS in those populations was calculated to be between 1 and 1,590 and 1 in 17,000. However, around the world the observed prevalence and incidence are much lower than those calculated from the individual mutation carrier rates observed in any given population. The discrepancy between the expected incidence and prevalence can be explained only in part by the neonatal and infancy deaths of the most severely affected children with SLOS and underascertainment of mild and atypical cases at the mild end of the spectrum. SLOS may be responsible for a high number of miscarriages. Estimates of the prevalence of SLOS at 16 weeks' gestation are similar to that observed at birth (approximately 1 in 60,000), suggesting that either reduced fertility of carrier couples or losses of affected embryos or fetuses in the first trimester play a significant role in reducing the second trimester prevalence of SLOS. One hypothesis postulated that null mutations of DHCR7 confer an advantage in increasing endogenous vitamin D synthesis (<a href="#6" class="mim-tip-reference" title="Kelley, R. I., Hennekam, R. C. M. <strong>The Smith Lemli-Opitz syndrome.</strong> J. Med. Genet. 37: 321-335, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10807690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10807690</a>] [<a href="https://doi.org/10.1136/jmg.37.5.321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10807690">Kelley and Hennekam, 2000</a>). Since osteomalacia was a common disease in Europe since antiquity, it is possible that individuals that were protected from this disease, especially in the northern parts of Europe, were at a survival advantage. <a href="#21" class="mim-tip-reference" title="Opitz, J. M., Gilbert-Barness, E., Ackerman, J., Lowichik, A. <strong>Cholesterol and development: the RSH ("Smith-Lemli-Opitz") syndrome and related conditions.</strong> Pediat. Path. Molec. Med. 21: 153-181, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11942534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11942534</a>] [<a href="https://doi.org/10.1080/15227950252852078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11942534">Opitz et al. (2002)</a> suggested that higher levels of 7-dehydrocholesterol in carrier females may have reduced the frequency of cephalopelvic disproportion in fetuses at risk for rickets secondary to maternal vitamin D deficiency and thus, provide a fertility advantage. <a href="#7" class="mim-tip-reference" title="Kelley, R. I., Herman, G. E. <strong>Inborn errors of sterol biosynthesis.</strong> Annu. Rev. Genomics Hum. Genet. 2: 299-341, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11701653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11701653</a>] [<a href="https://doi.org/10.1146/annurev.genom.2.1.299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11701653">Kelley and Herman (2001)</a> discussed the biases that may be at play in estimating the carrier rates of DHCR7 mutations based on the mutation spectrum observed in the affected population and assuming that it is representative of the frequencies of various mutations in carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11942534+10807690+16906538+11701653" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#27" class="mim-tip-reference" title="Wassif, C. A., Zhu, P., Kratz, L., Krakowiak, P. A., Battaile, K. P., Weight, F. F., Grinberg, A., Steiner, R. D., Nwokoro, N. A., Kelley, R. I., Stewart, R. R., Porter, F. D. <strong>Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith-Lemli-Opitz syndrome.</strong> Hum. Molec. Genet. 10: 555-564, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11230174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11230174</a>] [<a href="https://doi.org/10.1093/hmg/10.6.555" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11230174">Wassif et al. (2001)</a> developed a mouse model of RSH/SLOS by disruption of the 3-beta-hydroxysterol delta-7-reductase gene. As in human patients, the RSH/SLOS mouse has a marked reduction of serum and tissue cholesterol levels and a marked increase of serum and tissue 7-dehydrocholesterol levels. Phenotypic similarities between this mouse model and the human syndrome include intrauterine growth retardation, variable craniofacial anomalies including cleft palate, poor feeding with an uncoordinated suck, hypotonia, and decreased movement. Neurophysiologic studies showed that although the response of frontal cortex neurons to the neurotransmitter gamma-amino-n-butyric acid was normal, the response of these same neurons to glutamate was significantly impaired. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11230174" 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>Cholesterol-enriched lipid rafts play an important role in mast cell activation. <a href="#9" class="mim-tip-reference" title="Kovarova, M., Wassif, C. A., Odom, S., Liao, K., Porter, F. D., Rivera, J. <strong>Cholesterol deficiency in a mouse model of Smith-Lemli-Opitz syndrome reveals increased mast cell responsiveness.</strong> J Exp Med. 203: 1161-1171, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16618793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16618793</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16618793[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20051701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16618793">Kovarova et al. (2006)</a> observed that mast cells derived from Dhcr7 -/- mice showed constitutive cytokine production and hyperdegranulation after stimulation of Fcer1 (see FCER1A, <a href="/entry/147140">147140</a>). Dhcr7-deficient mast cells accumulated 7-DHC in lipid rafts, partially disrupting raft stability and displacing Lyn (<a href="/entry/165120">165120</a>) protein and activity. Downregulation of Lyn-dependent signaling events, such as phosphorylation of Csk-binding protein (PAG; <a href="/entry/605767">605767</a>), was associated with increased Fyn (<a href="/entry/137025">137025</a>) kinase activity and Akt (<a href="/entry/164730">164730</a>) phosphorylation. <a href="#9" class="mim-tip-reference" title="Kovarova, M., Wassif, C. A., Odom, S., Liao, K., Porter, F. D., Rivera, J. <strong>Cholesterol deficiency in a mouse model of Smith-Lemli-Opitz syndrome reveals increased mast cell responsiveness.</strong> J Exp Med. 203: 1161-1171, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16618793/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16618793</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16618793[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20051701" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16618793">Kovarova et al. (2006)</a> proposed that lipid raft dysfunction in SLOS may explain the observation of allergy in these patients due to increased mast cell sensitivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16618793" 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 G-to-C transversion in intron 8 of the DHCR7 gene results in a splice site defect and a null mutation, and is the most common mutant allele in Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>) (<a href="#32" class="mim-tip-reference" title="Wright, B. S., Nwokoro, N. A., Wassif, C. A., Porter, F. D., Waye, J. S., Eng, B., Nowaczyk, M. J. M. <strong>Carrier frequency of the RSH/Smith-Lemli-Opitz IVS8-1G-C mutation in African Americans. (Letter)</strong> Am. J. Med. Genet. 120A: 139-141, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12794707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12794707</a>] [<a href="https://doi.org/10.1002/ajmg.a.10207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12794707">Wright et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12794707" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In cell line A2SLO from a patient with severe SLOS, <a href="#26" class="mim-tip-reference" title="Wassif, C. A., Maslen, C., Kachilele-Linjewile, S., Lin, D., Linck, L. M., Connor, W. E., Steiner, R. D., Porter, F. D. <strong>Mutations in the human sterol delta-7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome.</strong> Am. J. Hum. Genet. 63: 55-62, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634533</a>] [<a href="https://doi.org/10.1086/301936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634533">Wassif et al. (1998)</a> identified a 134-bp insertion between nucleotides 788 and 789 of the DHCR7 gene. The insertion resulted in a frameshift, starting at amino acid 263, that precluded translation of the highly conserved carboxyl end of the protein. The cell line was homozygous for the insertion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9634533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with severe SLOS, the first child of unrelated parents, <a href="#28" class="mim-tip-reference" title="Waterham, H. R., Wijburg, F. A., Hennekam, R. C. M., Vreken, P., Poll-The, B. T., Dorland, L., Duran, M., Jira, P. E., Smeitink, J. A. M., Wevers, R. A., Wanders, R. J. A. <strong>Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene.</strong> Am. J. Hum. Genet. 63: 329-338, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683613</a>] [<a href="https://doi.org/10.1086/301982" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683613">Waterham et al. (1998)</a> found homozygosity for a 134-bp insertion in the DHCR7 gene after nucleotide 963. <a href="#34" class="mim-tip-reference" title="Yu, H., Tint, G. S., Salen, G., Patel, S. B. <strong>Detection of a common mutation in the RSH or Smith-Lemli-Opitz syndrome by a PCR-RFLP assay: IVS8-1G-C is found in over sixty percent of US propositi.</strong> Am. J. Med. Genet. 90: 347-350, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10710236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10710236</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000214)90:4<347::aid-ajmg16>3.0.co;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10710236">Yu et al. (2000)</a> noted that the IVS8-1G-C mutation results in abnormal splicing of the last exon, exon 9, with a 134-bp insertion of intron 8 sequences and a resultant frameshift with a premature translational stop. The more severe phenotype in this patient was consistent with the fact that the insertion occurred in a region strongly conserved among sterol reductases. Both parents were heterozygous for the insertion. <a href="#28" class="mim-tip-reference" title="Waterham, H. R., Wijburg, F. A., Hennekam, R. C. M., Vreken, P., Poll-The, B. T., Dorland, L., Duran, M., Jira, P. E., Smeitink, J. A. M., Wevers, R. A., Wanders, R. J. A. <strong>Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene.</strong> Am. J. Hum. Genet. 63: 329-338, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683613</a>] [<a href="https://doi.org/10.1086/301982" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683613">Waterham et al. (1998)</a> found the 134-bp insertion in compound heterozygous state in a child with SLOS, the other allele carrying the trp248-to-cys mutation (<a href="#0008">602858.0008</a>) in the DHCR7 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9683613+10710236" 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>Among 16 patients with severe SLOS (severity score greater than 50), <a href="#30" class="mim-tip-reference" title="Witsch-Baumgartner, M., Fitzky, B. U., Ogorelkova, M., Kraft, H. G., Moebius, F. F., Glossmann, H., Seedorf, U., Gillessen-Kaesbach, G., Hoffmann, G. F., Clayton, P., Kelley, R. I., Utermann, G. <strong>Mutational spectrum in the delta-7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome.</strong> Am. J. Hum. Genet. 66: 402-412, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677299[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677299">Witsch-Baumgartner et al. (2000)</a> found that 14 of 32 mutant alleles carried an IVS8-1G-C mutation in the DHCR7 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10677299" 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="#34" class="mim-tip-reference" title="Yu, H., Tint, G. S., Salen, G., Patel, S. B. <strong>Detection of a common mutation in the RSH or Smith-Lemli-Opitz syndrome by a PCR-RFLP assay: IVS8-1G-C is found in over sixty percent of US propositi.</strong> Am. J. Med. Genet. 90: 347-350, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10710236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10710236</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000214)90:4<347::aid-ajmg16>3.0.co;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10710236">Yu et al. (2000)</a> reported a simple PCR-based restriction endonuclease digestion assay for the rapid detection of this mutation, which they identified in 21 of 66 alleles. The authors concluded that the IVS8-1G-C transversion is a very common mutation in SLOS patients from the U.S. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10710236" 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="#29" class="mim-tip-reference" title="Witsch-Baumgartner, M., Ciara, E., Loffler, J., Menzel, H. J., Seedorf, U., Burn, J., Gillessen-Kaesbach, G., Hoffmann, G. F., Fitzky, B. U., Mundy, H., Clayton, P., Kelley, R. I., Krajewska-Walasek, M., Utermann, G. <strong>Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations.</strong> Europ. J. Hum. Genet. 9: 45-50, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175299</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175299">Witsch-Baumgartner et al. (2001)</a> detected the IVS8-1G-C mutation on 25 of 118 alleles (21.2%) in a study of 59 SLOS patients from Great Britain, Germany, Poland, and Austria. A west-east gradient was detected (Great Britain, 34.1% of alleles; Germany/Austria, 20.5%; Poland, 3.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene showed that 13 IVS8-1G-C chromosomes shared the same haplotype and therefore provided evidence for a founder effect. One IVS8-1G-C mutation was present in cis with a T93M mutation (<a href="#0009">602858.0009</a>) on a different haplotype. As one of the other T93M alleles was also characterized by this haplotype, the double mutant was consistent with a recombination event. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175299" 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="Krakowiak, P. A., Nwokoro, N. A., Wassif, C. A., Battaile, K. P., Nowaczyk, M. J. M., Connor, W. E., Maslen, C., Steiner, R. D., Porter, F. D. <strong>Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping.</strong> Am. J. Med. Genet. 94: 214-227, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10995508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10995508</a>]" pmid="10995508">Krakowiak et al. (2000)</a> detected this mutation in compound heterozygosity with thr289 to ile (<a href="#0015">602858.0015</a>) in 2 brothers with SLOS. <a href="#18" class="mim-tip-reference" title="Nowaczyk, M. J. M., Heshka, T., Eng, B., Feigenbaum, A. J., Waye, J. S. <strong>DHCR7 genotypes of cousins with Smith-Lemli-Opitz syndrome.</strong> Am. J. Med. Genet. 100: 162-163, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11298379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11298379</a>] [<a href="https://doi.org/10.1002/ajmg.1227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11298379">Nowaczyk et al. (2001)</a> found that the boys' female first cousin carried the IVS8-1G-C/T289I genotype as well. The 2 unrelated mothers were carriers of the IVS8-1G-C mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10995508+11298379" 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="#17" class="mim-tip-reference" title="Nowaczyk, M. J. M., Farrell, S. A., Sirkin, W. L., Velsher, L., Krakowiak, P. A., Waye, J. S., Porter, F. D. <strong>Smith-Lemli-Opitz (RHS) syndrome: holoprosencephaly and homozygous IVS8-1G-C genotype.</strong> Am. J. Med. Genet. 103: 75-80, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11562938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11562938</a>] [<a href="https://doi.org/10.1002/1096-8628(20010915)103:1<75::aid-ajmg1502>3.0.co;2-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11562938">Nowaczyk et al. (2001)</a> found the IVS8-1G-C mutation in homozygous state in a fetus and 2 newborns with severe SLOS and holoprosencephaly. They stated that of the 6 previously reported severely affected newborns with SLOS who were homozygous for this mutation, none had HPE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11562938" 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>The IVS8-1G-C mutation is the most frequently identified mutant allele, accounting for approximately one-third of reported SLOS alleles. <a href="#32" class="mim-tip-reference" title="Wright, B. S., Nwokoro, N. A., Wassif, C. A., Porter, F. D., Waye, J. S., Eng, B., Nowaczyk, M. J. M. <strong>Carrier frequency of the RSH/Smith-Lemli-Opitz IVS8-1G-C mutation in African Americans. (Letter)</strong> Am. J. Med. Genet. 120A: 139-141, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12794707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12794707</a>] [<a href="https://doi.org/10.1002/ajmg.a.10207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12794707">Wright et al. (2003)</a> screened for this mutation in African Americans and found a carrier frequency of 0.73% (10 of 1378), which predicted a homozygosity incidence of 1 of 75,061. They suggested that it is likely that the IVS8-1G-C allele appeared in the African American population through admixture. <a href="#29" class="mim-tip-reference" title="Witsch-Baumgartner, M., Ciara, E., Loffler, J., Menzel, H. J., Seedorf, U., Burn, J., Gillessen-Kaesbach, G., Hoffmann, G. F., Fitzky, B. U., Mundy, H., Clayton, P., Kelley, R. I., Krajewska-Walasek, M., Utermann, G. <strong>Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations.</strong> Europ. J. Hum. Genet. 9: 45-50, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175299</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175299">Witsch-Baumgartner et al. (2001)</a> suggested that this mutation is a founder mutation that arose in the British Isles. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11175299+12794707" 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="#24" class="mim-tip-reference" title="Scalco, F. B., Correa-Cerro, L. S., Wassif, C. A., Porter, F. D., Moretti-Ferreira, D. <strong>DHCR7 mutations in Brazilian Smith-Lemli-Opitz syndrome patients. (Letter)</strong> Am. J. Med. Genet. 136A: 278-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15952211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15952211</a>] [<a href="https://doi.org/10.1002/ajmg.a.30810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15952211">Scalco et al. (2005)</a> detected the IVS8-1G-C mutation on 10 of 28 alleles (36%) in a study of 14 SLOS patients from Brazil. In 7 patients, the IVS8-1G-C mutation was found in compound heterozygosity with the T93M mutation (<a href="/entry/602848#0009">602848.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15952211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By haplotype analysis of European alleles and comparison with the chimpanzee Dhcr7 ortholog, <a href="#31" class="mim-tip-reference" title="Witsch-Baumgartner, M., Schwentner, I., Gruber, M., Benlian, P., Bertranpetit, J., Bieth, E., Chevy, F., Clusellas, N., Estivill, X., Gasparini, G., Giros, M., Kelley, R. I., and 17 others. <strong>Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations.</strong> J. Med. Genet. 45: 200-209, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17965227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17965227</a>] [<a href="https://doi.org/10.1136/jmg.2007.053520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17965227">Witsch-Baumgartner et al. (2008)</a> estimated that the IVS8-1G-C mutation, which they called 964-1G-C, appeared about 3,000 years ago in northwest Europe. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17965227" 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="#26" class="mim-tip-reference" title="Wassif, C. A., Maslen, C., Kachilele-Linjewile, S., Lin, D., Linck, L. M., Connor, W. E., Steiner, R. D., Porter, F. D. <strong>Mutations in the human sterol delta-7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome.</strong> Am. J. Hum. Genet. 63: 55-62, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634533</a>] [<a href="https://doi.org/10.1086/301936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634533">Wassif et al. (1998)</a> found that a cell line (B3SLO) from a patient with severe Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>) was compound heterozygous for a 96-bp deletion and for insertion of a single cytosine between nucleotides 505 and 506 (<a href="#0003">602858.0003</a>). The deletion extended from nucleotide -77 to nucleotide 19. It potentially removed the start codon. Neither of the 2 ATGs present in the undeleted 5-prime region were in-frame, and the next in-frame ATG encoded amino acid 138. The 1-bp insertion resulted in both a frameshift starting at amino acid 170 and addition of 39 aberrant amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9634533" 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>For discussion of the 1-bp insertion in the DHCR7 gene (505_506insC) that was found in compound heterozygous state in a patient with severe Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>) by <a href="#26" class="mim-tip-reference" title="Wassif, C. A., Maslen, C., Kachilele-Linjewile, S., Lin, D., Linck, L. M., Connor, W. E., Steiner, R. D., Porter, F. D. <strong>Mutations in the human sterol delta-7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome.</strong> Am. J. Hum. Genet. 63: 55-62, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634533</a>] [<a href="https://doi.org/10.1086/301936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634533">Wassif et al. (1998)</a>, see <a href="#0002">602858.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9634533" 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=RCV000007181" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007181" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007181</a>
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<p>In cell line C4SLO from a patient with severe Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>), <a href="#26" class="mim-tip-reference" title="Wassif, C. A., Maslen, C., Kachilele-Linjewile, S., Lin, D., Linck, L. M., Connor, W. E., Steiner, R. D., Porter, F. D. <strong>Mutations in the human sterol delta-7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome.</strong> Am. J. Hum. Genet. 63: 55-62, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634533</a>] [<a href="https://doi.org/10.1086/301936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634533">Wassif et al. (1998)</a> identified insertion of a single thymidine between nucleotides 586 and 587 (586_587insT). The result of this insertion was both a frameshift starting at amino acid 197 and the addition of 12 aberrant amino acids. The mutation precluded normal translation of the highly conserved C-terminal half of the protein. The second mutation in the C4SLO cell line was not identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9634533" 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>.0005 SMITH-LEMLI-OPITZ SYNDROME</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> rs28938174 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28938174;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/rs28938174?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=rs28938174" 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=rs28938174" 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=RCV000007182 OR RCV000274996 OR RCV004585991" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007182, RCV000274996, RCV004585991" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007182...</a>
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<p>In a boy born to unrelated parents with features of Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>), <a href="#28" class="mim-tip-reference" title="Waterham, H. R., Wijburg, F. A., Hennekam, R. C. M., Vreken, P., Poll-The, B. T., Dorland, L., Duran, M., Jira, P. E., Smeitink, J. A. M., Wevers, R. A., Wanders, R. J. A. <strong>Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene.</strong> Am. J. Hum. Genet. 63: 329-338, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683613</a>] [<a href="https://doi.org/10.1086/301982" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683613">Waterham et al. (1998)</a> found compound heterozygosity for his119-to-leu and gly244-to-arg (<a href="#0006">602858.0006</a>) mutations in the delta-7-dehydrocholesterol reductase gene. The boy was hypotonic at birth and showed microcephaly, micrognathia, craniofacial abnormalities, postaxial polydactyly of both hands, bilateral syndactyly of the second and third toes, and ambiguous genitalia that appeared to be severe hypospadias with micropenis. At 1 year of age he showed severe developmental delay. The first of the amino acid substitutions in this patient was due to a 356A-T transversion inherited from the mother; the second was due to a 730G-A transition inherited from the father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9683613" 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 SMITH-LEMLI-OPITZ SYNDROME</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> rs121909764 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909764;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/rs121909764?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=rs121909764" 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=rs121909764" 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=RCV000007183 OR RCV001804715 OR RCV004748505" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007183, RCV001804715, RCV004748505" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007183...</a>
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<p>For discussion of the gly244-to-arg (G244R) mutation in the DHCR7 gene that was found in compound heterozygous state in a patient with Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>) by <a href="#28" class="mim-tip-reference" title="Waterham, H. R., Wijburg, F. A., Hennekam, R. C. M., Vreken, P., Poll-The, B. T., Dorland, L., Duran, M., Jira, P. E., Smeitink, J. A. M., Wevers, R. A., Wanders, R. J. A. <strong>Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene.</strong> Am. J. Hum. Genet. 63: 329-338, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683613</a>] [<a href="https://doi.org/10.1086/301982" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683613">Waterham et al. (1998)</a>, see <a href="#0005">602858.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9683613" 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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<span class="mim-font">
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<strong>.0007 MOVED TO <a href="/entry/602858#0001">602858.0001</a></strong>
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<strong>.0008 SMITH-LEMLI-OPITZ SYNDROME</strong>
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DHCR7, TRP248CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894212 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894212;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=rs104894212" 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=rs104894212" 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=RCV000007184" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007184" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007184</a>
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<p>In an infant with Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>), <a href="#28" class="mim-tip-reference" title="Waterham, H. R., Wijburg, F. A., Hennekam, R. C. M., Vreken, P., Poll-The, B. T., Dorland, L., Duran, M., Jira, P. E., Smeitink, J. A. M., Wevers, R. A., Wanders, R. J. A. <strong>Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene.</strong> Am. J. Hum. Genet. 63: 329-338, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683613</a>] [<a href="https://doi.org/10.1086/301982" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9683613">Waterham et al. (1998)</a> found compound heterozygosity for a 134-bp insertion (<a href="#0001">602858.0001</a>) and a 744G-T transversion that resulted in a trp248-to-cys substitution in the DHCR7 gene. (<a href="#34" class="mim-tip-reference" title="Yu, H., Tint, G. S., Salen, G., Patel, S. B. <strong>Detection of a common mutation in the RSH or Smith-Lemli-Opitz syndrome by a PCR-RFLP assay: IVS8-1G-C is found in over sixty percent of US propositi.</strong> Am. J. Med. Genet. 90: 347-350, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10710236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10710236</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(20000214)90:4<347::aid-ajmg16>3.0.co;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10710236">Yu et al. (2000)</a> noted that the IVS8-1G-C mutation (<a href="#0001">602858.0001</a>) resulted in abnormal splicing of the last exon, exon 9, with a 134-bp insertion of intron 8 sequences and a resultant frameshift with a premature translational stop.) The boy was born at term after a pregnancy complicated by intrauterine growth retardation. At birth, the boy was microcephalic and showed multiple dysmorphic features, including a broad nasal tip with anteverted nostrils, a cleft soft palate, broad alveolar ridges, micrognathia, syndactyly of the second and third toes, and a small penis with cryptorchidism. At 3 years of age, the boy had psychomotor retardation, severe failure to thrive, and feeding difficulties that still necessitated tube feeding. SLO syndrome was biochemically diagnosed on the basis of low plasma cholesterol and high 7-dehydrocholesterol concentrations, and was confirmed by the finding of greatly reduced 7-DHCR activity in cultured skin fibroblasts, as determined by 14-C-mevalonate incorporation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9683613+10710236" 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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<span class="mim-font">
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<strong>.0009 SMITH-LEMLI-OPITZ SYNDROME</strong>
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DHCR7, THR93MET
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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> rs80338853 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338853;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/rs80338853?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=rs80338853" 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=rs80338853" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000007185 OR RCV000079651 OR RCV000454251 OR RCV003985253" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007185, RCV000079651, RCV000454251, RCV003985253" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007185...</a>
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<p>In a patient with Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>), <a href="#3" class="mim-tip-reference" title="Fitzky, B. U., Witsch-Baumgartner, M., Erdel, M., Lee, J. N., Paik, Y.-K., Glossmann, H., Utermann, G., Moebius, F. F. <strong>Mutations in the delta-7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome.</strong> Proc. Nat. Acad. Sci. 95: 8181-8186, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9653161[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.14.8181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9653161">Fitzky et al. (1998)</a> identified a heterozygous C-to-T transition at nucleotide 278 of the DHCR7 gene, resulting in a thr93-to-met substitution (T93M). <a href="#2" class="mim-tip-reference" title="De Brasi, D., Esposito, T., Rossi, M., Parenti, G., Sperandeo, M. P., Zuppaldi, A., Bardaro, T., Ambruzzi, M. A., Zelante, L., Ciccodicola, A., Sebastio, G., D'Urso, M., Andria, G. <strong>Smith-Lemli-Opitz syndrome: evidence of T93M as a common mutation of delta-7-sterol reductase in Italy and report of three novel mutations.</strong> Europ. J. Hum. Genet. 7: 937-940, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10602371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10602371</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10602371">De Brasi et al. (1999)</a> found that T93M was the most frequent mutation in 9 Italian patients with SLOS, occurring in 7 of 18 alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10602371+9653161" 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="#29" class="mim-tip-reference" title="Witsch-Baumgartner, M., Ciara, E., Loffler, J., Menzel, H. J., Seedorf, U., Burn, J., Gillessen-Kaesbach, G., Hoffmann, G. F., Fitzky, B. U., Mundy, H., Clayton, P., Kelley, R. I., Krajewska-Walasek, M., Utermann, G. <strong>Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations.</strong> Europ. J. Hum. Genet. 9: 45-50, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175299</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175299">Witsch-Baumgartner et al. (2001)</a> detected the T93M mutation on 3 of 44 alleles (6.8%) in a study of 22 SLOS patients from Great Britain. The mutation was not detected in 22 SLOS patients from Germany/Austria or 15 patients from Poland. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175299" 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="#24" class="mim-tip-reference" title="Scalco, F. B., Correa-Cerro, L. S., Wassif, C. A., Porter, F. D., Moretti-Ferreira, D. <strong>DHCR7 mutations in Brazilian Smith-Lemli-Opitz syndrome patients. (Letter)</strong> Am. J. Med. Genet. 136A: 278-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15952211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15952211</a>] [<a href="https://doi.org/10.1002/ajmg.a.30810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15952211">Scalco et al. (2005)</a> detected the T93M mutation on 9 of 28 alleles (32%) in a study of 14 SLOS patients from Brazil. In 7 patients, the T93M mutation was found in compound heterozygosity with the IVS8-1G-C mutation (<a href="#0001">602858.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15952211" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By haplotype analysis of European alleles and comparison with the chimpanzee Dhcr7 ortholog, <a href="#31" class="mim-tip-reference" title="Witsch-Baumgartner, M., Schwentner, I., Gruber, M., Benlian, P., Bertranpetit, J., Bieth, E., Chevy, F., Clusellas, N., Estivill, X., Gasparini, G., Giros, M., Kelley, R. I., and 17 others. <strong>Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations.</strong> J. Med. Genet. 45: 200-209, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17965227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17965227</a>] [<a href="https://doi.org/10.1136/jmg.2007.053520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17965227">Witsch-Baumgartner et al. (2008)</a> estimated that the T93M mutation probably arose about 6,000 years ago in the eastern Mediterranean region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17965227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Kalb, S., Caglayan, A. O., Degerliyurt, A., Schmid, S., Ceylaner, S., Hatipoglu, N., Hinderhofer, K., Rehder, H., Kurtoglu, S., Ceylaner, G., Zschocke, J., Witsch-Baumgartner, M. <strong>High frequency of p.thr93met in Smith-Lemli-Opitz syndrome patients in Turkey. (Letter)</strong> Clin. Genet. 81: 598-601, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22211794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22211794</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2011.01750.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22211794">Kalb et al. (2012)</a> identified the T93M mutation in 9 (36%) of 26 mutant alleles from 13 Turkish patients with SLO syndrome. Three probands were homozygous for the mutation. No carriers of T93M were identified in 771 control individuals. The allele frequency was estimated to be no more than 1 in 420. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22211794" 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">rs104894213 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894213;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=rs104894213" 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=rs104894213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <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> rs11555217 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs11555217;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/rs11555217?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=rs11555217" 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=rs11555217" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 16 patients with severe Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>) (severity score greater than 50), <a href="#30" class="mim-tip-reference" title="Witsch-Baumgartner, M., Fitzky, B. U., Ogorelkova, M., Kraft, H. G., Moebius, F. F., Glossmann, H., Seedorf, U., Gillessen-Kaesbach, G., Hoffmann, G. F., Clayton, P., Kelley, R. I., Utermann, G. <strong>Mutational spectrum in the delta-7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome.</strong> Am. J. Hum. Genet. 66: 402-412, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677299[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10677299">Witsch-Baumgartner et al. (2000)</a> found that 5 of the 32 disease alleles carried a G-to-A transition at nucleotide 453 of the DHCR7 gene, resulting in a trp151-to-ter substitution (W151X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10677299" 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="#13" class="mim-tip-reference" title="Loffler, J., Trojovsky, A., Casati, B., Kroisel, P. M., Utermann, G. <strong>Homozygosity for the W151X stop mutation in the delta-7-sterol reductase gene (DHCR7) causing a lethal form of Smith-Lemli-Opitz syndrome: retrospective molecular diagnosis.</strong> Am. J. Med. Genet. 95: 174-177, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11078571/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11078571</a>] [<a href="https://doi.org/10.1002/1096-8628(20001113)95:2<174::aid-ajmg16>3.0.co;2-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11078571">Loffler et al. (2000)</a> reported 2 sibs with severe, lethal SLOS due to homozygosity for the null mutation W151X. One sib died at age 19 days, whereas the other was a pregnancy termination at 20 weeks' gestation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11078571" 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="#29" class="mim-tip-reference" title="Witsch-Baumgartner, M., Ciara, E., Loffler, J., Menzel, H. J., Seedorf, U., Burn, J., Gillessen-Kaesbach, G., Hoffmann, G. F., Fitzky, B. U., Mundy, H., Clayton, P., Kelley, R. I., Krajewska-Walasek, M., Utermann, G. <strong>Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations.</strong> Europ. J. Hum. Genet. 9: 45-50, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175299</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175299">Witsch-Baumgartner et al. (2001)</a> detected the W151X mutation on 19 of 118 alleles (16.1%) in a study of 59 SLOS patients from Great Britain, Germany, Poland, and Austria. An east-west gradient was detected (Poland, 33.3% of alleles; Germany/Austria, 18.2%; Great Britain, 2.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene showed that the W151X mutation occurred on 3 different haplotypes. As these haplotypes differed only at single nucleotide positions and therefore may be derived from the same ancestral haplotype, the authors could not distinguish between the possibility that this mutation is a recurrent mutation or is very old and has spread to different haplotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Ciara, E., Nowaczyk, M. J. M., Witsch-Baumgartner, M., Malunowicz, E., Popowska, E., Jezela-Stanek, A., Piotrowicz, M., Waye, J. S., Utermann, G., Krajewska-Walasek, M. <strong>DHCR7 mutations and genotype-phenotype correlation in 37 Polish patients with Smith-Lemli-Opitz syndrome.</strong> Clin. Genet. 66: 517-524, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15521979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15521979</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00350.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15521979">Ciara et al. (2004)</a> found the W151X mutation in 22 of 68 alleles (32%) in a study of 37 ethnic Polish patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15521979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By haplotype analysis of European alleles and comparison with the chimpanzee Dhcr7 ortholog, <a href="#31" class="mim-tip-reference" title="Witsch-Baumgartner, M., Schwentner, I., Gruber, M., Benlian, P., Bertranpetit, J., Bieth, E., Chevy, F., Clusellas, N., Estivill, X., Gasparini, G., Giros, M., Kelley, R. I., and 17 others. <strong>Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations.</strong> J. Med. Genet. 45: 200-209, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17965227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17965227</a>] [<a href="https://doi.org/10.1136/jmg.2007.053520" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17965227">Witsch-Baumgartner et al. (2008)</a> estimated that the W151X mutation appeared about 3,000 years ago in northeast Europe. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17965227" 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> rs80338859 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338859;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/rs80338859?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=rs80338859" 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=rs80338859" 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=RCV000007187 OR RCV001550331 OR RCV004748506" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007187, RCV001550331, RCV004748506" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007187...</a>
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<p>In 5 patients with Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>), <a href="#3" class="mim-tip-reference" title="Fitzky, B. U., Witsch-Baumgartner, M., Erdel, M., Lee, J. N., Paik, Y.-K., Glossmann, H., Utermann, G., Moebius, F. F. <strong>Mutations in the delta-7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome.</strong> Proc. Nat. Acad. Sci. 95: 8181-8186, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9653161[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.14.8181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9653161">Fitzky et al. (1998)</a> found a G-to-T transversion at nucleotide 976 of the DHCR7 gene, resulting in a val326-to-leu (V326L) amino acid substitution. In 3 of these patients the V326L mutation was found in compound heterozygous state, whereas in the other 2 patients the V326L mutation was found on 1 allele only. SSCP analysis failed to reveal a second mutation in these 2 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9653161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a screen of 32 patients with SLOS, <a href="#33" class="mim-tip-reference" title="Yu, H., Lee, M.-H., Starck, L., Elias, E. R., Irons, M., Salen, G., Patel, S. B., Tint, G. S. <strong>Spectrum of delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome.</strong> Hum. Molec. Genet. 9: 1385-1391, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1903 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814720</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814720">Yu et al. (2000)</a> found that the V326L mutation accounted for 5 of 64 alleles (7.8%), making it the third most common mutation observed in their cohort. The first and second most prevalent mutations were IVS8-1G-C (<a href="#0001">602858.0001</a>) and T93M (<a href="#0009">602858.0009</a>), respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10814720" 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="#29" class="mim-tip-reference" title="Witsch-Baumgartner, M., Ciara, E., Loffler, J., Menzel, H. J., Seedorf, U., Burn, J., Gillessen-Kaesbach, G., Hoffmann, G. F., Fitzky, B. U., Mundy, H., Clayton, P., Kelley, R. I., Krajewska-Walasek, M., Utermann, G. <strong>Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations.</strong> Europ. J. Hum. Genet. 9: 45-50, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175299</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175299">Witsch-Baumgartner et al. (2001)</a> detected the V326L mutation on 16 of 118 alleles (13.6%) in a study of 59 SLOS patients from Great Britain, Germany, Poland, and Austria. An east-west gradient was detected (Poland, 23.3% of alleles; Germany/Austria, 18.2%; Great Britain, 2.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene showed that 5 V326L chromosomes shared the same haplotype and therefore provided evidence for a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Ciara, E., Nowaczyk, M. J. M., Witsch-Baumgartner, M., Malunowicz, E., Popowska, E., Jezela-Stanek, A., Piotrowicz, M., Waye, J. S., Utermann, G., Krajewska-Walasek, M. <strong>DHCR7 mutations and genotype-phenotype correlation in 37 Polish patients with Smith-Lemli-Opitz syndrome.</strong> Clin. Genet. 66: 517-524, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15521979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15521979</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00350.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15521979">Ciara et al. (2004)</a> found the V326L mutation in 19 of 68 alleles (28%) in a study of 37 ethnic Polish patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15521979" 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>.0012 SMITH-LEMLI-OPITZ SYNDROME</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> rs750345068 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs750345068;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/rs750345068?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=rs750345068" 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=rs750345068" 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=RCV000169596" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000169596" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000169596</a>
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<p>Among 32 patients with Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>), <a href="#33" class="mim-tip-reference" title="Yu, H., Lee, M.-H., Starck, L., Elias, E. R., Irons, M., Salen, G., Patel, S. B., Tint, G. S. <strong>Spectrum of delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome.</strong> Hum. Molec. Genet. 9: 1385-1391, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1903 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814720</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814720">Yu et al. (2000)</a> found 1 patient with a G-to-A transition in exon 4 in one allele of the DHCR7 gene, resulting in a trp37-to-ter substitution (W37X). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10814720" 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>.0013 SMITH-LEMLI-OPITZ SYNDROME</strong>
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DHCR7, ARG352TRP
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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> rs80338860 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338860;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/rs80338860?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=rs80338860" 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=rs80338860" 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=RCV000007189 OR RCV000259783 OR RCV001252750 OR RCV003934805" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007189, RCV000259783, RCV001252750, RCV003934805" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007189...</a>
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<p><a href="#29" class="mim-tip-reference" title="Witsch-Baumgartner, M., Ciara, E., Loffler, J., Menzel, H. J., Seedorf, U., Burn, J., Gillessen-Kaesbach, G., Hoffmann, G. F., Fitzky, B. U., Mundy, H., Clayton, P., Kelley, R. I., Krajewska-Walasek, M., Utermann, G. <strong>Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations.</strong> Europ. J. Hum. Genet. 9: 45-50, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175299</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175299">Witsch-Baumgartner et al. (2001)</a> detected an R352W mutation on 7 (5.9%) of 118 alleles in a study of 59 patients with Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>) from Great Britain, Germany, Poland, and Austria. An east-west gradient was detected for this mutation (Poland, 13.3% of alleles; Germany/Austria, 6.8%; Great Britain, none). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175299" 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>.0014 SMITH-LEMLI-OPITZ SYNDROME</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> rs61757582 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61757582;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/rs61757582?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=rs61757582" 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=rs61757582" 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=RCV000007190 OR RCV000723830 OR RCV001266513 OR RCV003407290" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007190, RCV000723830, RCV001266513, RCV003407290" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007190...</a>
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<p><a href="#29" class="mim-tip-reference" title="Witsch-Baumgartner, M., Ciara, E., Loffler, J., Menzel, H. J., Seedorf, U., Burn, J., Gillessen-Kaesbach, G., Hoffmann, G. F., Fitzky, B. U., Mundy, H., Clayton, P., Kelley, R. I., Krajewska-Walasek, M., Utermann, G. <strong>Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations.</strong> Europ. J. Hum. Genet. 9: 45-50, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175299</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11175299">Witsch-Baumgartner et al. (2001)</a> detected an R404C mutation on 5 (4.2%) of 118 alleles of the DHCR7 gene in a study of 59 patients with Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>) from Great Britain, Germany, Poland, and Austria. A west-east gradient was detected for this mutation (Great Britain, 9.1% of alleles; Germany/Austria, 2.3%; Poland, none). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175299" 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>.0015 SMITH-LEMLI-OPITZ SYNDROME</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> rs121909765 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909765;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/rs121909765?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=rs121909765" 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=rs121909765" 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=RCV000007191 OR RCV000412788 OR RCV002371766" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007191, RCV000412788, RCV002371766" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007191...</a>
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<p>In 2 brothers with Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>) described by <a href="#20" class="mim-tip-reference" title="Nowaczyk, M. J. M., Whelan, D. T., Hill, R. E. <strong>Smith-Lemli-Opitz syndrome: phenotypic extreme with minimal clinical findings.</strong> Am. J. Med. Genet. 78: 419-423, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9714007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9714007</a>] [<a href="https://doi.org/10.1002/(sici)1096-8628(19980806)78:5<419::aid-ajmg5>3.0.co;2-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9714007">Nowaczyk et al. (1998)</a>, <a href="#10" class="mim-tip-reference" title="Krakowiak, P. A., Nwokoro, N. A., Wassif, C. A., Battaile, K. P., Nowaczyk, M. J. M., Connor, W. E., Maslen, C., Steiner, R. D., Porter, F. D. <strong>Mutation analysis and description of sixteen RSH/Smith-Lemli-Opitz syndrome patients: polymerase chain reaction-based assays to simplify genotyping.</strong> Am. J. Med. Genet. 94: 214-227, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10995508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10995508</a>]" pmid="10995508">Krakowiak et al. (2000)</a> detected a C-to-T transition at nucleotide position 866 of the DHCR7 gene, resulting in a change from threonine to isoleucine at codon 289 (T289I). The T289I mutation occurs between the sixth and seventh transmembrane domain of the DHCR7 protein. This mutation was found in compound heterozygosity with the IVS8-1G-C mutation (<a href="#0001">602858.0001</a>). <a href="#18" class="mim-tip-reference" title="Nowaczyk, M. J. M., Heshka, T., Eng, B., Feigenbaum, A. J., Waye, J. S. <strong>DHCR7 genotypes of cousins with Smith-Lemli-Opitz syndrome.</strong> Am. J. Med. Genet. 100: 162-163, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11298379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11298379</a>] [<a href="https://doi.org/10.1002/ajmg.1227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11298379">Nowaczyk et al. (2001)</a> extended study of these patients to their parents and female first cousin. The brothers' father carried the T289I missense mutation. The cousin, like the brothers, carried the IVS8-1G-C/T289I genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10995508+9714007+11298379" 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">rs121909766 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909766;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=rs121909766" 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=rs121909766" 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=RCV000007192 OR RCV003407291" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007192, RCV003407291" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007192...</a>
