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Entry
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- #143890 - HYPERCHOLESTEROLEMIA, FAMILIAL, 1; FHCL1
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- OMIM
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<p>
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<span class="h4">#143890</span>
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<br />
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<strong>Table of Contents</strong>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
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<a href="/clinicalSynopsis/143890"><strong>Clinical Synopsis</strong></a>
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<li role="presentation">
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<a href="/phenotypicSeries/PS143890"> <strong>Phenotypic Series</strong> </a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#pathogenesis">Pathogenesis</a>
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<a href="#diagnosis">Diagnosis</a>
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<a href="#clinicalManagement">Clinical Management</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneTherapy">Gene Therapy</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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<div 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><a href="https://clinicaltrials.gov/search?cond=HYPERCHOLESTEROLEMIA, FAMILIAL" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=22639&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK174884/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/2746" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=143890[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=391665" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<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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</a>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/disease/DOID:13810" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="http://www.informatics.jax.org/disease/143890" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/results?search_type=advanced&omia_id=000499,001160" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:13810" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></div>
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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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 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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</a>
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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:143890" 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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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<div 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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<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> 397915002<br />
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<strong>ICD10CM:</strong> E78.00<br />
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<strong>ORPHA:</strong> 391665<br />
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<strong>DO:</strong> 13810<br />
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">ICD+</a>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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143890
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</span>
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</span>
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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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HYPERCHOLESTEROLEMIA, FAMILIAL, 1; FHCL1
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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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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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FHC; FH<br />
|
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HYPERLIPOPROTEINEMIA, TYPE II<br />
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HYPERLIPOPROTEINEMIA, TYPE IIA<br />
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HYPER-LOW-DENSITY-LIPOPROTEINEMIA<br />
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HYPERCHOLESTEROLEMIC XANTHOMATOSIS, FAMILIAL<br />
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LDL RECEPTOR DISORDER
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="includedTitles" 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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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 2, INCLUDED; LDLCQ2, INCLUDED
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</span>
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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="phenotypeMap" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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<th>
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Gene/Locus
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</th>
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<th>
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Gene/Locus <br /> MIM number
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/1/1346?start=-3&limit=10&highlight=1346">
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1q23.3
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Hypercholesterolemia, familial, modifier of}
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/143890"> 143890 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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APOA2
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/107670"> 107670 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/5/139?start=-3&limit=10&highlight=139">
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5p13.1-p12
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Hypercholesterolemia, familial, modifier of}
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/143890"> 143890 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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GHR
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/600946"> 600946 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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<a href="/geneMap/7/173?start=-3&limit=10&highlight=173">
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7p14.3
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Hypercholesterolemia, susceptibility to}
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/143890"> 143890 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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GSBS
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/604088"> 604088 </a>
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
|
<span class="mim-font">
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<a href="/geneMap/8/152?start=-3&limit=10&highlight=152">
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8p21.2-p21.1
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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{Hypercholesterolemia, familial, due to LDLR defect, modifier of}
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<a href="/entry/143890"> 143890 </a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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EPHX2
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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<a href="/entry/132811"> 132811 </a>
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</span>
|
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</td>
|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
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<a href="/geneMap/19/288?start=-3&limit=10&highlight=288">
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19p13.2
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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LDL cholesterol level QTL2
|
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|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/143890"> 143890 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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LDLR
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/606945"> 606945 </a>
|
|
</span>
|
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</td>
|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
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<a href="/geneMap/19/288?start=-3&limit=10&highlight=288">
|
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19p13.2
|
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</a>
|
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</span>
|
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</td>
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<td>
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<span class="mim-font">
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Hypercholesterolemia, familial, 1
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/143890"> 143890 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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LDLR
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
<a href="/entry/606945"> 606945 </a>
|
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</span>
|
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group ">
|
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<a href="/clinicalSynopsis/143890" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
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<span class="caret"></span>
|
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<span class="sr-only">Toggle Dropdown</span>
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</button>
|
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</div>
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<div class="btn-group">
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|
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<a href="/phenotypicSeries/PS143890" class="btn btn-info" role="button"> Phenotypic Series </a>
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<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-info dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimPhenotypicSeriesFold" onclick="ga('send', 'event', 'Unfurl', 'PhenotypicSeries', 'omim.org')">
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<span class="caret"></span>
|
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<span class="sr-only">Toggle Dropdown</span>
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</button>
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</div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/143890" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
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<li><a href="/graph/radial/143890" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
|
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
|
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<p />
|
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</div>
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<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
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<div class="small" style="margin: 5px">
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<div>
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<div>
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<span class="h5 mim-font">
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<strong> INHERITANCE </strong>
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</span>
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<span class="mim-font">
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- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br /> -
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Autosomal recessive <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/258211005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">258211005</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0441748&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0441748</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000007" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000007</a>]</span><br />
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</span>
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</div>
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</div>
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</div>
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<div>
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<div>
|
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<span class="h5 mim-font">
|
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<strong> HEAD & NECK </strong>
|
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</span>
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</div>
|
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<div style="margin-left: 2em;">
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<div>
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<div>
|
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<span class="h5 mim-font">
|
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<em> Eyes </em>
|
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</span>
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</div>
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<div style="margin-left: 2em;">
|
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<span class="mim-font">
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- Corneal arcus <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/111522004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">111522004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/231924000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">231924000</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H18.41" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H18.41</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0003742&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0003742</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001084" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001084</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001084" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001084</a>]</span><br /> -
|
|
Xanthelasma <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/75594004" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">75594004</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/238951005" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">238951005</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/63103006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">63103006</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/H02.6" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">H02.6</a>]</span> <span class="mim-feature-ids hidden">[ICD9CM: <a href="https://purl.bioontology.org/ontology/ICD9CM/374.51" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD9CM\', \'domain\': \'bioontology.org\'})">374.51</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0302314&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0302314</a>, <a href="https://bioportal.bioontology.org/search?q=C0155210&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0155210</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001114" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001114</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001114" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001114</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