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<p>In a patient with Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>), <a href="#23" class="mim-tip-reference" title="Prasad, C., Marles, S., Prasad, A. N., Nikkel, S., Longstaffe, S., Peabody, D., Eng, B., Wright, S., Waye, J. S., Nowaczyk, M. J. M. <strong>Smith-Lemli-Opitz syndrome: new mutation with a mild phenotype.</strong> Am. J. Med. Genet. 108: 64-68, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11857552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11857552</a>] [<a href="https://doi.org/10.1002/ajmg.10211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11857552">Prasad et al. (2002)</a> found compound heterozygosity for the common IVS8-1G-C (<a href="#0001">602858.0001</a>) mutation and a tyr280-to-cys (Y280C) mutation in DHCR7. The exceptionally mildly affected female infant presented initially with feeding difficulties, failure to thrive, hypotonia, mild developmental delay, and oral tactile aversion. She had minor facial anomalies and 2-3 syndactyly of the toes in both feet. Plasma cholesterol was borderline low at 2.88 mmol/L. Elevated plasma 7-dehydrocholesterol level of 200.0 micromol/L confirmed the clinical diagnosis of SLOS. Since the common mutation in this patient was a known null mutation, the Y280C mutation was presumably associated with significant residual enzyme activity leading to milder expression of the clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11857552" 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> rs121909767 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909767;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/rs121909767?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=rs121909767" 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=rs121909767" 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=RCV000169218 OR RCV001528227" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000169218, RCV001528227" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000169218...</a>
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<p><a href="#11" class="mim-tip-reference" title="Langius, F. A. A., Waterham, H. R., Romeijn, G. J., Oostheim, W., de Barse, M. M. J., Dorland, L., Duran, M., Beemer, F. A., Wanders, R. J. A., Poll-The, B. T. <strong>Identification of 3 patients with a very mild form of Smith-Lemli-Opitz syndrome.</strong> Am. J. Med. Genet. 122A: 24-29, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12949967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12949967</a>] [<a href="https://doi.org/10.1002/ajmg.a.20207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12949967">Langius et al. (2003)</a> found compound heterozygosity for the common IVS8-1G-C null mutation (<a href="#0001">602858.0001</a>) and a novel mutation affecting translation initiation of met1 to leu (M1L) in the DHCR7 gene in 2 brothers with a very mild form of Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>). The 15-year-old brother was described as having a relatively high forehead and broad nasal bridge as well as a relatively small chin. He showed second and third toe syndactyly and hypospadias. The 10-year-old younger brother likewise had syndactyly of the second and third toes as well as clinodactyly of the left second finger. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12949967" 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> rs80338864 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338864;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/rs80338864?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=rs80338864" 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=rs80338864" 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=RCV000020435 OR RCV000790762" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020435, RCV000790762" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020435...</a>
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<p><a href="#11" class="mim-tip-reference" title="Langius, F. A. A., Waterham, H. R., Romeijn, G. J., Oostheim, W., de Barse, M. M. J., Dorland, L., Duran, M., Beemer, F. A., Wanders, R. J. A., Poll-The, B. T. <strong>Identification of 3 patients with a very mild form of Smith-Lemli-Opitz syndrome.</strong> Am. J. Med. Genet. 122A: 24-29, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12949967/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12949967</a>] [<a href="https://doi.org/10.1002/ajmg.a.20207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12949967">Langius et al. (2003)</a> described a 12-year-old girl with a very mild form of Smith-Lemli-Opitz (SLOS; <a href="/entry/270400">270400</a>) found to be caused by compound heterozygosity for the common IVS8-1G-C null mutation (<a href="#0001">602858.0001</a>) and a novel mutation, M1L (<a href="#0017">602858.0017</a>), in the DHCR7 gene. In addition, she was found to have a 1342G-A mutation, resulting in a glu448-to-lys (E448K) substitution. Head circumference was at the -3 standard deviations at birth and at the age of 12 she had bilateral second and third toe syndactyly and a high forehead. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12949967" 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>.0019 SMITH-LEMLI-OPITZ SYNDROME, MILD</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> rs184297154 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs184297154;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/rs184297154?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=rs184297154" 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=rs184297154" 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=RCV000815482 OR RCV002442731" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000815482, RCV002442731" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000815482...</a>
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<p>In a patient with very mild Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>), <a href="#33" class="mim-tip-reference" title="Yu, H., Lee, M.-H., Starck, L., Elias, E. R., Irons, M., Salen, G., Patel, S. B., Tint, G. S. <strong>Spectrum of delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome.</strong> Hum. Molec. Genet. 9: 1385-1391, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1903 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814720</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814720">Yu et al. (2000)</a> identified compound heterozygosity for 2 mutations in the DHCR7 gene: phe284 to leu (F284L), just outside the transmembrane domain on exon 8, and the more common val326 to leu (V326L; <a href="#0011">602858.0011</a>), in the transmembrane domain on exon 9. <a href="#16" class="mim-tip-reference" title="Mueller, C., Patel, S., Irons, M., Antshel, K., Salen, G., Tint, G. S., Bay, C. <strong>Normal cognition and behavior in a Smith-Lemli-Opitz syndrome patient who presented with Hirschsprung disease.</strong> Am. J. Med. Genet. 123A: 100-106, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14556255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14556255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14556255[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.20491" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14556255">Mueller et al. (2003)</a> described the clinical features of this patient. Developmentally, the child demonstrated mild delays in gross motor skills associated with mild hypotonia. Cognitive, language, and motor abilities were all within the low average range for her age, between the 14th and 18th centiles. She had not demonstrated temper tantrums, motor stereotypes, sleep disturbance, or hypersensitivity to light and sound as shown by many SLOS patients. The patient had presented at 12 days of age with poor feeding, abdominal distention, and jaundice. Colonic biopsy was consistent with Hirschsprung disease. Physical examination showed subtle 2,3 syndactyly. Her 7-dehydrocholesterol level was markedly elevated, and her cholesterol level was normal. Cholesterol supplementation implemented at 3 months of age resulted in increased cholesterol levels and reduced dehydrocholesterol levels. MRI of the brain showed no abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10814720+14556255" 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>.0020 SMITH-LEMLI-OPITZ SYNDROME, MILD</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> rs104886033 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104886033;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/rs104886033?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=rs104886033" 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=rs104886033" 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=RCV000169384 OR RCV000224026 OR RCV001267308 OR RCV003390651" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000169384, RCV000224026, RCV001267308, RCV003390651" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000169384...</a>
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<p>In a patient with a mild form of Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>), <a href="#24" class="mim-tip-reference" title="Scalco, F. B., Correa-Cerro, L. S., Wassif, C. A., Porter, F. D., Moretti-Ferreira, D. <strong>DHCR7 mutations in Brazilian Smith-Lemli-Opitz syndrome patients. (Letter)</strong> Am. J. Med. Genet. 136A: 278-281, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15952211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15952211</a>] [<a href="https://doi.org/10.1002/ajmg.a.30810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15952211">Scalco et al. (2005)</a> found a 1A-G transition, resulting in a met1-to-val (M1V) substitution of the initiator codon of the DHCR7 gene. The authors proposed that protein initiation at met59, which was demonstrated by <a href="#26" class="mim-tip-reference" title="Wassif, C. A., Maslen, C., Kachilele-Linjewile, S., Lin, D., Linck, L. M., Connor, W. E., Steiner, R. D., Porter, F. D. <strong>Mutations in the human sterol delta-7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome.</strong> Am. J. Hum. Genet. 63: 55-62, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634533</a>] [<a href="https://doi.org/10.1086/301936" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9634533">Wassif et al. (1998)</a> to result in a functional DHCR7 protein, could account for the mild phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15952211+9634533" 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>.0021 SMITH-LEMLI-OPITZ SYNDROME</strong>
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DHCR7, ARG352GLN
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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> rs121909768 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121909768;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/rs121909768?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=rs121909768" 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=rs121909768" 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=RCV000007197 OR RCV000254828" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007197, RCV000254828" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007197...</a>
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<p>In 7 unrelated Japanese patients with Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>), <a href="#14" class="mim-tip-reference" title="Matsumoto, Y., Morishima, K., Honda, A., Watabe, S., Yamamoto, M., Hara, M., Hasui, M., Saito, C., Takayanagi, T., Yamanaka, T., Saito, N., Kudo, H., Okamoto, N., Tsukahara, M., Matsuura, S. <strong>R352Q mutation of the DHCR7 gene is common among Japanese Smith-Lemli-Opitz syndrome patients.</strong> J. Hum. Genet. 50: 353-356, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16044199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16044199</a>] [<a href="https://doi.org/10.1007/s10038-005-0267-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16044199">Matsumoto et al. (2005)</a> identified a 1055G-A transition in exon 9 of the DHCR7 gene, resulting in an arg352-to-gln (R352Q) substitution within the eighth transmembrane domain, which is a highly conserved sterol-sensing region. Two patients were homozygous for the R352Q mutation, and it occurred in 9 of 14 mutant alleles. Haplotype analysis indicated a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16044199" 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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<span class="mim-font">
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<strong>.0022 SMITH-LEMLI-OPITZ SYNDROME</strong>
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DHCR7, IVS5DS, A-T, +3
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs786200926 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786200926;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=rs786200926" 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=rs786200926" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000023212" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023212" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023212</a>
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<p>In a girl with Smith-Lemli-Opitz syndrome (SLOS; <a href="/entry/270400">270400</a>), <a href="#8" class="mim-tip-reference" title="Koo, G., Conley, S. K., Wassif, C. A., Porter, F. D. <strong>Discordant phenotype and sterol biochemistry in Smith-Lemli-Opitz syndrome.</strong> Am. J. Med. Genet. 152A: 2094-2098, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20635399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20635399</a>] [<a href="https://doi.org/10.1002/ajmg.a.33540" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20635399">Koo et al. (2010)</a> identified compound heterozygosity for 2 mutations in the DHCR7 gene: the common IVS8-1G-C splice site mutation (<a href="#0001">602858.0001</a>) and an A-to-T transversion in intron 5 (IVS5+3A-T), resulting in the skipping of exon 5, a frameshift, and premature termination. RT-PCR studies of patient fibroblasts showed 3 bands, including a wildtype band, indicating that some residual wildtype protein was produced from the IVS5+3A-T mutation. However, patient fibroblasts showed a defect in sterol synthesis in cholesterol-deficient medium. The patient had a severe form of the disorder at birth, with multiple congenital anomalies affecting many organ systems, but after birth she showed less neurologic impairment than expected. She rolled from side to side at age 7 months, could stand with assistance at 11 months, and gained some fine motor control. Serum 7-dehydrocholesterol was increased at age 4 months but later fell to normal range, and serum cholesterol was normal. Compared to patients with a more severe phenotype and with a less severe phenotype, <a href="#8" class="mim-tip-reference" title="Koo, G., Conley, S. K., Wassif, C. A., Porter, F. D. <strong>Discordant phenotype and sterol biochemistry in Smith-Lemli-Opitz syndrome.</strong> Am. J. Med. Genet. 152A: 2094-2098, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20635399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20635399</a>] [<a href="https://doi.org/10.1002/ajmg.a.33540" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20635399">Koo et al. (2010)</a> observed a discordance in this patient: she was more severely affected, but had a lower 7-dehydrocholesterol/cholesterol ratio, which was usually observed in less severely affected individuals. <a href="#8" class="mim-tip-reference" title="Koo, G., Conley, S. K., Wassif, C. A., Porter, F. D. <strong>Discordant phenotype and sterol biochemistry in Smith-Lemli-Opitz syndrome.</strong> Am. J. Med. Genet. 152A: 2094-2098, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20635399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20635399</a>] [<a href="https://doi.org/10.1002/ajmg.a.33540" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20635399">Koo et al. (2010)</a> noted that there is a high need for cholesterol during embryonic development, which may have explained why this child was born with so many abnormalities. After birth, the residual enzyme activity conferred by the IVS5+3A-T mutation and the addition of dietary cholesterol may have been sufficient to allow some developmental acquisition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20635399" 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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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>REFERENCES</strong>
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<a id="Ciara2004" class="mim-anchor"></a>
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Ciara, E., Nowaczyk, M. J. M., Witsch-Baumgartner, M., Malunowicz, E., Popowska, E., Jezela-Stanek, A., Piotrowicz, M., Waye, J. S., Utermann, G., Krajewska-Walasek, M.
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<strong>DHCR7 mutations and genotype-phenotype correlation in 37 Polish patients with Smith-Lemli-Opitz syndrome.</strong>
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Clin. Genet. 66: 517-524, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15521979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15521979</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15521979" 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.1399-0004.2004.00350.x" target="_blank">Full Text</a>]
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<a id="De Brasi1999" class="mim-anchor"></a>
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De Brasi, D., Esposito, T., Rossi, M., Parenti, G., Sperandeo, M. P., Zuppaldi, A., Bardaro, T., Ambruzzi, M. A., Zelante, L., Ciccodicola, A., Sebastio, G., D'Urso, M., Andria, G.
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<strong>Smith-Lemli-Opitz syndrome: evidence of T93M as a common mutation of delta-7-sterol reductase in Italy and report of three novel mutations.</strong>
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Europ. J. Hum. Genet. 7: 937-940, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10602371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10602371</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10602371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200390" target="_blank">Full Text</a>]
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<a id="Fitzky1998" class="mim-anchor"></a>
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Fitzky, B. U., Witsch-Baumgartner, M., Erdel, M., Lee, J. N., Paik, Y.-K., Glossmann, H., Utermann, G., Moebius, F. F.
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<strong>Mutations in the delta-7-sterol reductase gene in patients with the Smith-Lemli-Opitz syndrome.</strong>
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Proc. Nat. Acad. Sci. 95: 8181-8186, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9653161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9653161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9653161[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9653161" 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/10.1073/pnas.95.14.8181" target="_blank">Full Text</a>]
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Freitas, F. P., Alborzinia, H., Dos Santos, A. F., Nepachalovich, P., Pedrera, L., Zilka, O., Inague, A., Klein, C., Aroua, N., Kaushal, K., Kast, B., Lorenz, S. M., and 35 others.
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<strong>7-Dehydrocholesterol is an endogenous suppressor of ferroptosis.</strong>
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Nature 626: 401-410, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38297129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38297129</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38297129" 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/s41586-023-06878-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2011.01750.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.33540" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20207" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11942534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11942534</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11942534" 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/10.1080/15227950252852078" target="_blank">Full Text</a>]
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<a id="22" class="mim-anchor"></a>
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<a id="Porter1996" class="mim-anchor"></a>
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Porter, J. A., Young, K. E., Beachy, P. A.
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<strong>Cholesterol modification of hedgehog signaling proteins in animal development.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8824192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8824192</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8824192" 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/10.1126/science.274.5285.255" target="_blank">Full Text</a>]
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<a id="Prasad2002" class="mim-anchor"></a>
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Prasad, C., Marles, S., Prasad, A. N., Nikkel, S., Longstaffe, S., Peabody, D., Eng, B., Wright, S., Waye, J. S., Nowaczyk, M. J. M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11857552/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11857552</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11857552" 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/10.1002/ajmg.10211" target="_blank">Full Text</a>]
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<a id="Scalco2005" class="mim-anchor"></a>
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<p class="mim-text-font">
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15952211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15952211</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15952211" 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/10.1002/ajmg.a.30810" target="_blank">Full Text</a>]
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<a id="Shefer1995" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7560069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7560069</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7560069" 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/10.1172/JCI118223" target="_blank">Full Text</a>]
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<a id="Wassif1998" class="mim-anchor"></a>
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Wassif, C. A., Maslen, C., Kachilele-Linjewile, S., Lin, D., Linck, L. M., Connor, W. E., Steiner, R. D., Porter, F. D.
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<strong>Mutations in the human sterol delta-7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome.</strong>
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Am. J. Hum. Genet. 63: 55-62, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9634533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9634533</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9634533" 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/10.1086/301936" target="_blank">Full Text</a>]
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Wassif, C. A., Zhu, P., Kratz, L., Krakowiak, P. A., Battaile, K. P., Weight, F. F., Grinberg, A., Steiner, R. D., Nwokoro, N. A., Kelley, R. I., Stewart, R. R., Porter, F. D.
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<strong>Biochemical, phenotypic and neurophysiological characterization of a genetic mouse model of RSH/Smith-Lemli-Opitz syndrome.</strong>
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Hum. Molec. Genet. 10: 555-564, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11230174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11230174</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11230174" 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/10.6.555" target="_blank">Full Text</a>]
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<a id="Waterham1998" class="mim-anchor"></a>
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Waterham, H. R., Wijburg, F. A., Hennekam, R. C. M., Vreken, P., Poll-The, B. T., Dorland, L., Duran, M., Jira, P. E., Smeitink, J. A. M., Wevers, R. A., Wanders, R. J. A.
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<strong>Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene.</strong>
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Am. J. Hum. Genet. 63: 329-338, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9683613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9683613</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9683613" 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/10.1086/301982" target="_blank">Full Text</a>]
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<a id="Witsch-Baumgartner2001" class="mim-anchor"></a>
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Witsch-Baumgartner, M., Ciara, E., Loffler, J., Menzel, H. J., Seedorf, U., Burn, J., Gillessen-Kaesbach, G., Hoffmann, G. F., Fitzky, B. U., Mundy, H., Clayton, P., Kelley, R. I., Krajewska-Walasek, M., Utermann, G.
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<strong>Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations.</strong>
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Europ. J. Hum. Genet. 9: 45-50, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11175299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11175299</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11175299" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200579" target="_blank">Full Text</a>]
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<a id="Witsch-Baumgartner2000" class="mim-anchor"></a>
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Witsch-Baumgartner, M., Fitzky, B. U., Ogorelkova, M., Kraft, H. G., Moebius, F. F., Glossmann, H., Seedorf, U., Gillessen-Kaesbach, G., Hoffmann, G. F., Clayton, P., Kelley, R. I., Utermann, G.
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<strong>Mutational spectrum in the delta-7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome.</strong>
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Am. J. Hum. Genet. 66: 402-412, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10677299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10677299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10677299[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10677299" 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/10.1086/302760" target="_blank">Full Text</a>]
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<a id="Witsch-Baumgartner2008" class="mim-anchor"></a>
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Witsch-Baumgartner, M., Schwentner, I., Gruber, M., Benlian, P., Bertranpetit, J., Bieth, E., Chevy, F., Clusellas, N., Estivill, X., Gasparini, G., Giros, M., Kelley, R. I., and 17 others.
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<strong>Age and origin of major Smith-Lemli-Opitz syndrome (SLOS) mutations in European populations.</strong>
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J. Med. Genet. 45: 200-209, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17965227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17965227</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17965227" 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.2007.053520" target="_blank">Full Text</a>]
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<a id="Wright2003" class="mim-anchor"></a>
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Wright, B. S., Nwokoro, N. A., Wassif, C. A., Porter, F. D., Waye, J. S., Eng, B., Nowaczyk, M. J. M.
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<strong>Carrier frequency of the RSH/Smith-Lemli-Opitz IVS8-1G-C mutation in African Americans. (Letter)</strong>
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Am. J. Med. Genet. 120A: 139-141, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12794707/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12794707</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12794707" 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/10.1002/ajmg.a.10207" target="_blank">Full Text</a>]
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<a id="Yu2000" class="mim-anchor"></a>
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Yu, H., Lee, M.-H., Starck, L., Elias, E. R., Irons, M., Salen, G., Patel, S. B., Tint, G. S.
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<strong>Spectrum of delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome.</strong>
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Hum. Molec. Genet. 9: 1385-1391, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1903 only, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814720/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814720</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10814720" 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/9.9.1385" target="_blank">Full Text</a>]
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<a id="Yu2000" class="mim-anchor"></a>
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Yu, H., Tint, G. S., Salen, G., Patel, S. B.
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<strong>Detection of a common mutation in the RSH or Smith-Lemli-Opitz syndrome by a PCR-RFLP assay: IVS8-1G-C is found in over sixty percent of US propositi.</strong>
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Am. J. Med. Genet. 90: 347-350, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10710236/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10710236</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10710236" 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/10.1002/(sici)1096-8628(20000214)90:4<347::aid-ajmg16>3.0.co;2-7" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<span class="mim-text-font">
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Bao Lige - updated : 03/04/2024
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 6/28/2012<br>Cassandra L. Kniffin - updated : 1/10/2011<br>Cassandra L. Kniffin - updated : 8/15/2008<br>Victor A. McKusick - updated : 6/18/2007<br>Paul J. Converse - updated : 1/29/2007<br>Cassandra L. Kniffin - updated : 11/8/2005<br>Victor A. McKusick - updated : 9/21/2005<br>Victor A. McKusick - updated : 3/31/2005<br>Victor A. McKusick - updated : 1/14/2004<br>Victor A. McKusick - updated : 9/30/2003<br>Victor A. McKusick - updated : 6/23/2003<br>Victor A. McKusick - updated : 2/8/2002<br>Victor A. McKusick - updated : 9/25/2001<br>George E. Tiller - updated : 5/29/2001<br>Anne M. Stumpf - updated : 5/10/2001<br>Michael B. Petersen - updated : 4/27/2001<br>Sonja A. Rasmussen - updated : 12/13/2000<br>Victor A. McKusick - updated : 10/4/2000<br>George E. Tiller - updated : 8/8/2000<br>Sonja A. Rasmussen - updated : 4/24/2000<br>Victor A. McKusick - updated : 3/31/2000<br>Matthew B. Gross - updated : 3/8/2000<br>Victor A. McKusick - updated : 2/9/2000<br>Victor A. McKusick - updated : 9/15/1998
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Creation Date:
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Victor A. McKusick : 7/16/1998
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mgross : 03/04/2024
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carol : 03/22/2023<br>alopez : 03/21/2023<br>carol : 10/12/2015<br>carol : 3/23/2015<br>mcolton : 3/20/2015<br>carol : 9/26/2013<br>alopez : 11/12/2012<br>terry : 10/2/2012<br>carol : 7/2/2012<br>ckniffin : 6/28/2012<br>wwang : 1/31/2011<br>ckniffin : 1/10/2011<br>terry : 1/20/2010<br>wwang : 4/16/2009<br>wwang : 8/19/2008<br>ckniffin : 8/15/2008<br>alopez : 6/19/2007<br>terry : 6/18/2007<br>carol : 6/11/2007<br>ckniffin : 6/8/2007<br>alopez : 1/29/2007<br>terry : 11/16/2006<br>wwang : 11/17/2005<br>ckniffin : 11/8/2005<br>wwang : 10/21/2005<br>wwang : 10/12/2005<br>terry : 9/21/2005<br>wwang : 3/31/2005<br>terry : 3/31/2005<br>carol : 2/3/2005<br>carol : 11/18/2004<br>tkritzer : 1/15/2004<br>terry : 1/14/2004<br>cwells : 9/30/2003<br>cwells : 7/1/2003<br>terry : 6/23/2003<br>carol : 9/10/2002<br>alopez : 2/19/2002<br>terry : 2/8/2002<br>carol : 10/30/2001<br>carol : 9/28/2001<br>terry : 9/25/2001<br>cwells : 6/4/2001<br>cwells : 5/29/2001<br>cwells : 5/24/2001<br>alopez : 5/10/2001<br>mcapotos : 5/2/2001<br>mcapotos : 4/27/2001<br>joanna : 4/20/2001<br>joanna : 4/18/2001<br>mcapotos : 12/13/2000<br>mcapotos : 12/13/2000<br>carol : 10/4/2000<br>terry : 10/4/2000<br>alopez : 8/8/2000<br>alopez : 8/8/2000<br>alopez : 8/8/2000<br>carol : 5/4/2000<br>mcapotos : 5/1/2000<br>terry : 4/24/2000<br>terry : 4/24/2000<br>terry : 4/21/2000<br>mgross : 4/10/2000<br>terry : 3/31/2000<br>carol : 3/8/2000<br>mgross : 3/8/2000<br>terry : 2/9/2000<br>carol : 10/7/1998<br>carol : 9/15/1998<br>terry : 8/5/1998<br>alopez : 7/17/1998
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<strong>*</strong> 602858
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7-DEHYDROCHOLESTEROL REDUCTASE; DHCR7
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STEROL DELTA-7-REDUCTASE
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<strong><em>HGNC Approved Gene Symbol: DHCR7</em></strong>
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<strong>SNOMEDCT:</strong> 43929004;
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<strong>ICD10CM:</strong> E78.72;
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Cytogenetic location: 11q13.4
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:71,427,287-71,449,043 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Phenotype
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Inheritance
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11q13.4
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Smith-Lemli-Opitz syndrome
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270400
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Autosomal recessive
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The DHCR7 gene encodes delta-7-sterol reductase (EC 1.3.1.21), the penultimate enzyme of mammalian sterol biosynthesis that converts 7-dehydrocholesterol (7-DHC) to cholesterol. This enzyme removes the C(7-8) double bond introduced by the sterol delta8-delta7 isomerases. In addition, its role in drug-induced malformations is known: inhibitors of the last step of cholesterol biosynthesis such as AY9944 and BM15766 severely impair brain development (Moebius et al., 1998). </p>
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<strong>Cloning and Expression</strong>