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|
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|
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|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> CARDIOVASCULAR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Heart </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Coronary artery disease presenting after age 30 years in heterozygotes, in childhood in homozygotes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1840434&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1840434</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> SKIN, NAILS, & HAIR </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<em> Skin </em>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
<span class="mim-font">
|
|
|
|
- Tendinous xanthomas presenting after age 20 years in heterozygotes, during first 4 years of life in homozygotes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1840432&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1840432</a>]</span><br /> -
|
|
Planar xanthomas in homozygotes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1840433&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1840433</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
</div>
|
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|
|
|
|
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|
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> LABORATORY ABNORMALITIES </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Hypercholesterolemia, 350-550 mg/L in heterozygotes, 650-1000 mg/L in homozygotes <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1840431&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1840431</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Incidence, 1 in 500 heterozygotes, 1 in 1,000,000 homozygotes<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the low density lipoprotein receptor gene (LDLR, <a href="/entry/606945#0001">606945.0001</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
<div id="mimPhenotypicSeriesFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="row">
|
|
<div class="col-lg-12 col-md-12 col-sm-12 col-xs-12">
|
|
<h5>
|
|
Hypercholesterolemia, familial
|
|
- <a href="/phenotypicSeries/PS143890">PS143890</a>
|
|
- 10 Entries
|
|
</h5>
|
|
</div>
|
|
</div>
|
|
|
|
<div class="row" style="margin-left: 0.125em; margin-right: 0.125em;">
|
|
<table class="table table-bordered table-condensed table-hover mim-table-padding">
|
|
<thead>
|
|
<tr>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Location</strong>
|
|
</th>
|
|
<th class="col-lg-5 col-md-5 col-sm-5 col-xs-6 text-nowrap">
|
|
<strong>Phenotype</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Inheritance</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />mapping key</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Phenotype<br />MIM number</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus</strong>
|
|
</th>
|
|
<th class="col-lg-1 col-md-1 col-sm-1 col-xs-1 text-nowrap">
|
|
<strong>Gene/Locus<br />MIM number</strong>
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/301?start=-3&limit=10&highlight=301"> 1p36.11 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603813"> Hypercholesterolemia, familial, 4 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603813"> 603813 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605747"> LDLRAP1 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605747"> 605747 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/646?start=-3&limit=10&highlight=646"> 1p32.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603776"> Hypercholesterolemia, familial, 3 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603776"> 603776 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607786"> PCSK9 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607786"> 607786 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/646?start=-3&limit=10&highlight=646"> 1p32.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603776"> {Low density lipoprotein cholesterol level QTL 1} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/603776"> 603776 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607786"> PCSK9 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607786"> 607786 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/1/1346?start=-3&limit=10&highlight=1346"> 1q23.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/143890"> {Hypercholesterolemia, familial, modifier of} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/143890"> 143890 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/107670"> APOA2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/107670"> 107670 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/2/80?start=-3&limit=10&highlight=80"> 2p24.1 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/144010"> Hypercholesterolemia, familial, 2 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/144010"> 144010 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/107730"> APOB </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/107730"> 107730 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/5/139?start=-3&limit=10&highlight=139"> 5p13.1-p12 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/143890"> {Hypercholesterolemia, familial, modifier of} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/143890"> 143890 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600946"> GHR </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/600946"> 600946 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/geneMap/7/173?start=-3&limit=10&highlight=173"> 7p14.3 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/143890"> {Hypercholesterolemia, susceptibility to} </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
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<p>A number sign (#) is used with this entry because familial hypercholesterolemia-1 (FHCL1) can be caused by heterozygous, compound heterozygous, or homozygous mutation in the low density lipoprotein receptor gene (LDLR; <a href="/entry/606945">606945</a>) on chromosome 19p13.</p>
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<p>Familial hypercholesterolemia is characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL), which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis). The disorder occurs in 2 clinical forms: homozygous and heterozygous (<a href="#69" class="mim-tip-reference" title="Hobbs, H. H., Brown, M. S., Goldstein, J. L. <strong>Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.</strong> Hum. Mutat. 1: 445-466, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301956</a>] [<a href="https://doi.org/10.1002/humu.1380010602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301956">Hobbs et al., 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301956" 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 FHCL1 phenotype can be modified by mutation in other genes. For example, in individuals with the LDLR mutation IVS14+1G-A (<a href="/entry/606945#0063">606945.0063</a>), the phenotype can be altered by a SNP in the APOA2 gene (<a href="/entry/107670#0002">107670.0002</a>), a SNP in the EPHX2 gene (<a href="/entry/132811#0001">132811.0001</a>), or a SNP in the GHR gene (<a href="/entry/600946#0028">600946.0028</a>).</p><p><strong><em>Genetic Heterogeneity of Familial Hypercholesterolemia</em></strong></p><p>
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Other forms of monogenic familial hypercholesterolemia include FHCL2 (<a href="/entry/144010">144010</a>), caused by mutation in the APOB gene (<a href="/entry/107730">107730</a>); FHCL3 (<a href="/entry/603776">603776</a>), caused by mutation in the PCSK9 gene (<a href="/entry/607786">607786</a>); and FHCL4 (<a href="/entry/603813">603813</a>), caused by mutation in the LDLRAP1 gene (<a href="/entry/605747">605747</a>).</p>
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<p>Individuals with heterozygous familial hypercholesterolemia develop tendinous xanthomas, corneal arcus, and coronary artery disease; the last usually becomes evident in the fourth or fifth decade. Homozygous individuals have a more severe clinical picture with earlier presentation, usually in the first 2 decades of life (<a href="#69" class="mim-tip-reference" title="Hobbs, H. H., Brown, M. S., Goldstein, J. L. <strong>Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.</strong> Hum. Mutat. 1: 445-466, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1301956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1301956</a>] [<a href="https://doi.org/10.1002/humu.1380010602" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1301956">Hobbs et al., 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1301956" 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 ranges of serum cholesterol and LDL-cholesterol are, in mg per dl, 250-450 and 200-400 in heterozygotes, greater than 500 and greater than 450 in homozygous affecteds, and 150-250 and 75-175 in homozygous unaffecteds, with some positive correlation with age (<a href="#85" class="mim-tip-reference" title="Khachadurian, A. K. <strong>The inheritance of essential familial hypercholesterolemia.</strong> Am. J. Med. 37: 402-407, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14209286/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14209286</a>] [<a href="https://doi.org/10.1016/0002-9343(64)90196-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14209286">Khachadurian, 1964</a>; <a href="#95" class="mim-tip-reference" title="Kwiterovich, P. O., Jr., Fredrickson, D. S., Levy, R. I. <strong>Familial hypercholesterolemia (one form of familial type II hyperlipoproteinemia): a study of its biochemical, genetic, and clinical presentation in childhood.</strong> J. Clin. Invest. 53: 1237-1249, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4363406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4363406</a>] [<a href="https://doi.org/10.1172/JCI107670" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4363406">Kwiterovich et al., 1974</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4363406+14209286" 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 homozygous familial hypercholesterolemia, the aortic root is prone to develop atherosclerotic plaque at an early age. Such plaques can accumulate in unusual sites, such as the ascending aorta and around the coronary ostia. <a href="#133" class="mim-tip-reference" title="Summers, R. M., Andrasko-Bourgeois, J., Feuerstein, I. M., Hill, S. C., Jones, E. C., Busse, M. K., Wise, B., Bove, K. E., Rishforth, B. A., Tucker, E., Spray, T. L., Hoeg, J. M. <strong>Evaluation of the aortic root by MRI: insights from patients with homozygous familial hypercholesterolemia.</strong> Circulation 98: 509-518, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9714107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9714107</a>] [<a href="https://doi.org/10.1161/01.cir.98.6.509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9714107">Summers et al. (1998)</a> evaluated the aortic root using MRI imaging in a blinded, prospective study of 17 homozygous FH patients and 12 healthy controls. When patient age and body mass index were taken into account, 53% of patients with homozygous FH had increased aortic wall thickness compared to controls; this was thought to result from a combination of medial hyperplasia and plaque formation. Supravalvular aortic stenosis was seen in 41% of patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9714107" 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="#78" class="mim-tip-reference" title="Houlston, R., Quiney, J., Mount, J., Watts, G. F., Lewis, B. <strong>Lipoprotein(a) and coronary heart disease in familial hypercholesterolaemia. (Letter)</strong> Lancet 332: 405 only, 1988. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2899819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2899819</a>] [<a href="https://doi.org/10.1016/s0140-6736(88)92884-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2899819">Houlston et al. (1988)</a> studied the relationship of lipoprotein(a) (<a href="/entry/152200">152200</a>) levels and coronary heart disease in patients with familial hypercholesterolemia. Individuals with coronary artery disease had a significantly higher mean lipoprotein(a) concentration than those without coronary heart disease, suggesting that lipoprotein(a) measurements may help predict the risk of coronary heart disease in individuals with familial hypercholesterolemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2899819" 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="Deramo, V. A., Sergott, R. C., Augsburger, J. J., Foroozan, R., Savino, P. J., Leone, A. <strong>Ischemic optic neuropathy as the first manifestation of elevated cholesterol levels in young patients.</strong> Ophthalmology 110: 1041-1045, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750110</a>] [<a href="https://doi.org/10.1016/S0161-6420(03)00079-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12750110">Deramo et al. (2003)</a> investigated the relationship between nonarteritic ischemic optic neuropathy (NAION; <a href="/entry/258660">258660</a>) and serum lipid levels in 37 consecutive patients diagnosed with NAION at or below age 50 years and 74 age- and gender-matched controls. They found that hypercholesterolemia was a risk factor in these patients and suggested that NAION might be the first manifestation of a previously unrecognized lipid disorder. The patients had experienced a focal, microvascular central nervous system ischemic event at a relatively young age. <a href="#34" class="mim-tip-reference" title="Deramo, V. A., Sergott, R. C., Augsburger, J. J., Foroozan, R., Savino, P. J., Leone, A. <strong>Ischemic optic neuropathy as the first manifestation of elevated cholesterol levels in young patients.</strong> Ophthalmology 110: 1041-1045, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12750110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12750110</a>] [<a href="https://doi.org/10.1016/S0161-6420(03)00079-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12750110">Deramo et al. (2003)</a> suggested that aggressive treatment of lipid abnormalities might be warranted in these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12750110" 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>By studies of cultured fibroblasts from homozygotes, <a href="#53" class="mim-tip-reference" title="Goldstein, J. L., Brown, M. S. <strong>Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol.</strong> Proc. Nat. Acad. Sci. 70: 2804-2808, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4355366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4355366</a>] [<a href="https://doi.org/10.1073/pnas.70.10.2804" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4355366">Goldstein and Brown (1973)</a> and <a href="#16" class="mim-tip-reference" title="Brown, M. S., Goldstein, J. L. <strong>Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme at reductase activity.</strong> Proc. Nat. Acad. Sci. 71: 788-792, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4362634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4362634</a>] [<a href="https://doi.org/10.1073/pnas.71.3.788" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4362634">Brown and Goldstein (1974)</a> showed that the basic defect concerns the cell membrane receptor for LDL. Normally, LDL is bound at the cell membrane and taken into the cell ending up in lysosomes where the protein is degraded and the cholesterol is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. In familial hypercholesterolemia, there is a binding defect due to a dysfunctional receptor. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. <a href="#63" class="mim-tip-reference" title="Harders-Spengel, K., Wood, C. B., Thompson, G. R., Myant, N. B., Soutar, A. K. <strong>Difference in saturable binding of low density lipoprotein to liver membranes from normocholesterolemic subjects and patients with heterozygous familial hypercholesterolemia.</strong> Proc. Nat. Acad. Sci. 79: 6355-6359, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6292899/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6292899</a>] [<a href="https://doi.org/10.1073/pnas.79.20.6355" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6292899">Harders-Spengel et al. (1982)</a> presented evidence that the receptor defect is present on liver membranes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4355366+6292899+4362634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine the influences of intrauterine and genetic factors on atherogenic lipid profiles in later life, <a href="#81" class="mim-tip-reference" title="Ijzerman, R. G., Stehouwer, C. D. A., Van Weissenbruch, M. M., De Geus, E. J., Boomsma, D. I. <strong>Evidence for genetic factors explaining the association between birth weight and low-density lipoprotein cholesterol and possible intrauterine factors influencing the association between birth weight and high-density lipoprotein cholesterol: analysis in twins.</strong> J. Clin. Endocr. Metab. 86: 5479-5484, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11701725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11701725</a>] [<a href="https://doi.org/10.1210/jcem.86.11.7996" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11701725">Ijzerman et al. (2001)</a> investigated 53 dizygotic and 61 monozygotic adolescent twin pairs. They found an association between low birth weight and high levels of total cholesterol, LDL cholesterol, and apolipoprotein B that persisted in the intrapair analysis in dizygotic twin pairs but was reversed within monozygotic twin pairs. Furthermore, they found that the association between low birth weight and low levels of HDL cholesterol tended to persist in the intrapair analysis in both dizygotic and monozygotic twins. These data suggested that genetic factors may account for the association of low birth weight with high levels of total cholesterol, LDL cholesterol, and apolipoprotein B, whereas intrauterine factors possibly play a role in the association of low birth weight with low levels of HDL cholesterol. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11701725" 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="#50" class="mim-tip-reference" title="Garcia-Otin, A. L., Cofan, M., Junyent, M., Recalde, D., Cenarro, A., Povovi, M., Ros, E., Civeira, F. <strong>Increased intestinal cholesterol absorption in autosomal dominant hypercholesterolemia and no mutations in the low-density lipoprotein receptor or apolipoprotein B genes.</strong> J. Clin. Endocr. Metab. 92: 3667-3673, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17566095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17566095</a>] [<a href="https://doi.org/10.1210/jc.2006-2567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17566095">Garcia-Otin et al. (2007)</a> determined serum noncholesterol sterols in normolipidemic control subjects and in well-phenotyped patients with dyslipidemias, including autosomal dominant hypercholesterolemia (ADH) with and without known genetic defects and familial combined hyperlipidemia (FCHL; <a href="/entry/144250">144250</a>). Intestinal cholesterol absorption was highest in ADH without known defect, followed by ADH with known defect, then controls, and then FCHL. <a href="#50" class="mim-tip-reference" title="Garcia-Otin, A. L., Cofan, M., Junyent, M., Recalde, D., Cenarro, A., Povovi, M., Ros, E., Civeira, F. <strong>Increased intestinal cholesterol absorption in autosomal dominant hypercholesterolemia and no mutations in the low-density lipoprotein receptor or apolipoprotein B genes.</strong> J. Clin. Endocr. Metab. 92: 3667-3673, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17566095/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17566095</a>] [<a href="https://doi.org/10.1210/jc.2006-2567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17566095">Garcia-Otin et al. (2007)</a> concluded that intestinal cholesterol absorption might play a role in the lipid abnormalities of patients with autosomal dominant hypercholesterolemia without identified genetic defects. They suggested that serum noncholesterol sterols are a useful tool for the differential diagnosis of genetic hypercholesterolemias. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17566095" 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="#80" class="mim-tip-reference" title="Humphries, S. E., Kessling, A. M., Horsthemke, B., Donald, J. A., Seed, M., Jowett, N., Holm, M., Galton, D. J., Wynn, V., Williamson, R. <strong>A common DNA polymorphism of the low-density lipoprotein (LDL) receptor gene and its use in diagnosis.</strong> Lancet 325: 1003-1005, 1985. Note: Originally Volume I.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2859461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2859461</a>] [<a href="https://doi.org/10.1016/s0140-6736(85)91611-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2859461">Humphries et al. (1985)</a> found a RFLP of the LDL receptor gene using the restriction enzyme PvuII. About 30% of persons are heterozygous for the polymorphism which is, therefore, useful in family studies and early diagnosis of FHC. <a href="#127" class="mim-tip-reference" title="Schuster, H., Stiefenhofer, B., Wolfram, G., Keller, C., Humphries, S., Huber, A., Zollner, N. <strong>Four DNA polymorphisms in the LDL-receptor gene and their use in diagnosis of familial hypercholesterolemia.</strong> Hum. Genet. 82: 69-72, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2565869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2565869</a>] [<a href="https://doi.org/10.1007/BF00288276" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2565869">Schuster et al. (1989)</a> also used RFLPs of the LDLR gene in the diagnosis of FH. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2565869+2859461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Bhatnagar, D., Morgan, J., Siddiq, S., Mackness, M. I., Miller, J. P., Durrington, P. N. <strong>Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia.</strong> Brit. Med. J. 321: 1497-1500, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11118175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11118175</a>] [<a href="https://doi.org/10.1136/bmj.321.7275.1497" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11118175">Bhatnagar et al. (2000)</a> reported a case-finding experience in the UK among relatives of patients with familial hypercholesterolemia by a nurse-led genetic register. By performing cholesterol tests on 200 relatives, 121 new patients with familial hypercholesterolemia were discovered. The newly diagnosed patients were younger than the probands and were generally detected before they had clinically overt atherosclerosis. A case was made for organizing a genetic register approach, linking lipid clinics nationally. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11118175" 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="#141" class="mim-tip-reference" title="Umans-Eckenhausen, M. A. W., Defesche, J. C., Sijbrands, E. J. G., Scheerder, R. L. J. M., Kastelein, J. J. P. <strong>Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands.</strong> Lancet 357: 165-168, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11213091/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11213091</a>] [<a href="https://doi.org/10.1016/S0140-6736(00)03587-X" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11213091">Umans-Eckenhausen et al. (2001)</a> found that in the Netherlands targeted family screening with DNA analysis proved to be highly effective in identifying patients with hypercholesterolemia. Most of the identified patients sought treatment and were successfully started on cholesterol-lowering treatment to lower the risk of premature cardiovascular disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11213091" 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="#115" class="mim-tip-reference" title="Newson, A. J., Humphries, S. E. <strong>Cascade testing in familial hypercholesterolaemia: how should family members be contacted?</strong> Europ. J. Hum. Genet. 13: 401-408, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657617</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201360" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15657617">Newson and Humphries (2005)</a> discussed cascade testing in familial hypercholesterolemia. They questioned whether and how family members should be contacted for testing. The implications of the test results for life planning, employment, or ability to obtain life insurance are concerns. The pros and cons of cascade testing were reviewed by <a href="#30" class="mim-tip-reference" title="de Wert, G. <strong>Whose information is it anyway? (Commentary)</strong> Europ. J. Hum. Genet. 13: 397-398, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15702129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15702129</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201373" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15702129">de Wert (2005)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15702129+15657617" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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<a href="#144" class="mim-tip-reference" title="Vergotine, J., Thiart, R., Langenhoven, E., Hillermann, R., De Jong, G., Kotze, M. J. <strong>Prenatal diagnosis of familial hypercholesterolemia: importance of DNA analysis in the high-risk South African population.</strong> Genet. Counsel. 12: 121-127, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11491306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11491306</a>]" pmid="11491306">Vergotine et al. (2001)</a> demonstrated the feasibility of prenatal diagnosis of homozygous familial hypercholesterolemia in the Afrikaner population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11491306" 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="#130" class="mim-tip-reference" title="Starzl, T. E., Bilheimer, D. W., Bahnson, H. T., Shaw, B. W., Jr., Hardesty, R. L., Griffith, B. P., Iwatsuki, S., Zitelli, B. J., Gartner, J. C., Jr., Malatack, J. J., Urbach, A. H. <strong>Heart-liver transplantation in a patient with familial hypercholesterolaemia.</strong> Lancet 323: 1382-1383, 1984. Note: Originally Volume I.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6145836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6145836</a>] [<a href="https://doi.org/10.1016/s0140-6736(84)91876-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6145836">Starzl et al. (1984)</a> performed both heart transplant and liver transplant in a 6.75-year-old girl with homozygous familial hypercholesterolemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6145836" 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="#139" class="mim-tip-reference" title="Tonstad, S., Knudtzon, J., Sivertsen, M., Refsum, H., Ose, L. <strong>Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia.</strong> J. Pediat. 129: 42-49, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8757561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8757561</a>] [<a href="https://doi.org/10.1016/s0022-3476(96)70188-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8757561">Tonstad et al. (1996)</a> conducted a double-blind placebo-controlled trial over 1 year using 8 grams of cholestyramine in prepubertal children (aged 6-11 years) with familial hypercholesterolemia. After 1 year of a low-fat, low-cholesterol diet, children with a family history of premature cardiovascular disease had LDL cholesterol levels at or greater than 4.9 mmol/liter, while children without such a family history had LDL cholesterol levels at or greater than 4.1 mmol/liter. The LDL cholesterol levels in the test group lowered by 16.9% (95% confidence interval), compared with a 1.4% increase in the placebo group. Growth velocity was not adversely affected in the treatment group, although folate and 25-hydroxyvitamin D deficiency were noted among a small number of treated children. Additionally, a boy who had an appendectomy 3 months before the study required surgery for intestinal obstruction after he had taken the first 2 cholestyramine doses. Given the number of gastrointestinal side effects, <a href="#139" class="mim-tip-reference" title="Tonstad, S., Knudtzon, J., Sivertsen, M., Refsum, H., Ose, L. <strong>Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia.</strong> J. Pediat. 129: 42-49, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8757561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8757561</a>] [<a href="https://doi.org/10.1016/s0022-3476(96)70188-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8757561">Tonstad et al. (1996)</a> recommended caution in starting cholestyramine after abdominal surgery in children. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8757561" 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="#26" class="mim-tip-reference" title="Cuchel, M., Bloedon, L. T., Szapary, P. O., Kolansky, D. M., Wolfe, M. L., Sarkis, A., Millar, J. S., Ikewaki, K., Siegelman, E. S., Gregg, R. E., Rader, D. J. <strong>Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia.</strong> New Eng. J. Med. 356: 148-156, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17215532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17215532</a>] [<a href="https://doi.org/10.1056/NEJMoa061189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17215532">Cuchel et al. (2007)</a> treated 6 patients with homozygous familial hypercholesterolemia with an inhibitor of microsomal triglyceride transfer protein (<a href="/entry/157147">157147</a>). A reduction of LDL cholesterol levels was observed, owing to reduced production of apolipoprotein B. However, the therapy was associated with elevated liver aminotransferase levels and hepatic fat accumulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17215532" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Statin Therapy</em></strong></p><p>