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<p>Wassif et al. (1998) cloned a cDNA encoding human sterol delta-7-reductase (DHCR7) on the basis of its homology with the sterol delta-7-reductase from Arabidopsis thaliana, and they confirmed the enzymatic function of the human gene product by expression in fibroblasts. </p><p>Waterham et al. (1998) identified a partial transcript coding for human 7-dehydrocholesterol reductase by searching the EST database with the amino acid sequence of an A. thaliana enzyme. They isolated the remaining 5-prime sequence by 5-prime RACE. By heterologous expression of the cDNA in Saccharomyces cerevisiae, they confirmed that it coded for 7-dehydrocholesterol reductase. </p><p>Moebius et al. (1998) cloned the DHCR7 gene. The deduced protein is membrane-bound with a predicted molecular mass of 55 kD and 6 to 9 putative transmembrane segments. The protein is structurally related to plant and yeast sterol reductases. In adults, the ubiquitously transcribed mRNA is most abundant in adrenal gland, liver, testis, and brain. Although important in vertebrates, the enzyme is absent from yeast. Microsomes from Saccharomyces cerevisiae strains heterologously expressing the human cDNA removed the C(7-8) double bond in 7-dehydrocholesterol. The conversion to cholesterol depends on NADPH and is potently inhibited by AY9944, BM15766, and triparanol. </p>
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<strong>Mapping</strong>
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<p>Using radiation hybrid mapping, Wassif et al. (1998) mapped the DHCR7 gene to chromosome 11q12-q13. By FISH, Waterham et al. (1998) assigned the DHCR7 gene to 11q13. </p><p>Fitzky et al. (1998) characterized the human and mouse DHCR7 genes and assigned them to syntenic regions on 11q13 and 7F5, respectively, by FISH. </p>
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<strong>Gene Function</strong>
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<p>Porter et al. (1996) demonstrated that cholesterol is the lipophilic moiety covalently attached to the N-terminal signaling domain of hedgehog proteins (SHH, 600725; IHH, 600726) during autoprocessing and that the C-terminal domain acts as an intramolecular cholesterol transferase. They postulated that some of the effects of perturbed cholesterol biosynthesis on animal development may be due to the fact that cholesterol is used to modify embryonic signaling proteins. They postulated that in SLO syndrome, where cholesterol biosynthesis is defective, there may be defective modification of the hedgehog proteins and perhaps other similarly processed proteins. Porter et al. (1996) postulated further that the spectrum of developmental malformations seen in SLO syndrome may be due to loss of hedgehog protein function. </p><p>Using knockout screens in mouse Pfa1 cells, Freitas et al. (2024) identified Dhcr7 as a proferroptotic gene. DHCR7 knockout in the human ferroptosis fibrosarcoma cell line HT1080 led to accumulation of 7-DHC and resistance to ferroptosis, whereas reexpression of DHCR7 abolished 7-DHC concentrations and resensitized cells to ferroptosis. The accumulated 7-DHC in response to DHCR7 knockout functioned as an antiferroptotic metabolite that blocked peroxidation of phospholipids, resulting in truncated phospholipids that prevented execution of ferroptosis to protect cells. In addition, 7-DHC accumulation increased cell fitness and appeared to have in impact on lymphoma growth in a mouse model. </p><p>By knockdown screens in HEK293T cells, Li et al. (2024) independently identified DHCR7 as a proferroptotic gene. DHCR7 knockout strongly suppressed ferroptosis, whereas reexpression of DHCR7 reversed ferroptosis resistance in DHCR7-knockout cells. Loss of DHCR7 resulted in accumulation of 7-DHC, which protected the cells from ferroptosis by inhibiting peroxidation of phospholipids. 7-DHC was also involved in regulation of tumor ferroptosis and protection of kidneys from ischemia-reperfusion injury in a mouse model. </p>
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<strong>Molecular Genetics</strong>
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<p>Children with the Smith-Lemli-Opitz syndrome (SLOS; 270400) have elevated serum 7-DHC levels and low serum cholesterol levels. In cholesterol biosynthesis, 7-DHC is converted to cholesterol by the enzyme sterol delta-7-reductase. Liver microsomes from an SLOS homozygote were shown by Shefer et al. (1995) to have reduced activity of this enzyme. </p><p>In 3 unrelated patients with SLOS, Wassif et al. (1998) identified 4 different mutations in the DHCR7 gene (602858.0001-602858.0004). Fitzky et al. (1998) identified mutations in the DHCR7 gene (see, e.g., 602858.0009 and 602858.0011) in patients with SLOS. Waterham et al. (1998) identified homozygous and compound heterozygous mutations in the DHCR7 gene, including the intron 8 splice-site mutation (602858.0001), in patients with SLOS. </p><p>De Brasi et al. (1999) stated that 19 mutations in the DHCR7 gene had been described; among these, mutations impairing the activity of the C terminus appeared to be the most severe. They performed mutation analysis of the DHCR7 gene in 9 Italian SLOS patients and identified 3 novel mutations. They found that the T93M mutation (602858.0009) was the most frequent (7 of 18 alleles) in their survey. </p><p>In 84 patients with clinically and biochemically characterized SLOS, Witsch-Baumgartner et al. (2000) identified 40 different mutations in the DHCR7 gene. All but 1 of their patients were white, the exception having mostly American Cherokee heritage. On the basis of mutation type and expression studies, the authors grouped the mutations into 4 classes: nonsense and splice site mutations resulting in putative null alleles, missense mutations in the transmembrane domains, mutations in the fourth cytoplasmic loop, and mutations in the C-terminal endoplasmic reticulum (ER) domain. All but 1 of the tested missense mutations reduced protein stability. The mildest clinical phenotypes were associated with transmembrane and C-terminal ER domain mutations, and the most severe types were associated with null alleles and mutations in the fourth cytoplasmic loop. Most homozygotes for null alleles had severe SLOS; 1 patient had a moderate phenotype. Homozygosity for null mutations in the DHCR7 gene appeared compatible with life, suggesting that cholesterol may be synthesized in the absence of this enzyme or that exogenous sources of cholesterol can be used. Given that only a few null mutations exist, the authors were surprised to find that 2 of them, IVS8-1G-C (602858.0001) and trp151 to ter (602858.0011), accounted for more than one-third of all mutant alleles. In a note added in proof, Witsch-Baumgartner et al. (2000) stated that 7 additional DHCR7 mutations had been detected in 12 patients with SLOS. </p><p>Yu et al. (2000) reported a simple PCR-based restriction endonuclease digestion assay for rapid detection of the IVS8-1G-C mutation. This mutation results in abnormal splicing of exon 9 with a 134-bp insertion of intron 8 sequences, a resultant frameshift, and a premature translation stop (602858.0001). The authors identified this mutation in 21 of 33 SLOS propositi (21 of 66 alleles). Since none of their patients was homozygous for this mutation, the authors hypothesized that homozygosity for the mutation may often be prenatally lethal. They also screened unrelated normal individuals for the prevalence of this mutation, including 90 American Caucasians, 120 Finnish Caucasians, 121 Sierra Leone Africans, 95 Han Chinese, and 103 Japanese. One IVS8-1G-C mutation was identified in the American Caucasian population; none was observed in the other populations. Yu et al. (2000) concluded that the IVS8-1G-C transversion is a very common mutation in SLOS patients from the U.S. </p><p>Yu et al. (2000) screened an additional 32 patients with SLOS, 28 from the U.S.A. and 4 from Sweden. Twenty missense mutations, 1 nonsense mutation (602858.0012), and 1 splice-site mutation involving the exon 9 acceptor site (IVS8-1G-C; 602858.0001) were detected. All probands were heterozygous for mutations. Three mutations accounted for 54% of those observed in their cohort, the splice acceptor site mutation IVS8-1G-C (22/64 alleles, 34%), T93M (602858.0009) (8/64, 12.5%), and V326L (602858.0011) (5/64, 7.8%). Severity of SLOS was negatively correlated with both plasma cholesterol and relative plasma cholesterol, but not with 7-dehydrocholesterol, the immediate precursor, confirming previous observations. However, no correlation was observed between mutations and phenotype, suggesting that the degree of severity may be affected by other factors. The authors estimated that 33 to 42% of the variation in the SLOS severity score is accounted for by variation in plasma cholesterol, suggesting that factors other than plasma cholesterol are additionally involved in determining severity. </p><p>Krakowiak et al. (2000) reported clinical and molecular data concerning 16 patients with SLOS of varying phenotypic severity. In each they identified mutations in both alleles. They found 6 previously undescribed mutations. They also reported rapid PCR-based assays developed to detect 4 of the recurring mutations and 6 others. </p><p>Witsch-Baumgartner et al. (2001) reported mutation analysis of the DHCR7 gene in 59 SLOS patients, 28 of whom had previously been reported (Witsch-Baumgartner et al., 2000). Fifteen patients were from Poland, 22 from Germany/Austria, and 22 from Great Britain. Mutations were detected on 114 of 118 SLOS chromosomes (96.6%). Altogether, 35 different mutations were identified, but in all 3 populations 3 mutations accounted for more than 50% of SLOS alleles. The mutation spectra were, however, significantly different across these populations. W151X (602858.0010) was the most frequent mutation in the Polish population (33.3%), had an intermediate frequency in German/Austrian patients (18.2%), and was rare in British patients (2.3%). The V326L mutation (602858.0011) showed the same east-west gradient. In contrast, IVS8-1G-C (602858.0001) was most frequent in Britain (34.1%), intermediate in Germany/Austria (20.5%), and rare in Poland (3.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene gave evidence for both recurrent mutations and founder effects; all IVS8-1G-C and V326L alleles shared the same haplotype, whereas the W151X allele occurred on different haplotypes. Witsch-Baumgartner et al. (2001) concluded that the distribution pattern of DHCR7 mutations in Europe may reflect ancient and modern migrations in Europe. </p><p>Among 37 ethnic Polish patients with SLOS, Ciara et al. (2004) found that 2 mutations, W151X (602858.0010), present in 22 of 68 alleles (32%), and V326L (602858.0011), present in 19 of 68 alleles (28%), accounted for 60% of all mutations observed in this group. </p><p>Scalco et al. (2005) reported on DHCR7 mutation analysis of 14 Brazilian SLOS patients. The most frequent mutations in this population were the IVS8-1G-C (602858.0001) and T93M (602858.0009) mutations. A mutation disrupting the normal initiation codon (M1V; 602858.0020) was identified in a mildly affected child. Langius et al. (2003) had reported a mutation in the initiator methionine (M1L; 602858.0017) in 3 patients who were also mildly affected. Wassif et al. (1998) had previously shown that initiation of translation at met59 gives rise to a functional protein. Both Langius et al. (2003) and Scalco et al. (2005) suspected that protein initiation at met59 allows for synthesis of a functional DHCR7 enzyme, accounting for the mild nature of the disorder in these mutations of the initiator methionine. </p><p>Nowaczyk et al. (2006) pointed out that the carrier rate for the most frequently occurring DHCR7 mutation causing SLOS, IVS8-1G-C (602858.0001), is approximately 1 in 100 for the Caucasian population of North America and possibly as high as 1 in 50 to 1 in 30 in central European populations. Based on the frequencies and the proportion of this mutation observed in various patient populations, the expected incidence of SLOS in those populations was calculated to be between 1 and 1,590 and 1 in 17,000. However, around the world the observed prevalence and incidence are much lower than those calculated from the individual mutation carrier rates observed in any given population. The discrepancy between the expected incidence and prevalence can be explained only in part by the neonatal and infancy deaths of the most severely affected children with SLOS and underascertainment of mild and atypical cases at the mild end of the spectrum. SLOS may be responsible for a high number of miscarriages. Estimates of the prevalence of SLOS at 16 weeks' gestation are similar to that observed at birth (approximately 1 in 60,000), suggesting that either reduced fertility of carrier couples or losses of affected embryos or fetuses in the first trimester play a significant role in reducing the second trimester prevalence of SLOS. One hypothesis postulated that null mutations of DHCR7 confer an advantage in increasing endogenous vitamin D synthesis (Kelley and Hennekam, 2000). Since osteomalacia was a common disease in Europe since antiquity, it is possible that individuals that were protected from this disease, especially in the northern parts of Europe, were at a survival advantage. Opitz et al. (2002) suggested that higher levels of 7-dehydrocholesterol in carrier females may have reduced the frequency of cephalopelvic disproportion in fetuses at risk for rickets secondary to maternal vitamin D deficiency and thus, provide a fertility advantage. Kelley and Herman (2001) discussed the biases that may be at play in estimating the carrier rates of DHCR7 mutations based on the mutation spectrum observed in the affected population and assuming that it is representative of the frequencies of various mutations in carriers. </p>
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<p>Wassif et al. (2001) developed a mouse model of RSH/SLOS by disruption of the 3-beta-hydroxysterol delta-7-reductase gene. As in human patients, the RSH/SLOS mouse has a marked reduction of serum and tissue cholesterol levels and a marked increase of serum and tissue 7-dehydrocholesterol levels. Phenotypic similarities between this mouse model and the human syndrome include intrauterine growth retardation, variable craniofacial anomalies including cleft palate, poor feeding with an uncoordinated suck, hypotonia, and decreased movement. Neurophysiologic studies showed that although the response of frontal cortex neurons to the neurotransmitter gamma-amino-n-butyric acid was normal, the response of these same neurons to glutamate was significantly impaired. </p><p>Cholesterol-enriched lipid rafts play an important role in mast cell activation. Kovarova et al. (2006) observed that mast cells derived from Dhcr7 -/- mice showed constitutive cytokine production and hyperdegranulation after stimulation of Fcer1 (see FCER1A, 147140). Dhcr7-deficient mast cells accumulated 7-DHC in lipid rafts, partially disrupting raft stability and displacing Lyn (165120) protein and activity. Downregulation of Lyn-dependent signaling events, such as phosphorylation of Csk-binding protein (PAG; 605767), was associated with increased Fyn (137025) kinase activity and Akt (164730) phosphorylation. Kovarova et al. (2006) proposed that lipid raft dysfunction in SLOS may explain the observation of allergy in these patients due to increased mast cell sensitivity. </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">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>22 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>
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<span class="mim-font">
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<strong>.0001 SMITH-LEMLI-OPITZ SYNDROME</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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DHCR7, IVS8AS, G-C, -1
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<br />
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SNP: rs80338863,
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ClinVar: RCV000007178