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The 'statin' drugs are potent competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme-A reductase and have proven useful in the treatment of hypercholesterolemia (<a href="#8" class="mim-tip-reference" title="Betteridge, D. J., Reckless, J. P. D., Krone, W., Galton, D. J. <strong>Compactin inhibits cholesterol synthesis in lymphocytes and intestinal mucosa from patients with familial hypercholesterolaemia.</strong> Lancet 312: 1342-1343, 1978. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/82843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">82843</a>] [<a href="https://doi.org/10.1016/s0140-6736(78)91977-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="82843">Betteridge et al., 1978</a>; <a href="#58" class="mim-tip-reference" title="Goldstein, J. L., Brown, M. S. <strong>Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis.</strong> Circulation 76: 504-507, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3621516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3621516</a>] [<a href="https://doi.org/10.1161/01.cir.76.3.504" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3621516">Goldstein and Brown, 1987</a>; <a href="#72" class="mim-tip-reference" title="Hoeg, J. M., Brewer, H. B., Jr. <strong>3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the treatment of hypercholesterolemia.</strong> JAMA 258: 3532-3536, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3316727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3316727</a>]" pmid="3316727">Hoeg and Brewer, 1987</a>). <a href="#15" class="mim-tip-reference" title="Brorholt-Petersen, J. U., Jensen, H. K., Raungaard, B., Gregersen, N., Faergeman, O. <strong>LDL-receptor gene mutations and the hypocholesterolemic response to statin therapy.</strong> Clin. Genet. 59: 397-405, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11453971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11453971</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2001.590604.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11453971">Brorholt-Petersen et al. (2001)</a> tested the hypothesis that the cholesterol lowering effect of statin therapy is a function of the particular type of LDLR mutation. They studied the response to treatment with fluvastatin in 28 patients with heterozygous FH as a result of a receptor-negative mutation (trp23 to ter; <a href="/entry/606945#0060">606945.0060</a>) and in 30 patients with a receptor-binding defective mutation (trp66 to gly; <a href="/entry/606945#0003">606945.0003</a>). They found no statistically significant differences. A tabulation of the results of this and earlier studies suggested that differences in treatment response as an apparent function of LDLR gene mutation type occur mainly in populations with recent genetic admixture. The authors suggested that in such populations persons with the same mutation in the LDLR gene are also more likely to share other but undetermined genetic variations affecting the pharmacology of statins. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11453971+3316727+3621516+82843" 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="Chaves, F. J., Real, J. T., Garcia-Garcia, A. B., Civera, M., Armengod, M. E., Ascaso, J. F., Carmena, R. <strong>Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol.</strong> J. Clin. Endocr. Metab. 86: 4926-4932, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11600564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11600564</a>] [<a href="https://doi.org/10.1210/jcem.86.10.7899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11600564">Chaves et al. (2001)</a> examined the presence of mutations in the LDLR gene among subjects clinically diagnosed with FH and analyzed whether the molecular diagnosis helped to predict the response to simvastatin treatment in their FH population. They conducted a randomized clinical trial with simvastatin in 42 genetically diagnosed subjects with FH, with 22 classified as carriers of null mutations and 20 with defective mutations. A mutation causing FH was identified in 46 probands (84%). In 41 of them (89%), a total of 28 point mutations were detected, 13 of which had not been previously described. FH with null mutations showed a poor response to simvastatin treatment. The mean percentage reduction of plasma total and LDL cholesterol levels in these subjects was significantly lower than in subjects with defective mutations. Subjects with FH with null mutations (class I) showed lower plasma HDL cholesterol values and a poor LDL cholesterol response to simvastatin treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11600564" 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="#66" class="mim-tip-reference" title="Hedman, M., Matikainen, T., Fohr, A., Lappi, M., Piippo, S., Nuutinen, M., Antikainen, M. <strong>Efficacy and safety of pravastatin in children and adolescents with heterozygous familial hypercholesterolemia: a prospective clinical follow-up study.</strong> J. Clin. Endocr. Metab. 90: 1942-1952, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657370</a>] [<a href="https://doi.org/10.1210/jc.2004-1541" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15657370">Hedman et al. (2005)</a> studied the efficacy and safety for up to 2 years of pravastatin treatment in 19 girls and 11 boys with autosomal dominant familial hypercholesterolemia. Pravastatin was started at 10 mg/d, with a forced titration by 10 mg at 2, 4, 6, and 12 months until the target cholesterol level of less than 194 mg/dl was reached. By 2, 4, 6, 12, and 24 months of treatment, the total cholesterol levels had, respectively, decreased by 19, 20, 23, 27 and 26%, and the LDL cholesterol levels had decreased by 25, 27, 29, 33, and 32% compared with the dietary baseline values. The side effects were mild, and no clinically significant elevations in alanine aminotransferase, creatine kinase, or creatinine were seen. The authors concluded that the efficacy in children with slight or moderate hypercholesterolemia was satisfactory, but in children with severe hypercholesterolemia it was insufficient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15657370" 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="#101" class="mim-tip-reference" title="Luirink, I. K., Wiegman, A., Kusters, D. M., Hof, M. H., Groothoff, J. W., de Groot, E., Kastelein, J. J. P., Hutten, B. A. <strong>20-year follow-up of statins in children with familial hypercholesterolemia.</strong> New Eng. J. Med. 381: 1547-1556, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31618540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31618540</a>] [<a href="https://doi.org/10.1056/NEJMoa1816454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31618540">Luirink et al. (2019)</a> reported a 20-year follow-up study of statin therapy in children with familial hypercholesterolemia. A total of 214 patients with familial hypercholesterolemia, genetically confirmed in 98% as due to mutations in either LDLR or APOB (see FHCL2, <a href="/entry/144010">144010</a>), who were previously participants in a placebo-controlled trial evaluating the 2-year efficacy and safety of pravastatin, were invited for follow-up, together with their 95 unaffected sibs. The incidence of cardiovascular disease among the patients with familial hypercholesterolemia was compared with that among their 156 affected parents. The mean LDL cholesterol level in the patients had decreased from 237.3 to 160.7 mg per deciliter, a decrease of 32% from the baseline level; treatment goal of LDL cholesterol less than 100 mg per deciliter was achieved in 37 patients (20%). Mean progression of carotid intima-media thickness over the entire follow-up period was 0.0056 mm per year in patients with familial hypercholesterolemia and 0.0057 mm per year in sibs (mean difference adjusted for sex, -0.0001 mm per year). The cumulative incidence of cardiovascular events and of death from cardiovascular causes at 39 years of age was lower among the patients with familial hypercholesterolemia than among their affected parents (1% vs 26% and 0% vs 7%, respectively). <a href="#101" class="mim-tip-reference" title="Luirink, I. K., Wiegman, A., Kusters, D. M., Hof, M. H., Groothoff, J. W., de Groot, E., Kastelein, J. J. P., Hutten, B. A. <strong>20-year follow-up of statins in children with familial hypercholesterolemia.</strong> New Eng. J. Med. 381: 1547-1556, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31618540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31618540</a>] [<a href="https://doi.org/10.1056/NEJMoa1816454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31618540">Luirink et al. (2019)</a> concluded that initiation of statin therapy during childhood in patients with familial hypercholesterolemia slowed the progression of carotid intima-media thickness and reduced the risk of cardiovascular disease in adulthood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31618540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Inclisiran</em></strong></p><p>
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<a href="#120" class="mim-tip-reference" title="Ray, K. K., Wright, R. S., Kallend, D., Koenig, W., Leiter, L. A., Raal, F. J., Bisch, J. A., Richardson, T., Jaros, M., Wijngaard, P. L. J., Kastelein, J. J. P. <strong>Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol.</strong> New Eng. J. Med. 382: 1507-1519, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32187462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32187462</a>] [<a href="https://doi.org/10.1056/NEJMoa1912387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32187462">Ray et al. (2020)</a> reported the results of 2 phase 3 trials of inclisiran, a small interfering RNA that reduces hepatic synthesis of PCSK9 (<a href="/entry/607786">607786</a>). <a href="#120" class="mim-tip-reference" title="Ray, K. K., Wright, R. S., Kallend, D., Koenig, W., Leiter, L. A., Raal, F. J., Bisch, J. A., Richardson, T., Jaros, M., Wijngaard, P. L. J., Kastelein, J. J. P. <strong>Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol.</strong> New Eng. J. Med. 382: 1507-1519, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32187462/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32187462</a>] [<a href="https://doi.org/10.1056/NEJMoa1912387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32187462">Ray et al. (2020)</a> enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540. A total of 1,561 and 1,617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (+/- SD) LDL cholesterol levels at baseline were 104.7 +/- 38.3 mg per deciliter and 105.5 +/- 39.1 mg per deciliter, respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% in the ORION-10 trial and by 49.9% in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% and 49.2% (p less than 0.001 for all comparisons vs placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo. Nevertheless such reactions were generally mild, and none were severe or persistent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32187462" 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="#118" class="mim-tip-reference" title="Raal, F. J., Kallend, D., Ray, K. K., Turner, T., Koenig, W., Wright, R. S., Wijngaard, P. L. J., Curcio, D., Jaros, M. J., Leiter, L. A., Kastelein, J. J. P. <strong>Inclisiran for the treatment of heterozygous familial hypercholesterolemia.</strong> New Eng. J. Med. 382: 1520-1530, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32197277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32197277</a>] [<a href="https://doi.org/10.1056/NEJMoa1913805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32197277">Raal et al. (2020)</a> performed a phase 3, double-blind clinical trial of inclisiran in which 482 adults with heterozygous familial hypercholesterolemia were randomly assigned in a 1:1 ratio to receive either subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. The patients included 15 LDLR (<a href="/entry/606945">606945</a>) homozygotes, 131 patients with LDLR variants, 11 patients with APOB (<a href="/entry/107730">107730</a>) variants, and 91 patients who either did not have detectable variants or had no genetic testing done. The 2 primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% in the inclisiran group and an increase of 8.2% in the placebo group, for a between-group difference of minus 47.9 percentage points. The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% in the inclisiran group and an increase of 6.2% in the placebo group. There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32197277" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Evinacumab</em></strong></p><p>
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<a href="#35" class="mim-tip-reference" title="Dewey, F. E., Gusarova, V., Dunbar, R. L., O'Dushlaine, C., Schurmann, C., Gottesman, O., McCarthy, S., Van Hout, C. V., Bruse, S., Dansky, H. M., Leader, J. B., Murray, M. F., and 45 others. <strong>Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease.</strong> New Eng. J. Med. 377: 211-221, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28538136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28538136</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28538136[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/10.1056/NEJMoa1612790" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28538136">Dewey et al. (2017)</a> tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28538136" 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="#119" class="mim-tip-reference" title="Raal, F. J., Rosenson, R. S., Reeskamp, L. F., Hovingh, G. K., Kastelein, J. J. P., Rubba, P., Ali, S., Banerjee, P., Chan, K.-C., Gipe, D. A., Khilla, N., Pordy, R., Weinreich, D. M., Yancopoulos, G. D., Zhang, Y., Gaudet, D. <strong>Evinacumab for homozygous familial hypercholesterolemia.</strong> New Eng. J. Med. 383: 711-720, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32813947/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32813947</a>] [<a href="https://doi.org/10.1056/NEJMoa2004215" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32813947">Raal et al. (2020)</a> performed a double-blind, placebo-controlled, phase 3 trial in which 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy were randomly assigned in a 2:1 ratio to receive an intravenous infusion of evinacumab, a monoclonal antibody against ANGPTL3, at a dose of 15 mg per kg of body weight every 4 weeks or placebo. Patients with homozygous or compound heterozygous LDLR (<a href="/entry/606945">606945</a>) mutations were most frequent, but those with biallelic APOB (<a href="/entry/107730">107730</a>) or PCSK9 (<a href="/entry/607786">607786</a>) variants were also eligible. Only two-thirds of patients were genotyped. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24. The mean baseline LDL cholesterol level in the 2 groups was 255.1 mg per dL, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points; the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per dL. The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null-null variants in LDLR (-43.4% vs +16.2%) and in those with non-null variants (-49.1% vs -3.8%). Adverse events were similar in the 2 groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32813947" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Evolocumab</em></strong></p><p>