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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>A G-to-C transversion in intron 8 of the DHCR7 gene results in a splice site defect and a null mutation, and is the most common mutant allele in Smith-Lemli-Opitz syndrome (SLOS; 270400) (Wright et al., 2003). </p><p>In cell line A2SLO from a patient with severe SLOS, Wassif et al. (1998) identified a 134-bp insertion between nucleotides 788 and 789 of the DHCR7 gene. The insertion resulted in a frameshift, starting at amino acid 263, that precluded translation of the highly conserved carboxyl end of the protein. The cell line was homozygous for the insertion. </p><p>In a patient with severe SLOS, the first child of unrelated parents, Waterham et al. (1998) found homozygosity for a 134-bp insertion in the DHCR7 gene after nucleotide 963. Yu et al. (2000) noted that the IVS8-1G-C mutation results in abnormal splicing of the last exon, exon 9, with a 134-bp insertion of intron 8 sequences and a resultant frameshift with a premature translational stop. The more severe phenotype in this patient was consistent with the fact that the insertion occurred in a region strongly conserved among sterol reductases. Both parents were heterozygous for the insertion. Waterham et al. (1998) found the 134-bp insertion in compound heterozygous state in a child with SLOS, the other allele carrying the trp248-to-cys mutation (602858.0008) in the DHCR7 gene. </p><p>Among 16 patients with severe SLOS (severity score greater than 50), Witsch-Baumgartner et al. (2000) found that 14 of 32 mutant alleles carried an IVS8-1G-C mutation in the DHCR7 gene. </p><p>Yu et al. (2000) reported a simple PCR-based restriction endonuclease digestion assay for the rapid detection of this mutation, which they identified in 21 of 66 alleles. The authors concluded that the IVS8-1G-C transversion is a very common mutation in SLOS patients from the U.S. </p><p>Witsch-Baumgartner et al. (2001) detected the IVS8-1G-C mutation on 25 of 118 alleles (21.2%) in a study of 59 SLOS patients from Great Britain, Germany, Poland, and Austria. A west-east gradient was detected (Great Britain, 34.1% of alleles; Germany/Austria, 20.5%; Poland, 3.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene showed that 13 IVS8-1G-C chromosomes shared the same haplotype and therefore provided evidence for a founder effect. One IVS8-1G-C mutation was present in cis with a T93M mutation (602858.0009) on a different haplotype. As one of the other T93M alleles was also characterized by this haplotype, the double mutant was consistent with a recombination event. </p><p>Krakowiak et al. (2000) detected this mutation in compound heterozygosity with thr289 to ile (602858.0015) in 2 brothers with SLOS. Nowaczyk et al. (2001) found that the boys' female first cousin carried the IVS8-1G-C/T289I genotype as well. The 2 unrelated mothers were carriers of the IVS8-1G-C mutation. </p><p>Nowaczyk et al. (2001) found the IVS8-1G-C mutation in homozygous state in a fetus and 2 newborns with severe SLOS and holoprosencephaly. They stated that of the 6 previously reported severely affected newborns with SLOS who were homozygous for this mutation, none had HPE. </p><p>The IVS8-1G-C mutation is the most frequently identified mutant allele, accounting for approximately one-third of reported SLOS alleles. Wright et al. (2003) screened for this mutation in African Americans and found a carrier frequency of 0.73% (10 of 1378), which predicted a homozygosity incidence of 1 of 75,061. They suggested that it is likely that the IVS8-1G-C allele appeared in the African American population through admixture. Witsch-Baumgartner et al. (2001) suggested that this mutation is a founder mutation that arose in the British Isles. </p><p>Scalco et al. (2005) detected the IVS8-1G-C mutation on 10 of 28 alleles (36%) in a study of 14 SLOS patients from Brazil. In 7 patients, the IVS8-1G-C mutation was found in compound heterozygosity with the T93M mutation (602848.0009). </p><p>By haplotype analysis of European alleles and comparison with the chimpanzee Dhcr7 ortholog, Witsch-Baumgartner et al. (2008) estimated that the IVS8-1G-C mutation, which they called 964-1G-C, appeared about 3,000 years ago in northwest Europe. </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>.0002 SMITH-LEMLI-OPITZ SYNDROME</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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DHCR7, 96-BP DEL
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<br />
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ClinVar: RCV000007179
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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>Wassif et al. (1998) found that a cell line (B3SLO) from a patient with severe Smith-Lemli-Opitz syndrome (SLOS; 270400) was compound heterozygous for a 96-bp deletion and for insertion of a single cytosine between nucleotides 505 and 506 (602858.0003). The deletion extended from nucleotide -77 to nucleotide 19. It potentially removed the start codon. Neither of the 2 ATGs present in the undeleted 5-prime region were in-frame, and the next in-frame ATG encoded amino acid 138. The 1-bp insertion resulted in both a frameshift starting at amino acid 170 and addition of 39 aberrant amino acids. </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>.0003 SMITH-LEMLI-OPITZ SYNDROME</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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DHCR7, 1-BP INS, 505C
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<br />
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ClinVar: RCV000007180
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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 insertion in the DHCR7 gene (505_506insC) that was found in compound heterozygous state in a patient with severe Smith-Lemli-Opitz syndrome (SLOS; 270400) by Wassif et al. (1998), see 602858.0002. </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>.0004 SMITH-LEMLI-OPITZ SYNDROME</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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DHCR7, 1-BP INS, 586T
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<br />
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ClinVar: RCV000007181
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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>In cell line C4SLO from a patient with severe Smith-Lemli-Opitz syndrome (SLOS; 270400), Wassif et al. (1998) identified insertion of a single thymidine between nucleotides 586 and 587 (586_587insT). The result of this insertion was both a frameshift starting at amino acid 197 and the addition of 12 aberrant amino acids. The mutation precluded normal translation of the highly conserved C-terminal half of the protein. The second mutation in the C4SLO cell line was not identified. </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>.0005 SMITH-LEMLI-OPITZ SYNDROME</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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DHCR7, HIS119LEU
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<br />
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SNP: rs28938174,
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gnomAD: rs28938174,
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ClinVar: RCV000007182, RCV000274996, RCV004585991
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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>In a boy born to unrelated parents with features of Smith-Lemli-Opitz syndrome (SLOS; 270400), Waterham et al. (1998) found compound heterozygosity for his119-to-leu and gly244-to-arg (602858.0006) mutations in the delta-7-dehydrocholesterol reductase gene. The boy was hypotonic at birth and showed microcephaly, micrognathia, craniofacial abnormalities, postaxial polydactyly of both hands, bilateral syndactyly of the second and third toes, and ambiguous genitalia that appeared to be severe hypospadias with micropenis. At 1 year of age he showed severe developmental delay. The first of the amino acid substitutions in this patient was due to a 356A-T transversion inherited from the mother; the second was due to a 730G-A transition inherited from the father. </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 SMITH-LEMLI-OPITZ SYNDROME</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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DHCR7, GLY244ARG
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<br />
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SNP: rs121909764,
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gnomAD: rs121909764,
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ClinVar: RCV000007183, RCV001804715, RCV004748505
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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>For discussion of the gly244-to-arg (G244R) mutation in the DHCR7 gene that was found in compound heterozygous state in a patient with Smith-Lemli-Opitz syndrome (SLOS; 270400) by Waterham et al. (1998), see 602858.0005. </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-text-font">
|
|
<strong>.0007 MOVED TO 602858.0001</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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<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>
|
|
<span class="mim-font">
|
|
<strong>.0008 SMITH-LEMLI-OPITZ SYNDROME</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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|
DHCR7, TRP248CYS
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<br />
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|
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SNP: rs104894212,
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|
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ClinVar: RCV000007184
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an infant with Smith-Lemli-Opitz syndrome (SLOS; 270400), Waterham et al. (1998) found compound heterozygosity for a 134-bp insertion (602858.0001) and a 744G-T transversion that resulted in a trp248-to-cys substitution in the DHCR7 gene. (Yu et al. (2000) noted that the IVS8-1G-C mutation (602858.0001) resulted in abnormal splicing of the last exon, exon 9, with a 134-bp insertion of intron 8 sequences and a resultant frameshift with a premature translational stop.) The boy was born at term after a pregnancy complicated by intrauterine growth retardation. At birth, the boy was microcephalic and showed multiple dysmorphic features, including a broad nasal tip with anteverted nostrils, a cleft soft palate, broad alveolar ridges, micrognathia, syndactyly of the second and third toes, and a small penis with cryptorchidism. At 3 years of age, the boy had psychomotor retardation, severe failure to thrive, and feeding difficulties that still necessitated tube feeding. SLO syndrome was biochemically diagnosed on the basis of low plasma cholesterol and high 7-dehydrocholesterol concentrations, and was confirmed by the finding of greatly reduced 7-DHCR activity in cultured skin fibroblasts, as determined by 14-C-mevalonate incorporation. </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>
|
|
<span class="mim-font">
|
|
<strong>.0009 SMITH-LEMLI-OPITZ SYNDROME</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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DHCR7, THR93MET
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<br />
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SNP: rs80338853,
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gnomAD: rs80338853,
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ClinVar: RCV000007185, RCV000079651, RCV000454251, RCV003985253
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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>In a patient with Smith-Lemli-Opitz syndrome (SLOS; 270400), Fitzky et al. (1998) identified a heterozygous C-to-T transition at nucleotide 278 of the DHCR7 gene, resulting in a thr93-to-met substitution (T93M). De Brasi et al. (1999) found that T93M was the most frequent mutation in 9 Italian patients with SLOS, occurring in 7 of 18 alleles. </p><p>Witsch-Baumgartner et al. (2001) detected the T93M mutation on 3 of 44 alleles (6.8%) in a study of 22 SLOS patients from Great Britain. The mutation was not detected in 22 SLOS patients from Germany/Austria or 15 patients from Poland. </p><p>Scalco et al. (2005) detected the T93M mutation on 9 of 28 alleles (32%) in a study of 14 SLOS patients from Brazil. In 7 patients, the T93M mutation was found in compound heterozygosity with the IVS8-1G-C mutation (602858.0001). </p><p>By haplotype analysis of European alleles and comparison with the chimpanzee Dhcr7 ortholog, Witsch-Baumgartner et al. (2008) estimated that the T93M mutation probably arose about 6,000 years ago in the eastern Mediterranean region. </p><p>Kalb et al. (2012) identified the T93M mutation in 9 (36%) of 26 mutant alleles from 13 Turkish patients with SLO syndrome. Three probands were homozygous for the mutation. No carriers of T93M were identified in 771 control individuals. The allele frequency was estimated to be no more than 1 in 420. </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>
|
|
<span class="mim-font">
|
|
<strong>.0010 SMITH-LEMLI-OPITZ SYNDROME</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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DHCR7, TRP151TER
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<br />
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SNP: rs104894213, rs11555217,
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gnomAD: rs11555217,
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ClinVar: RCV000007186
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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>In 16 patients with severe Smith-Lemli-Opitz syndrome (SLOS; 270400) (severity score greater than 50), Witsch-Baumgartner et al. (2000) found that 5 of the 32 disease alleles carried a G-to-A transition at nucleotide 453 of the DHCR7 gene, resulting in a trp151-to-ter substitution (W151X). </p><p>Loffler et al. (2000) reported 2 sibs with severe, lethal SLOS due to homozygosity for the null mutation W151X. One sib died at age 19 days, whereas the other was a pregnancy termination at 20 weeks' gestation. </p><p>Witsch-Baumgartner et al. (2001) detected the W151X mutation on 19 of 118 alleles (16.1%) in a study of 59 SLOS patients from Great Britain, Germany, Poland, and Austria. An east-west gradient was detected (Poland, 33.3% of alleles; Germany/Austria, 18.2%; Great Britain, 2.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene showed that the W151X mutation occurred on 3 different haplotypes. As these haplotypes differed only at single nucleotide positions and therefore may be derived from the same ancestral haplotype, the authors could not distinguish between the possibility that this mutation is a recurrent mutation or is very old and has spread to different haplotypes. </p><p>Ciara et al. (2004) found the W151X mutation in 22 of 68 alleles (32%) in a study of 37 ethnic Polish patients. </p><p>By haplotype analysis of European alleles and comparison with the chimpanzee Dhcr7 ortholog, Witsch-Baumgartner et al. (2008) estimated that the W151X mutation appeared about 3,000 years ago in northeast Europe. </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>
|
|
<span class="mim-font">
|
|
<strong>.0011 SMITH-LEMLI-OPITZ SYNDROME</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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DHCR7, VAL326LEU
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<br />
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SNP: rs80338859,
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gnomAD: rs80338859,
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ClinVar: RCV000007187, RCV001550331, RCV004748506
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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 5 patients with Smith-Lemli-Opitz syndrome (SLOS; 270400), Fitzky et al. (1998) found a G-to-T transversion at nucleotide 976 of the DHCR7 gene, resulting in a val326-to-leu (V326L) amino acid substitution. In 3 of these patients the V326L mutation was found in compound heterozygous state, whereas in the other 2 patients the V326L mutation was found on 1 allele only. SSCP analysis failed to reveal a second mutation in these 2 patients. </p><p>In a screen of 32 patients with SLOS, Yu et al. (2000) found that the V326L mutation accounted for 5 of 64 alleles (7.8%), making it the third most common mutation observed in their cohort. The first and second most prevalent mutations were IVS8-1G-C (602858.0001) and T93M (602858.0009), respectively. </p><p>Witsch-Baumgartner et al. (2001) detected the V326L mutation on 16 of 118 alleles (13.6%) in a study of 59 SLOS patients from Great Britain, Germany, Poland, and Austria. An east-west gradient was detected (Poland, 23.3% of alleles; Germany/Austria, 18.2%; Great Britain, 2.3%). Haplotype analysis using 8 single-nucleotide polymorphisms in the coding sequence of the DHCR7 gene showed that 5 V326L chromosomes shared the same haplotype and therefore provided evidence for a founder effect. </p><p>Ciara et al. (2004) found the V326L mutation in 19 of 68 alleles (28%) in a study of 37 ethnic Polish patients. </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>.0012 SMITH-LEMLI-OPITZ SYNDROME</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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DHCR7, TRP37TER
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<br />
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SNP: rs750345068,
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gnomAD: rs750345068,
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ClinVar: RCV000169596
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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>Among 32 patients with Smith-Lemli-Opitz syndrome (SLOS; 270400), Yu et al. (2000) found 1 patient with a G-to-A transition in exon 4 in one allele of the DHCR7 gene, resulting in a trp37-to-ter substitution (W37X). </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>.0013 SMITH-LEMLI-OPITZ SYNDROME</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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DHCR7, ARG352TRP
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<br />
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SNP: rs80338860,
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gnomAD: rs80338860,
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ClinVar: RCV000007189, RCV000259783, RCV001252750, RCV003934805
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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>Witsch-Baumgartner et al. (2001) detected an R352W mutation on 7 (5.9%) of 118 alleles in a study of 59 patients with Smith-Lemli-Opitz syndrome (SLOS; 270400) from Great Britain, Germany, Poland, and Austria. An east-west gradient was detected for this mutation (Poland, 13.3% of alleles; Germany/Austria, 6.8%; Great Britain, none). </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>.0014 SMITH-LEMLI-OPITZ SYNDROME</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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DHCR7, ARG404CYS
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<br />
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SNP: rs61757582,
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gnomAD: rs61757582,
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ClinVar: RCV000007190, RCV000723830, RCV001266513, RCV003407290
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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>Witsch-Baumgartner et al. (2001) detected an R404C mutation on 5 (4.2%) of 118 alleles of the DHCR7 gene in a study of 59 patients with Smith-Lemli-Opitz syndrome (SLOS; 270400) from Great Britain, Germany, Poland, and Austria. A west-east gradient was detected for this mutation (Great Britain, 9.1% of alleles; Germany/Austria, 2.3%; Poland, none). </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>.0015 SMITH-LEMLI-OPITZ SYNDROME</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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DHCR7, THR289ILE
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<br />
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SNP: rs121909765,
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gnomAD: rs121909765,
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ClinVar: RCV000007191, RCV000412788, RCV002371766
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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 2 brothers with Smith-Lemli-Opitz syndrome (SLOS; 270400) described by Nowaczyk et al. (1998), Krakowiak et al. (2000) detected a C-to-T transition at nucleotide position 866 of the DHCR7 gene, resulting in a change from threonine to isoleucine at codon 289 (T289I). The T289I mutation occurs between the sixth and seventh transmembrane domain of the DHCR7 protein. This mutation was found in compound heterozygosity with the IVS8-1G-C mutation (602858.0001). Nowaczyk et al. (2001) extended study of these patients to their parents and female first cousin. The brothers' father carried the T289I missense mutation. The cousin, like the brothers, carried the IVS8-1G-C/T289I genotype. </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>.0016 SMITH-LEMLI-OPITZ SYNDROME</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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DHCR7, TYR280CYS
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<br />
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SNP: rs121909766,
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ClinVar: RCV000007192, RCV003407291
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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>In a patient with Smith-Lemli-Opitz syndrome (SLOS; 270400), Prasad et al. (2002) found compound heterozygosity for the common IVS8-1G-C (602858.0001) mutation and a tyr280-to-cys (Y280C) mutation in DHCR7. The exceptionally mildly affected female infant presented initially with feeding difficulties, failure to thrive, hypotonia, mild developmental delay, and oral tactile aversion. She had minor facial anomalies and 2-3 syndactyly of the toes in both feet. Plasma cholesterol was borderline low at 2.88 mmol/L. Elevated plasma 7-dehydrocholesterol level of 200.0 micromol/L confirmed the clinical diagnosis of SLOS. Since the common mutation in this patient was a known null mutation, the Y280C mutation was presumably associated with significant residual enzyme activity leading to milder expression of the clinical phenotype. </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>.0017 SMITH-LEMLI-OPITZ SYNDROME, MILD</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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|
DHCR7, MET1LEU
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<br />
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|
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SNP: rs121909767,
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|
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gnomAD: rs121909767,
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|
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ClinVar: RCV000169218, RCV001528227
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|
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|
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</span>
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</div>
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Langius et al. (2003) found compound heterozygosity for the common IVS8-1G-C null mutation (602858.0001) and a novel mutation affecting translation initiation of met1 to leu (M1L) in the DHCR7 gene in 2 brothers with a very mild form of Smith-Lemli-Opitz syndrome (SLOS; 270400). The 15-year-old brother was described as having a relatively high forehead and broad nasal bridge as well as a relatively small chin. He showed second and third toe syndactyly and hypospadias. The 10-year-old younger brother likewise had syndactyly of the second and third toes as well as clinodactyly of the left second finger. </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>
|
|
<span class="mim-font">
|
|
<strong>.0018 SMITH-LEMLI-OPITZ SYNDROME, MILD</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
DHCR7, GLU448LYS
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|
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|
|
|
<br />
|
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|
|
SNP: rs80338864,
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|
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|
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gnomAD: rs80338864,
|
|
|
|
|
|
ClinVar: RCV000020435, RCV000790762
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Langius et al. (2003) described a 12-year-old girl with a very mild form of Smith-Lemli-Opitz (SLOS; 270400) found to be caused by compound heterozygosity for the common IVS8-1G-C null mutation (602858.0001) and a novel mutation, M1L (602858.0017), in the DHCR7 gene. In addition, she was found to have a 1342G-A mutation, resulting in a glu448-to-lys (E448K) substitution. Head circumference was at the -3 standard deviations at birth and at the age of 12 she had bilateral second and third toe syndactyly and a high forehead. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 SMITH-LEMLI-OPITZ SYNDROME, MILD</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
DHCR7, PHE284LEU
|
|
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|
|
|
<br />
|
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|
|
SNP: rs184297154,
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|
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|
|
gnomAD: rs184297154,
|
|
|
|
|
|
ClinVar: RCV000815482, RCV002442731
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with very mild Smith-Lemli-Opitz syndrome (SLOS; 270400), Yu et al. (2000) identified compound heterozygosity for 2 mutations in the DHCR7 gene: phe284 to leu (F284L), just outside the transmembrane domain on exon 8, and the more common val326 to leu (V326L; 602858.0011), in the transmembrane domain on exon 9. Mueller et al. (2003) described the clinical features of this patient. Developmentally, the child demonstrated mild delays in gross motor skills associated with mild hypotonia. Cognitive, language, and motor abilities were all within the low average range for her age, between the 14th and 18th centiles. She had not demonstrated temper tantrums, motor stereotypes, sleep disturbance, or hypersensitivity to light and sound as shown by many SLOS patients. The patient had presented at 12 days of age with poor feeding, abdominal distention, and jaundice. Colonic biopsy was consistent with Hirschsprung disease. Physical examination showed subtle 2,3 syndactyly. Her 7-dehydrocholesterol level was markedly elevated, and her cholesterol level was normal. Cholesterol supplementation implemented at 3 months of age resulted in increased cholesterol levels and reduced dehydrocholesterol levels. MRI of the brain showed no abnormalities. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 SMITH-LEMLI-OPITZ SYNDROME, MILD</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
DHCR7, MET1VAL
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|
|
|
|
<br />
|
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|
|
SNP: rs104886033,
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|
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|
|
|
gnomAD: rs104886033,
|
|
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|
|
|
ClinVar: RCV000169384, RCV000224026, RCV001267308, RCV003390651
|
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with a mild form of Smith-Lemli-Opitz syndrome (SLOS; 270400), Scalco et al. (2005) found a 1A-G transition, resulting in a met1-to-val (M1V) substitution of the initiator codon of the DHCR7 gene. The authors proposed that protein initiation at met59, which was demonstrated by Wassif et al. (1998) to result in a functional DHCR7 protein, could account for the mild phenotype. </p>
|
|
</span>
|
|
</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>.0021 SMITH-LEMLI-OPITZ SYNDROME</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">
|
|
|
|
DHCR7, ARG352GLN
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|
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<br />
|
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|
|
SNP: rs121909768,
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|
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|
|
|
gnomAD: rs121909768,
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|
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|
|
|
ClinVar: RCV000007197, RCV000254828
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|
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 7 unrelated Japanese patients with Smith-Lemli-Opitz syndrome (SLOS; 270400), Matsumoto et al. (2005) identified a 1055G-A transition in exon 9 of the DHCR7 gene, resulting in an arg352-to-gln (R352Q) substitution within the eighth transmembrane domain, which is a highly conserved sterol-sensing region. Two patients were homozygous for the R352Q mutation, and it occurred in 9 of 14 mutant alleles. Haplotype analysis indicated a founder effect. </p>
|
|
</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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|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 SMITH-LEMLI-OPITZ SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
|
DHCR7, IVS5DS, A-T, +3
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<br />
|
|
|
|
SNP: rs786200926,
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|
|
ClinVar: RCV000023212
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|
|
|
|
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</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with Smith-Lemli-Opitz syndrome (SLOS; 270400), Koo et al. (2010) identified compound heterozygosity for 2 mutations in the DHCR7 gene: the common IVS8-1G-C splice site mutation (602858.0001) and an A-to-T transversion in intron 5 (IVS5+3A-T), resulting in the skipping of exon 5, a frameshift, and premature termination. RT-PCR studies of patient fibroblasts showed 3 bands, including a wildtype band, indicating that some residual wildtype protein was produced from the IVS5+3A-T mutation. However, patient fibroblasts showed a defect in sterol synthesis in cholesterol-deficient medium. The patient had a severe form of the disorder at birth, with multiple congenital anomalies affecting many organ systems, but after birth she showed less neurologic impairment than expected. She rolled from side to side at age 7 months, could stand with assistance at 11 months, and gained some fine motor control. Serum 7-dehydrocholesterol was increased at age 4 months but later fell to normal range, and serum cholesterol was normal. Compared to patients with a more severe phenotype and with a less severe phenotype, Koo et al. (2010) observed a discordance in this patient: she was more severely affected, but had a lower 7-dehydrocholesterol/cholesterol ratio, which was usually observed in less severely affected individuals. Koo et al. (2010) noted that there is a high need for cholesterol during embryonic development, which may have explained why this child was born with so many abnormalities. After birth, the residual enzyme activity conferred by the IVS5+3A-T mutation and the addition of dietary cholesterol may have been sufficient to allow some developmental acquisition. </p>
|
|
</span>
|
|
</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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
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Wright, B. S., Nwokoro, N. A., Wassif, C. A., Porter, F. D., Waye, J. S., Eng, B., Nowaczyk, M. J. M.
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<strong>Carrier frequency of the RSH/Smith-Lemli-Opitz IVS8-1G-C mutation in African Americans. (Letter)</strong>
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Am. J. Med. Genet. 120A: 139-141, 2003.
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[PubMed: 12794707]
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[Full Text: https://doi.org/10.1002/ajmg.a.10207]
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Yu, H., Lee, M.-H., Starck, L., Elias, E. R., Irons, M., Salen, G., Patel, S. B., Tint, G. S.
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<strong>Spectrum of delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome.</strong>
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Hum. Molec. Genet. 9: 1385-1391, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1903 only, 2000.
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[PubMed: 10814720]
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[Full Text: https://doi.org/10.1093/hmg/9.9.1385]
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Yu, H., Tint, G. S., Salen, G., Patel, S. B.
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<strong>Detection of a common mutation in the RSH or Smith-Lemli-Opitz syndrome by a PCR-RFLP assay: IVS8-1G-C is found in over sixty percent of US propositi.</strong>
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Am. J. Med. Genet. 90: 347-350, 2000.
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[PubMed: 10710236]
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[Full Text: https://doi.org/10.1002/(sici)1096-8628(20000214)90:4<347::aid-ajmg16>3.0.co;2-7]
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Bao Lige - updated : 03/04/2024<br>Cassandra L. Kniffin - updated : 6/28/2012<br>Cassandra L. Kniffin - updated : 1/10/2011<br>Cassandra L. Kniffin - updated : 8/15/2008<br>Victor A. McKusick - updated : 6/18/2007<br>Paul J. Converse - updated : 1/29/2007<br>Cassandra L. Kniffin - updated : 11/8/2005<br>Victor A. McKusick - updated : 9/21/2005<br>Victor A. McKusick - updated : 3/31/2005<br>Victor A. McKusick - updated : 1/14/2004<br>Victor A. McKusick - updated : 9/30/2003<br>Victor A. McKusick - updated : 6/23/2003<br>Victor A. McKusick - updated : 2/8/2002<br>Victor A. McKusick - updated : 9/25/2001<br>George E. Tiller - updated : 5/29/2001<br>Anne M. Stumpf - updated : 5/10/2001<br>Michael B. Petersen - updated : 4/27/2001<br>Sonja A. Rasmussen - updated : 12/13/2000<br>Victor A. McKusick - updated : 10/4/2000<br>George E. Tiller - updated : 8/8/2000<br>Sonja A. Rasmussen - updated : 4/24/2000<br>Victor A. McKusick - updated : 3/31/2000<br>Matthew B. Gross - updated : 3/8/2000<br>Victor A. McKusick - updated : 2/9/2000<br>Victor A. McKusick - updated : 9/15/1998
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Victor A. McKusick : 7/16/1998
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