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<a href="#122" class="mim-tip-reference" title="Santos, R. D., Ruzza, A., Hovingh, G. K., Wiegman, A., Mach, F., Kurtz, C. E., Hamer, A., Bridges, I., Bartuli, A., Bergeron, J., Szamosi, T., Santra, S., Stefanutti, C., Descamps, O. S., Greber-Platzer, S., Luirink, I., Kastelein, J. J. P., Gaudet, D. <strong>Evolocumab in pediatric heterozygous familial hypercholesterolemia.</strong> New Eng. J. Med. 383: 1317-1327, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32865373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32865373</a>] [<a href="https://doi.org/10.1056/NEJMoa2019910" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32865373">Santos et al. (2020)</a> studied evolocumab, a human monoclonal antibody directed against PCSK9 (<a href="/entry/607786">607786</a>), in a 24-week, randomized, double-blind, placebo-controlled trial in 157 pediatric patients aged 10 to 17 years with heterozygous familial hypercholesterolemia. The patients had received stable lipid-lowering treatment for at least 4 weeks before screening and had an LDL cholesterol level of 130 mg per deciliter or more and a triglyceride level of 400 mg per deciliter or less. At week 24, the mean percent change from baseline in LDL cholesterol level was -44.5% in the evolocumab group (104 patients) and -6.2% in the placebo group (53 patients), for a difference of -38.3 percentage points (p less than 0.001). The absolute change in the LDL cholesterol level was -77.5 mg per deciliter (-2.0 mmol per liter) in the evolocumab group and -9.0 mg per deciliter (-0.2 mmol per liter) in the placebo group, for a difference of -68.6 mg per deciliter. Results for all secondary lipid variables were significantly better with evolocumab than with placebo, and the incidence of adverse events that occurred during the treatment period was similar in both groups. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32865373" 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="#145" class="mim-tip-reference" title="Wilson, J. M., Grossman, M., Raper, S. E., Baker, J. R., Jr., Newton, R. S., Thoene, J. G. <strong>Clinical protocol: ex vivo gene therapy of familial hypercholesterolemia.</strong> Hum. Gene Ther. 3: 179-222, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1391038/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1391038</a>] [<a href="https://doi.org/10.1089/hum.1992.3.2-179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1391038">Wilson et al. (1992)</a> presented a detailed clinical protocol for the ex vivo gene therapy of familial hypercholesterolemia. The approach, which they proposed to use to treat homozygous FH patients with symptomatic coronary artery disease who have a relatively poor prognosis but can tolerate a noncardiac surgical procedure with acceptable risks, involves recovery of hepatocytes from the patient and reimplanting them after genetic correction by a retrovirus-mediated gene transfer. Not only were the technical details of vectors and viruses, transduction and delivery of hepatocytes, evaluation of engraftment and rejection, etc., discussed, but also assessment of risks versus benefits and informed consent for both adult and child patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1391038" 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="#62" class="mim-tip-reference" title="Grossman, M., Raper, S. E., Kozarsky, K., Stein, E. A., Engelhardt, J. F., Muller, D., Lupien, P. J., Wilson, J. M. <strong>Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia.</strong> Nature Genet. 6: 335-341, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8054972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8054972</a>] [<a href="https://doi.org/10.1038/ng0494-335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8054972">Grossman et al. (1994)</a> reported a 29-year-old woman with FH caused by mutation in the LDLR gene (<a href="/entry/606945#0003">606945.0003</a>) who underwent hepatocyte-directed ex vivo gene therapy with LDLR-expressing retroviruses. She tolerated the procedures well, liver biopsy after 4 months showed engraftment of the transgene, and there was no clinical or pathologic evidence for autoimmune hepatitis. The patient showed an improvement in serum lipids up to 18 months after the treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8054972" 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>Three independent linkage studies, by <a href="#117" class="mim-tip-reference" title="Ott, J., Schrott, H. G., Goldstein, J. L., Hazzard, W. R., Allen, F. H., Falk, C. T., Motulsky, A. G. <strong>Linkage studies in a large kindred with familial hypercholesterolemia.</strong> Am. J. Hum. Genet. 26: 598-603, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4213615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4213615</a>]" pmid="4213615">Ott et al. (1974)</a>, <a href="#4" class="mim-tip-reference" title="Berg, K., Heiberg, A. <strong>Linkage studies on familial hyperlipoproteinemia with xanthomatosis: normal lipoprotein markers and the C3 polymorphism.</strong> Cytogenet. Cell Genet. 16: 266-270, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/975887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">975887</a>] [<a href="https://doi.org/10.1159/000130606" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="975887">Berg and Heiberg (1976)</a>, and <a href="#42" class="mim-tip-reference" title="Elston, R. C., Namboodiri, K. K., Go, R. C. P., Siervogel, R. M., Glueck, C. J. <strong>Probable linkage between essential familial hypercholesterolemia and third complement component (C3).</strong> Cytogenet. Cell Genet. 16: 294-297, 1976.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/975893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">975893</a>] [<a href="https://doi.org/10.1159/000130613" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="975893">Elston et al. (1976)</a>, strongly suggested loose linkage between familial hypercholesterolemia and the third component of complement; C3 (<a href="/entry/120700">120700</a>) has been mapped to chromosome 19 by somatic cell hybridization. <a href="#37" class="mim-tip-reference" title="Donald, J. A., Humphries, S. E., Tippett, P., Noades, J. E., Ball, S. <strong>Linkage relationships of familial hypercholesterolemia and chromosome 19 markers. (Abstract)</strong> Cytogenet. Cell Genet. 37: 452 only, 1984."None>Donald et al. (1984)</a> presented further data on HC-C3 linkage, bringing the combined male-female lod score to a maximum of 3.79 at theta 0.25. C3 and FHC are about 20 cM apart; APOE (<a href="/entry/107741">107741</a>) and C3 are about 15 cM apart. FHC is not closely linked to APOE, suggesting that these 2 loci are on opposite sides of C3. The LDLR gene was regionalized to 19p13.1-p13.3 by in situ hybridization (<a href="#100" class="mim-tip-reference" title="Lindgren, V., Luskey, K. L., Russell, D. W., Francke, U. <strong>Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase with cDNA probes.</strong> Proc. Nat. Acad. Sci. 82: 8567-8571, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3866240/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3866240</a>] [<a href="https://doi.org/10.1073/pnas.82.24.8567" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3866240">Lindgren et al., 1985</a>). Judging by the sequence of loci suggested by linkage data (pter--FHC--C3--APOE/APOC2), the location of FHC (LDLR) is probably 19p13.2-p13.12 and of C3, 19p13.2-p13.11. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=975893+4213615+3866240+975887" 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="#98" class="mim-tip-reference" title="Leppert, M. F., Hasstedt, S. J., Holm, T., O'Connell, P., Wu, L., Ash, O., Williams, R. R., White, R. <strong>A DNA probe for the LDL receptor gene is tightly linked to hypercholesterolemia in a pedigree with early coronary disease.</strong> Am. J. Hum. Genet. 39: 300-306, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2876626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2876626</a>]" pmid="2876626">Leppert et al. (1986)</a> found tight linkage between a RFLP of the LDL receptor gene and dominantly inherited hypercholesterolemia; specifically, no exception to cosegregation was found between high-LDL cholesterol phenotype and a unique allele at the LDLR locus. The maximum lod score was 7.52 at theta = 0. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2876626" 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 adult Dutch, Swedish, and Australian twin samples totaling 410 dizygotic twin pairs, <a href="#3" class="mim-tip-reference" title="Beekman, M., Heijmans, B. T., Martin, N. G., Whitfield, J. B., Pedersen, N. L., DeFaire, U., Snieder, H., Lakenberg, N., Suchiman, H. E. D., de Knijff, P., Frants, R. R., van Ommen, G. J. B., Kluft, C., Vogler, G. P., Boomsma, D. I., Slagboom, P. E. <strong>Evidence for a QTL on chromosome 19 influencing LDL cholesterol levels in the general population.</strong> Europ. J. Hum. Genet. 11: 845-850, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14571269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14571269</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14571269">Beekman et al. (2003)</a> found consistent evidence for linkage between chromosome 19 and LDL cholesterol levels, with maximum lod scores of 4.5, 1.7, and 2.1, respectively. No linkage was observed in an adolescent Dutch twin sample of 83 dizygotic twin pairs. Combined analysis of the adult samples increased the maximum lod to 5.7 at 60 cM from pter. <a href="#3" class="mim-tip-reference" title="Beekman, M., Heijmans, B. T., Martin, N. G., Whitfield, J. B., Pedersen, N. L., DeFaire, U., Snieder, H., Lakenberg, N., Suchiman, H. E. D., de Knijff, P., Frants, R. R., van Ommen, G. J. B., Kluft, C., Vogler, G. P., Boomsma, D. I., Slagboom, P. E. <strong>Evidence for a QTL on chromosome 19 influencing LDL cholesterol levels in the general population.</strong> Europ. J. Hum. Genet. 11: 845-850, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14571269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14571269</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14571269">Beekman et al. (2003)</a> concluded that there is strong evidence for the presence of a QTL on chromosome 19 with a major effect on LDL cholesterol levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14571269" 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="#75" class="mim-tip-reference" title="Horsthemke, B., Beisiegel, U., Dunning, A., Havinga, J. R., Williamson, R., Humphries, S. <strong>Unequal crossing-over between two Alu-repetitive DNA sequences in the low-density-lipoprotein-receptor gene: a possible mechanism for the defect in a patient with familial hypercholesterolaemia.</strong> Europ. J. Biochem. 164: 77-81, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3549308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3549308</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1987.tb10995.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3549308">Horsthemke et al. (1987)</a> analyzed DNA from 70 patients in the UK with heterozygous familial hypercholesterolemia. In most, the restriction fragment pattern of the LDLR gene was indistinguishable from the normal; however, 3 patients were found to have a deletion of about 1 kb in the central portion of the gene. In 2 patients, the deletion included all or part of exon 5 (<a href="/entry/606945#0027">606945.0027</a>); in the third, the deletion included exon 7 (<a href="/entry/606945#0033">606945.0033</a>). Including a previously described patient with a deletion in the 3-prime part of the gene, these results indicated that 4 of 70 patients, or 6%, have deletions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3549308" 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="#70" class="mim-tip-reference" title="Hobbs, H. H., Russell, D. W., Brown, M. S., Goldstein, J. L. <strong>The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein.</strong> Annu. Rev. Genet. 24: 133-170, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2088165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2088165</a>] [<a href="https://doi.org/10.1146/annurev.ge.24.120190.001025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2088165">Hobbs et al. (1990)</a> reviewed the many mutations found in the LDLR gene as the cause of familial hypercholesterolemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2088165" 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="#142" class="mim-tip-reference" title="Varret, M., Abifadel, M., Rabes, J.-P., Boileau, C. <strong>Genetic heterogeneity of autosomal dominant hypercholesterolemia.</strong> Clin. Genet. 73: 1-13, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18028451/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18028451</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00915.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18028451">Varret et al. (2008)</a> reviewed 17 published studies of autosomal dominant hypercholesterolemia and evaluated the contribution of mutations in the LDLR, APOB, and PCSK9 genes. They noted that the proportion of subjects without an identified mutation ranged from 12% to 72%, suggesting the existence of further genetic heterogeneity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18028451" 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 diagnosed with probable heterozygous FH, <a href="#13" class="mim-tip-reference" title="Bourbon, M., Sun, X.-M., Soutar, A. K. <strong>A rare polymorphism in the low density lipoprotein (LDL) gene that affects mRNA splicing.</strong> Atherosclerosis 195: e17-e20, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17335829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17335829</a>] [<a href="https://doi.org/10.1016/j.atherosclerosis.2007.01.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17335829">Bourbon et al. (2007)</a> analyzed the LDLR gene and identified a novel variant initially assumed to be a silent polymorphism (R385R; <a href="/entry/606945#0065">606945.0065</a>); however, analysis of mRNA from the patient's cells showed that the mutation introduces a new splice site predicted to cause premature termination of the protein. The R385R mutation was also found in a Chinese homozygous FH patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17335829" 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="Defesche, J. C., Schuurman, E. J. M., Klaaijsen, L. N., Khoo, K. L., Wiegman, A., Stalenhoef, A. F. H. <strong>Silent exonic mutations in the low-density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing.</strong> Clin. Genet. 73: 573-578, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18400033/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18400033</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.00999.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18400033">Defesche et al. (2008)</a> analyzed the LDLR gene in 1,350 patients clinically diagnosed with familial hypercholesterolemia who were negative for functional DNA variation in the LDLR, APOB (<a href="/entry/107730">107730</a>), and PCSK9 (<a href="/entry/607786">607786</a>) genes. The authors examined the effects of 128 seemingly neutral exonic and intronic DNA variants and identified 2 synonymous variants in LDLR, R385R and G186G (<a href="/entry/606945#0066">606945.0066</a>), that clearly affected splice sites and segregated with hypercholesterolemia in all families examined. The R385R variant was found in 2 probands of Chinese origin, whereas G186G was found in 35 Dutch probands, 2 of whom were homozygous for the variant and had a more severe phenotype, with myocardial infarction occurring in both before the age of 20 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18400033" 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="#94" class="mim-tip-reference" title="Kulseth, M. A., Berge, K. E., Bogsrud, M. P., Leren, T. P. <strong>Analysis of LDLR mRNA in patients with familial hypercholesterolemia revealed a normal mutation in intron 14, which activates a cryptic splice site.</strong> J. Hum. Genet. 55: 676-680, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20703241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20703241</a>] [<a href="https://doi.org/10.1038/jhg.2010.87" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20703241">Kulseth et al. (2010)</a> performed RNA analysis in 30 unrelated patients with clinically defined hypercholesterolemia but without any LDLR mutations detected by standard DNA analysis; sequencing of RT-PCR products from an index patient revealed an insertion of 81 bp from the 5-prime end of intron 14 of LDLR, and DNA sequencing of exons 13 and 14 detected an splice site mutation in intron 14 (<a href="/entry/606945#0067">606945.0067</a>). Twelve of 23 family members tested were heterozygous for the mutation, and carriers had significantly increased total cholesterol levels compared to noncarriers. <a href="#94" class="mim-tip-reference" title="Kulseth, M. A., Berge, K. E., Bogsrud, M. P., Leren, T. P. <strong>Analysis of LDLR mRNA in patients with familial hypercholesterolemia revealed a normal mutation in intron 14, which activates a cryptic splice site.</strong> J. Hum. Genet. 55: 676-680, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20703241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20703241</a>] [<a href="https://doi.org/10.1038/jhg.2010.87" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20703241">Kulseth et al. (2010)</a> analyzed an additional 550 index patients and identified the same splice site mutation in 3 more probands. In 1 proband's family, the mutation was found in 6 of 7 tested family members, who all had LDL cholesterol levels above the 97th percentile. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20703241" 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="#36" class="mim-tip-reference" title="Do, R., Stitziel, N. O., Won, H.-H., Berg Jorgensen, A., Duga, S., Merlini, P. A., Kiezun, A., Farrall, M., Goel, A., Zuk, O., Guella, I., Asselta, R., and 82 others. <strong>Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.</strong> Nature 518: 102-106, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25487149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25487149</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25487149[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature13917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25487149">Do et al. (2015)</a> sequenced the protein-coding regions of 9,793 genomes from patients with myocardial infarction (MI) at an early age (50 years or younger in males and 60 years or younger in females) along with MI-free controls. They identified 2 genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exomewide significance: LDLR (<a href="/entry/606945">606945</a>) and APOA5 (<a href="/entry/606368">606368</a>). Carriers of rare nonsynonymous mutations in LDLR were at 4.2-fold increased risk for MI, while carriers of null alleles in LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbor a rare, damaging mutation in LDLR; this estimate is similar to one made by <a href="#61" class="mim-tip-reference" title="Goldstein, J. L., Schrott, H. G., Hazzard, W. R., Bierman, E. L., Motulsky, A. G. <strong>Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia.</strong> J. Clin. Invest. 52: 1544-1568, 1973.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4718953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4718953</a>] [<a href="https://doi.org/10.1172/JCI107332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4718953">Goldstein et al. (1973)</a> using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol greater than 190 mg/dl. Carriers of rare nonsynonymous mutations in APOA5 were at 2.2-fold increased risk for MI. When compared with noncarriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides (see <a href="/entry/145750">145750</a>). Evidence has connected MI risk with coding-sequence mutations at 2 genes functionally related to APOA5, namely lipoprotein lipase (LPL; <a href="/entry/609708">609708</a>) and apolipoprotein C-III (APOC3; <a href="/entry/107720">107720</a>). <a href="#36" class="mim-tip-reference" title="Do, R., Stitziel, N. O., Won, H.-H., Berg Jorgensen, A., Duga, S., Merlini, P. A., Kiezun, A., Farrall, M., Goel, A., Zuk, O., Guella, I., Asselta, R., and 82 others. <strong>Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.</strong> Nature 518: 102-106, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25487149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25487149</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25487149[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature13917" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25487149">Do et al. (2015)</a> concluded that LDL cholesterol as well as disordered metabolism of triglyceride-rich lipoproteins contributes to myocardial infarction risk. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4718953+25487149" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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A SNP in the promoter region of the G-substrate gene (GSBS; <a href="/entry/604088#0001">604088.0001</a>) correlated with elevated plasma total cholesterol levels.</p><p>A SNP in intron 17 of the ITIH4 gene (<a href="/entry/600564#0001">600564.0001</a>) was associated with hypercholesterolemia susceptibility in a Japanese population.</p>
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<p><a href="#52" class="mim-tip-reference" title="Goldstein, J. L., Brown, M. S., Stone, N. J. <strong>Genetics of the LDL receptor: evidence that the mutations affecting binding and internalization are allelic.</strong> Cell 12: 629-641, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/200368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">200368</a>] [<a href="https://doi.org/10.1016/0092-8674(77)90263-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="200368">Goldstein et al. (1977)</a> found that both receptor-absent and receptor-defective mutants occur and they concluded that some of the 'homozygotes' are in fact genetic compounds. An internalization mutant of the LDL receptor binds LDL but is unable to facilitate passage of LDL to the inside of the cell. A patient was found to be a genetic compound, having inherited the internalization mutant from the father and the binding mutant from the mother. From the fact that an individual was shown by family studies to be a genetic compound and that complementation did not occur, <a href="#52" class="mim-tip-reference" title="Goldstein, J. L., Brown, M. S., Stone, N. J. <strong>Genetics of the LDL receptor: evidence that the mutations affecting binding and internalization are allelic.</strong> Cell 12: 629-641, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/200368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">200368</a>] [<a href="https://doi.org/10.1016/0092-8674(77)90263-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="200368">Goldstein et al. (1977)</a> concluded that the gene for binding of LDL and the gene for internalization of LDL are allelic mutations at the structural locus for the LDL receptor. <a href="#113" class="mim-tip-reference" title="Miyake, Y., Tajima, S., Yamamura, T., Yamamoto, A. <strong>Homozygous familial hypercholesterolemia mutant with a defect in internalization of low density lipoprotein.</strong> Proc. Nat. Acad. Sci. 78: 5151-5155, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6272292/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6272292</a>] [<a href="https://doi.org/10.1073/pnas.78.8.5151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6272292">Miyake et al. (1981)</a> found homozygosity for the internalization defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=200368+6272292" 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 LDL receptor is synthesized as a 120-kD glycoprotein precursor that undergoes change to a 160-kD mature glycoprotein through the covalent addition of a 40-kD protein. <a href="#137" class="mim-tip-reference" title="Tolleshaug, H., Goldstein, J. L., Schneider, W. J., Brown, M. S. <strong>Posttranslational processing of the LDL receptor and its genetic disruption in familial hypercholesterolemia.</strong> Cell 30: 715-724, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6291781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6291781</a>] [<a href="https://doi.org/10.1016/0092-8674(82)90276-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6291781">Tolleshaug et al. (1982)</a> reported a heterozygous child who inherited one allele from his mother which produced an abnormal 120-kD protein that could not be further processed, and one allele from his father which produced an elongated 170-kD precursor that underwent an increase in molecular weight to form an abnormally large receptor of 210 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6291781" 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="#99" class="mim-tip-reference" title="Levy, R. A., Ostlund, R. E., Jr., Semenkovich, C. F., Witztum, J. L. <strong>Diversity in expression of heterozygous familial hypercholesterolemia: characterization of a unique kindred.</strong> J. Clin. Invest. 78: 96-101, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3722389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3722389</a>] [<a href="https://doi.org/10.1172/JCI112579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3722389">Levy et al. (1986)</a> reported 2 brothers with a unique genetic compound form of 'homozygous' hypercholesterolemia in which the mother had typical FHC and the father and 3 of his close relatives had what they termed the HMWR (high molecular weight receptor) trait. In these persons 2 types of functional LDL receptors were found in cultured skin fibroblasts: one with molecular weight of 140,000 and one with molecular weight of 176,000. Curiously and puzzlingly, the compound heterozygotes and the regular heterozygotes for the HMWR showed increased cholesterol synthesis, which the authors suggested may play a significant role in the pathology of the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3722389" 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="#49" class="mim-tip-reference" title="Funahashi, T., Miyake, Y., Yamamoto, A., Matsuzawa, Y., Kishino, B. <strong>Mutations of the low density lipoprotein receptor in Japanese kindreds with familial hypercholesterolemia.</strong> Hum. Genet. 79: 103-108, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3391611/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3391611</a>] [<a href="https://doi.org/10.1007/BF00280546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3391611">Funahashi et al. (1988)</a> studied 16 Japanese kindreds with homozygous FHC. Ten had a receptor-negative form of the disease; 5 had a receptor-defective form; and 1 represented an internalization defect. The receptor-defective group, in which residual amounts of functional receptors were produced, showed a lower tendency to coronary artery disease than the receptor-negative group. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3391611" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Modifiers</em></strong></p><p>
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<a href="#44" class="mim-tip-reference" title="Feussner, G., Dobmeyer, J., Nissen, H., Hansen, T. S. <strong>Unusual Xanthomas in a young patient with heterozygous familial hypercholesterolemia and type III hyperlipoproteinemia.</strong> Am. J. Med. Genet. 65: 149-154, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8911609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8911609</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19961016)65:2<149::AID-AJMG14>3.0.CO;2-Q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8911609">Feussner et al. (1996)</a> described a 20-year-old man with a combination of heterozygous FH caused by splice mutation (<a href="/entry/606945#0054">606945.0054</a>) and type III hyperlipoproteinemia (<a href="/entry/107741">107741</a>). He presented with multiple xanthomas of the elbows, interphalangeal joints and interdigital webs of the hands. Active lipid-lowering therapy caused regression of the xanthomas and significant decrease of cholesterol and triglycerides. Flat xanthomas of the interdigital webs were described in 3 of 4 formerly reported patients with a combination of these disorders of lipoprotein metabolism. <a href="#44" class="mim-tip-reference" title="Feussner, G., Dobmeyer, J., Nissen, H., Hansen, T. S. <strong>Unusual Xanthomas in a young patient with heterozygous familial hypercholesterolemia and type III hyperlipoproteinemia.</strong> Am. J. Med. Genet. 65: 149-154, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8911609/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8911609</a>] [<a href="https://doi.org/10.1002/(SICI)1096-8628(19961016)65:2<149::AID-AJMG14>3.0.CO;2-Q" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8911609">Feussner et al. (1996)</a> proposed that the presence of these xanthomas should suggest compound heterozygosity (actually double heterozygosity) for FH and type III hyperlipoproteinemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8911609" 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="#123" class="mim-tip-reference" title="Sass, C., Giroux, L.-M., Ma, Y., Roy, M., Lavigne, J., Lussier-Cacan, S., Davignon, J., Minnich, A. <strong>Evidence for a cholesterol-lowering gene in a French-Canadian kindred with familial hypercholesterolemia.</strong> Hum. Genet. 96: 21-26, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7607649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7607649</a>] [<a href="https://doi.org/10.1007/BF00214181" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7607649">Sass et al. (1995)</a> described a 4-generation French-Canadian kindred with familial hypercholesterolemia in which 2 of the 8 heterozygotes for a 5-kb deletion (exons 2 and 3) in the LDLR gene were found to have normal LDL-cholesterol levels. Analyses showed that it was unlikely that variation in the genes encoding apolipoprotein B (<a href="/entry/107730">107730</a>), HMG-CoA reductase (HMGCR; <a href="/entry/142910">142910</a>), apoAI-CIII-AIV (see APOA1; <a href="/entry/107680">107680</a>), or lipoprotein lipase was responsible for the cholesterol-lowering effect. Expression of the LDL receptor, as assessed in vitro with measurements of activity and mRNA levels, was similar in normolipidemic and hyperlipidemic subjects carrying the deletion. Analysis of the apoE isoforms (<a href="/entry/107741">107741</a>), on the other hand, revealed that most of the E2 allele carriers in this family, including the 2 normolipidemic 5-kb deletion carriers, had LDL cholesterol levels substantially lower than subjects with the other apoE isoforms. Thus, this kindred provided evidence for the existence of a gene or genes, including the apoE2 allele, with profound effects on LDL-cholesterol levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7607649" 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="#143" class="mim-tip-reference" title="Vergopoulos, A., Bajari, T., Jouma, M., Knoblauch, H., Aydin, A., Bahring, S., Mueller-Myhsok, B., Dresel, A., Joubran, R., Luft, F. C., Schuster, H. <strong>A xanthomatosis-susceptibility gene may exist in a Syrian family with familial hypercholesterolemia.</strong> Europ. J. Hum. Genet. 5: 315-323, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9412789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9412789</a>]" pmid="9412789">Vergopoulos et al. (1997)</a> presented findings suggesting the existence of a xanthomatosis susceptibility gene in a consanguineous Syrian kindred containing 6 individuals with homozygous FH (see <a href="/entry/602247">602247</a>). Half of the homozygotes had giant xanthomas, while half did not, even though their LDL-cholesterol concentrations were elevated to similar degrees (more than 14 mmol/l). Heterozygous FH individuals in this family were also clearly distinguishable with respect to xanthoma size. By DNA analysis they identified a hitherto undescribed mutation in the LDLR gene in this family: a T-to-C transition at nucleotide 1999 in codon 646 of exon 14, resulting in an arginine for cysteine substitution. Segregation analysis suggested that a separate susceptibility gene may explain the formation of giant xanthomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9412789" 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 13-year-old girl with severe hypercholesterolemia, <a href="#40" class="mim-tip-reference" title="Ekstrom, U., Abrahamson, M., Floren, C.-H., Tollig, H., Wettrell, G., Nilsson, G., Sun, X.-M., Soutar, A. K., Nilsson-Ehle, P. <strong>An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F).</strong> Clin. Genet. 55: 332-339, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10422803/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10422803</a>] [<a href="https://doi.org/10.1034/j.1399-0004.1999.550506.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10422803">Ekstrom et al. (1999)</a> demonstrated compound heterozygosity for a cys240-to-phe mutation (<a href="/entry/606945#0059">606945.0059</a>) and a tyr167-to-ter mutation (<a href="/entry/606945#0045">606945.0045</a>) in the LDLR gene. Her 2 heterozygous sibs also carried the C240F mutation, but only one of them was hypercholesterolemic. The authors concluded that there may be cholesterol-lowering mechanisms that are activated by mutations in other genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10422803" 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="#90" class="mim-tip-reference" title="Knoblauch, H., Muller-Myhsok, B., Busjahn, A., Ben Avi, L., Bahring, S., Baron, H., Heath, S. C., Uhlmann, R., Faulhaber, H.-D., Shpitzen, S., Aydin, A., Reshef, A., and 11 others. <strong>A cholesterol-lowering gene maps to chromosome 13q.</strong> Am. J. Hum. Genet. 66: 157-166, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10631147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10631147</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10631147[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/10.1086/302704" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10631147">Knoblauch et al. (2000)</a> studied an Arab family that carried the tyr807-to-cys substitution (<a href="/entry/606945#0019">606945.0019</a>). In this family, some heterozygous persons had normal LDL levels, while some homozygous individuals had LDL levels similar to those persons with heterozygous FH. The authors presented evidence for the existence of a cholesterol-lowering gene on 13q (<a href="/entry/604595">604595</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10631147" 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="#134" class="mim-tip-reference" title="Takada, D., Emi, M., Ezura, Y., Nobe, Y., Kawamura, K., Iino, Y., Katayama, Y., Xin, Y., Wu, L. L., Larringa-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. N. <strong>Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred.</strong> J. Hum. Genet. 47: 656-664, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522687</a>] [<a href="https://doi.org/10.1007/s100380200101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522687">Takada et al. (2002)</a> demonstrated that a SNP of the promoter of the APOA2 gene, -265T-C (<a href="/entry/107670#0002">107670.0002</a>), influenced the level of total cholesterol and low density lipoprotein (LDL) cholesterol in members with the IVS14+1G-A mutation (<a href="/entry/606945#0063">606945.0063</a>) in the LDLR gene causing hypercholesterolemia. Strikingly lower total cholesterol and LDL cholesterol values were observed among most of the LDLR mutation carriers who were simultaneously homozygous for the -265C allele of the APOA2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12522687" 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 the same large family reported by <a href="#134" class="mim-tip-reference" title="Takada, D., Emi, M., Ezura, Y., Nobe, Y., Kawamura, K., Iino, Y., Katayama, Y., Xin, Y., Wu, L. L., Larringa-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. N. <strong>Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred.</strong> J. Hum. Genet. 47: 656-664, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522687</a>] [<a href="https://doi.org/10.1007/s100380200101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522687">Takada et al. (2002)</a>, <a href="#135" class="mim-tip-reference" title="Takada, D., Ezura, Y., Ono, S., Iino, Y., Katayama, Y., Xin, Y., Wu, L. L., Larringa-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. M., Emi, M. <strong>Growth hormone receptor variant (L526I) modifies plasma HDL cholesterol phenotype in familial hypercholesterolemia: intra-familial association study in an eight-generation hyperlipidemic kindred.</strong> Am. J. Med. Genet. 121A: 136-140, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12910492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12910492</a>] [<a href="https://doi.org/10.1002/ajmg.a.20172" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12910492">Takada et al. (2003)</a> found that a SNP in the GHR gene, resulting in a L526I (<a href="/entry/600946#0028">600946.0028</a>) substitution, influenced plasma levels of high density lipoprotein (HDL) cholesterol in affected family members with the IVS14+1G-A mutation. The lowest levels of plasma HDL were observed among leu/leu homozygotes, highest levels among ile/ile homozygotes, and intermediate levels among leu/ile heterozygotes. No such effect was observed among noncarriers of the LDLR mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12910492+12522687" 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 the pedigree reported by <a href="#134" class="mim-tip-reference" title="Takada, D., Emi, M., Ezura, Y., Nobe, Y., Kawamura, K., Iino, Y., Katayama, Y., Xin, Y., Wu, L. L., Larringa-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. N. <strong>Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred.</strong> J. Hum. Genet. 47: 656-664, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12522687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12522687</a>] [<a href="https://doi.org/10.1007/s100380200101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12522687">Takada et al. (2002)</a>, <a href="#124" class="mim-tip-reference" title="Sato, K., Emi, M., Ezura, Y., Fujita, Y., Takada, D., Ishigami, T., Umemura, S., Xin, Y., Wu, L. L., Larrinaga-Shum, S., Stephenson, S. H., Hunt, S. C., Hopkins, P. N. <strong>Soluble epoxide hydrolase variant (glu287arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred.</strong> J. Hum. Genet. 49: 29-34, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14673705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14673705</a>] [<a href="https://doi.org/10.1007/s10038-003-0103-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14673705">Sato et al. (2004)</a> demonstrated a significant modification of the phenotype of familial hypercholesterolemia resulting from the IVS14+1G-A mutation by the arg287 variation in the EPHX2 gene (<a href="/entry/132811#0001">132811.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14673705+12522687" 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>In most populations the frequency of the homozygote is 1 in a million (probably a minimal estimate, being a prevalence figure rather than incidence at birth) and the frequency of heterozygotes not less than 1 in 500. Thus, heterozygous familial hypercholesterolemia is the most frequent mendelian disorder, being more frequent than either cystic fibrosis or sickle cell anemia which, in different populations, are often given that distinction. Among survivors of myocardial infarction, the frequency of heterozygotes is about 1 in 20.</p><p><a href="#128" class="mim-tip-reference" title="Seftel, H. C., Baker, S. G., Sandler, M. P., Forman, M. B., Joffe, B. I., Mendelsohn, D., Jenkins, T., Mieny, C. J. <strong>A host of hypercholesterolaemic homozygotes in South Africa.</strong> Brit. Med. J. 281: 633-636, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7437743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7437743</a>] [<a href="https://doi.org/10.1136/bmj.281.6241.633" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7437743">Seftel et al. (1980)</a> pointed to a high frequency of hypercholesterolemic homozygotes in South Africa. In a 7-year period, 34 homozygotes were seen in one clinic in Johannesburg. All were Afrikaners and most lived in Transvaal Province. The authors calculated the frequency of heterozygotes and homozygotes to be 1 in 100 and 1 in 30,000, respectively. The oldest of their patients was a 46-year-old woman. Of the 34, six were age 30 or older. The authors concluded that the high frequency of the gene is attributable to founder effect, as in the case of porphyria variegata (<a href="/entry/176200">176200</a>), lipoid proteinosis (<a href="/entry/247100">247100</a>), and sclerosteosis (<a href="/entry/269500">269500</a>). <a href="#140" class="mim-tip-reference" title="Torrington, M., Botha, J. L. <strong>Familial hypercholesterolaemia and church affiliation. (Letter)</strong> Lancet 318: 1120 only, 1981. Note: Originally Volume II.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6118572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6118572</a>] [<a href="https://doi.org/10.1016/s0140-6736(81)91330-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6118572">Torrington and Botha (1981)</a> found that 20 of 26 families with FHC (77%) belonged to the Gereformeerde Kerk, whereas according to the 1970 census only 5% of the Afrikaans-speaking white population of South Africa belonged to this religious group. Again, the data were consistent with a founder effect. Using the LDLR activity of lymphocytes, <a href="#131" class="mim-tip-reference" title="Steyn, K., Weight, M. J., Dando, B. R., Christopher, K. J., Rossouw, J. E. <strong>The use of low density lipoprotein receptor activity of lymphocytes to determine the prevalence of familial hypercholesterolaemia in a rural South African community.</strong> J. Med. Genet. 26: 32-36, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2918524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2918524</a>] [<a href="https://doi.org/10.1136/jmg.26.1.32" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2918524">Steyn et al. (1989)</a> calculated the prevalence of heterozygous FHC in the permanent residents of a predominantly Afrikaans-speaking community in South Africa to be 1 in 71--the highest prevalence reported to date. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6118572+7437743+2918524" 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 the Saguenay-Lac-Saint-Jean region of Quebec Province, <a href="#29" class="mim-tip-reference" title="De Braekeleer, M. <strong>Hereditary disorders in Saguenay-Lac-St-Jean (Quebec, Canada).</strong> Hum. Hered. 41: 141-146, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1937486/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1937486</a>] [<a href="https://doi.org/10.1159/000153992" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1937486">De Braekeleer (1991)</a> estimated the prevalence of familial hypercholesterolemia as 1/122, compared to the usually used frequency of 1/500 for European populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1937486" 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="#32" class="mim-tip-reference" title="Defesche, J. C., Kastelein, J. J. P. <strong>Molecular epidemiology of familial hypercholesterolaemia. (Letter)</strong> Lancet 352: 1643-1644, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9853432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9853432</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)61443-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9853432">Defesche and Kastelein (1998)</a> stated that more than 350 different mutations had been found in patients with familial hypercholesterolemia. They tabulated the preferential geographic distribution that has been demonstrated for some of the LDL receptor mutations. For example, in the West of Scotland about half of the index cases of FH were found to have the cys163-to-tyr mutation (<a href="/entry/606945#0058">606945.0058</a>). <a href="#32" class="mim-tip-reference" title="Defesche, J. C., Kastelein, J. J. P. <strong>Molecular epidemiology of familial hypercholesterolaemia. (Letter)</strong> Lancet 352: 1643-1644, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9853432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9853432</a>] [<a href="https://doi.org/10.1016/S0140-6736(05)61443-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9853432">Defesche and Kastelein (1998)</a> commented on the geographic associations of LDL receptor mutations within the Netherlands. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9853432" 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>Deletion of gly197 (<a href="/entry/606945#0005">606945.0005</a>) is the most prevalent LDL receptor mutation causing familial hypercholesterolemia in Ashkenazi Jewish individuals. Studying index cases from Israel, South Africa, Russia, the Netherlands, and the United States, <a href="#38" class="mim-tip-reference" title="Durst, R., Colombo, R., Shpitzen, S., Ben Avi, L., Friedlander, Y., Wexler, R., Raal, F. J., Marais, D. A., Defesche, J. C., Mandelshtam, M. Y., Kotze, M. J., Leitersdorf, E., Meiner, V. <strong>Recent origin and spread of a common Lithuanian mutation, G197del LDLR, causing familial hypercholesterolemia: positive selection is not always necessary to account for disease incidence among Ashkenazi Jews.</strong> Am. J. Hum. Genet. 68: 1172-1188, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309683</a>] [<a href="https://doi.org/10.1086/320123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11309683">Durst et al. (2001)</a> found that all traced their ancestry to Lithuania. A highly conserved haplotype was identified in chromosomes carrying this deletion, suggesting a common founder. When 2 methods were used for analysis of linkage disequilibrium between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the deletion was found to be 20 +/- 7 generations, so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 14th century. This corresponds with the founding of the Jewish community of Lithuania (1338 A.D.), as well as with the great demographic expansion of Ashkenazi Jewish individuals in eastern Europe, which followed this settlement. <a href="#38" class="mim-tip-reference" title="Durst, R., Colombo, R., Shpitzen, S., Ben Avi, L., Friedlander, Y., Wexler, R., Raal, F. J., Marais, D. A., Defesche, J. C., Mandelshtam, M. Y., Kotze, M. J., Leitersdorf, E., Meiner, V. <strong>Recent origin and spread of a common Lithuanian mutation, G197del LDLR, causing familial hypercholesterolemia: positive selection is not always necessary to account for disease incidence among Ashkenazi Jews.</strong> Am. J. Hum. Genet. 68: 1172-1188, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11309683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11309683</a>] [<a href="https://doi.org/10.1086/320123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11309683">Durst et al. (2001)</a> could find no evidence supporting a selective evolutionary metabolic advantage. Therefore, the founder effect in a rapidly expanding population from a limited number of families remains a simple, parsimonious hypothesis explaining the spread of this mutation in Ashkenazi Jewish individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11309683" 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="#87" class="mim-tip-reference" title="Kingsley, D. M., Krieger, M. <strong>Receptor-mediated endocytosis of low density lipoprotein: somatic cell mutants define multiple genes required for expression of surface-receptor activity.</strong> Proc. Nat. Acad. Sci. 81: 5454-5458, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6089204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6089204</a>] [<a href="https://doi.org/10.1073/pnas.81.17.5454" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6089204">Kingsley and Krieger (1984)</a> identified 4 different types of mutant Chinese hamster ovary cells with defective LDL receptor function. One locus, called ldlA, apparently represents the structural gene for LDL receptor, whereas the others--ldlB, ldlC, and ldlD--appear to have defects involved in either regulation, synthesis, transport, recycling, or turnover of LDL receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6089204" 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 Watanabe heritable hyperlipidemic (WHHL) rabbit has a genetic deficiency of LDL receptors and is therefore a superb experimental model (<a href="#74" class="mim-tip-reference" title="Hornick, C. A., Kita, T., Hamilton, R. L., Kane, J. P., Havel, R. J. <strong>Secretion of lipoproteins from the liver of normal and Watanabe heritable hyperlipidemic rabbits.</strong> Proc. Nat. Acad. Sci. 80: 6096-6100, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6577469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6577469</a>] [<a href="https://doi.org/10.1073/pnas.80.19.6096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6577469">Hornick et al., 1983</a>). <a href="#88" class="mim-tip-reference" title="Kita, T., Nagano, Y., Yokode, M., Ishii, K., Kume, N., Ooshima, A., Yoshida, H., Kawai, C. <strong>Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbits, an animal model for familial hypercholesterolemia.</strong> Proc. Nat. Acad. Sci. 84: 5928-5931, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3475709/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3475709</a>] [<a href="https://doi.org/10.1073/pnas.84.16.5928" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3475709">Kita et al. (1987)</a> found that probucol prevented the progression of atherosclerosis in the Watanabe rabbit by limiting oxidative LDL modification and foam cell transformation of macrophages. Probucol was originally developed as an antioxidant. <a href="#146" class="mim-tip-reference" title="Yamamoto, T., Bishop, R. W., Brown, M. S., Goldstein, J. L., Russell, D. W. <strong>Deletion in cysteine-rich region of LDL receptor impedes transport to cell surface in WHHL rabbit.</strong> Science 232: 1230-1237, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3010466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3010466</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=3010466[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/10.1126/science.3010466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3010466">Yamamoto et al. (1986)</a> showed that the defect in the Watanabe heritable hyperlipidemic rabbit is a mutant receptor for LDL that is not transported to the cell surface at a normal rate. Cloning and sequencing of complementary cDNAs from normal and Watanabe rabbits showed that the defect arises from an in-frame deletion of 12 nucleotides that eliminates 4 amino acids from the cysteine-rich ligand binding domain of the LDL receptor. <a href="#146" class="mim-tip-reference" title="Yamamoto, T., Bishop, R. W., Brown, M. S., Goldstein, J. L., Russell, D. W. <strong>Deletion in cysteine-rich region of LDL receptor impedes transport to cell surface in WHHL rabbit.</strong> Science 232: 1230-1237, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3010466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3010466</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=3010466[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/10.1126/science.3010466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3010466">Yamamoto et al. (1986)</a> detected a similar mutation by S1 nuclease mapping of LDL receptor mRNA from a patient with familial hypercholesterolemia whose receptor also failed to be transported to the cell surface. These findings suggested to <a href="#146" class="mim-tip-reference" title="Yamamoto, T., Bishop, R. W., Brown, M. S., Goldstein, J. L., Russell, D. W. <strong>Deletion in cysteine-rich region of LDL receptor impedes transport to cell surface in WHHL rabbit.</strong> Science 232: 1230-1237, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3010466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3010466</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=3010466[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/10.1126/science.3010466" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3010466">Yamamoto et al. (1986)</a> that animal cells may have fail-safe mechanisms that prevent surface expression of improperly folded proteins with unpaired or improperly bonded cysteine residues. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6577469+3475709+3010466" 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="#125" class="mim-tip-reference" title="Scanu, A. M., Khalil, A., Neven, L., Tidore, M., Dawson, G., Pfaffinger, D., Jackson, E., Carey, K. D., McGill, H. C., Fless, G. M. <strong>Genetically determined hypercholesterolemia in a rhesus monkey family due to a deficiency of the LDL receptor.</strong> J. Lipid Res. 29: 1671-1681, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3244017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3244017</a>]" pmid="3244017">Scanu et al. (1988)</a> investigated hypercholesterolemia due to deficiency of the LDL receptor in a family of rhesus monkeys. <a href="#79" class="mim-tip-reference" title="Hummel, M., Li, Z., Pfaffinger, D., Neven, L., Scanu, A. M. <strong>Familial hypercholesterolemia in a rhesus monkey pedigree: molecular basis of low density lipoprotein receptor deficiency.</strong> Proc. Nat. Acad. Sci. 87: 3122-3126, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2326270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2326270</a>] [<a href="https://doi.org/10.1073/pnas.87.8.3122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2326270">Hummel et al. (1990)</a> used PCR to analyze the mutation carried by members of a family of rhesus monkeys with spontaneous hypercholesterolemia and low density lipoprotein receptor deficiency. Affected monkeys are heterozygous for a nonsense mutation in exon 6, changing codon 284 from TGG to TAG. The G-to-A transition creates a new SpeI restriction site. LDLR RNA is reduced by about 50% on quantitative analysis of RNA obtained at liver biopsy in affected animals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2326270+3244017" 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="#73" class="mim-tip-reference" title="Hofmann, S. L., Russell, D. W., Brown, M. S., Goldstein, J. L., Hammer, R. E. <strong>Overexpression of low density lipoprotein (LDL) receptor eliminates LDL from plasma in transgenic mice.</strong> Science 239: 1277-1281, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3344433/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3344433</a>] [<a href="https://doi.org/10.1126/science.3344433" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3344433">Hofmann et al. (1988)</a> found that overexpression of LDL receptors caused elimination of both apoE and apoB, the 2 ligands, from the plasma in transgenic mice derived from fertilized eggs injected with the LDLR gene under control of the mouse metallothionein-I promoter. They speculated that overexpression of other receptors, such as those for insulin (<a href="/entry/147670">147670</a>) or transferrin (<a href="/entry/190000">190000</a>), might have pathologic effects leading to a 'ligand steal' syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3344433" 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="#25" class="mim-tip-reference" title="Chowdhury, J. R., Grossman, M., Gupta, S., Chowdhury, N. R., Baker, J. R., Jr., Wilson, J. M. <strong>Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits.</strong> Science 254: 1802-1805, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1722351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1722351</a>] [<a href="https://doi.org/10.1126/science.1722351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1722351">Chowdhury et al. (1991)</a> used the Watanabe rabbit for the development of liver-directed gene therapy based on transplantation of autologous hepatocytes that had been genetically corrected ex vivo with recombinant retroviruses. Animals transplanted with LDLR-transduced autologous hepatocytes demonstrated a 30 to 50% decrease in total serum cholesterol that persisted for the duration of the experiment (122 days). Recombinant-derived LDLR RNA was harvested from tissues with no diminution for up to 6.5 months after transplantation. <a href="#83" class="mim-tip-reference" title="Ishibashi, S., Brown, M. S., Goldstein, J. L., Hammer, R. E. <strong>Hypercholesterolemia in LDL receptor knockout mice and its reversal by adenovirus-mediated gene delivery.</strong> J. Clin. Invest. 92: 883-893, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8349823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8349823</a>] [<a href="https://doi.org/10.1172/JCI116663" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8349823">Ishibashi et al. (1993)</a> developed a new animal model for homozygous FH through targeted disruption of the LDLR gene in mice. Homozygous LDL receptor-deficient mice showed delayed clearance of VLDL, intermediate density lipoproteins (IDL), and LDL from plasma. As a result, total plasma cholesterol level rose from 108 mg/dl in wildtype mice to 236 mg/dl in homozygous deficient mice. Adult mice did not exhibit gross evidence of xanthomatosis, however, and the extent of aortic atherosclerosis was minimal. On the other hand, <a href="#84" class="mim-tip-reference" title="Ishibashi, S., Goldstein, J. L., Brown, M. S., Herz, J., Burns, D. K. <strong>Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice.</strong> J. Clin. Invest. 93: 1885-1893, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8182121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8182121</a>] [<a href="https://doi.org/10.1172/JCI117179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8182121">Ishibashi et al. (1994)</a> showed that in mice homozygous for the targeted disruption of the LDLR gene who were fed a diet high in cholesterol, total plasma cholesterol rose from 246 to more than 1,500 mg/dl. In wildtype littermates fed the same diet, total plasma cholesterol remained less than 160 mg/dl. After 7 months, the homozygous deficient mice developed massive xanthomatous infiltration of the skin and subcutaneous tissue. The aorta and coronary ostia exhibited gross atheromata, and the aortic valve leaflets were thickened by cholesterol-laden macrophages. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8182121+1722351+8349823" 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>Mice homozygous for targeted replacement with human APOE2 (<a href="/entry/107741#0001">107741.0001</a>), regardless of age or gender, develop type III hyperlipoproteinemia, whereas homozygosity for APOE2 results in HLP in no more than 10% in humans, predominantly in adult males. By generating mice homozygous for human APOE2 and heterozygous for human LDLR and mouse Ldlr, <a href="#91" class="mim-tip-reference" title="Knouff, C., Malloy, S., Wilder, J., Altenburg, M. K., Maeda, N. <strong>Doubling expression of the low density lipoprotein receptor by truncation of the 3-prime-untranslated region sequence ameliorates type III hyperlipoproteinemia in mice expressing the Human ApoE2 isoform.</strong> J. Biol. Chem. 276: 3856-3862, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11076954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11076954</a>] [<a href="https://doi.org/10.1074/jbc.M009423200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11076954">Knouff et al. (2001)</a> achieved increased stability of mRNA in liver associated with a truncation of the 3-prime-UTR of LDLR. Plasma lipoprotein levels were normal in the LDLR heterozygotes. <a href="#91" class="mim-tip-reference" title="Knouff, C., Malloy, S., Wilder, J., Altenburg, M. K., Maeda, N. <strong>Doubling expression of the low density lipoprotein receptor by truncation of the 3-prime-untranslated region sequence ameliorates type III hyperlipoproteinemia in mice expressing the Human ApoE2 isoform.</strong> J. Biol. Chem. 276: 3856-3862, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11076954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11076954</a>] [<a href="https://doi.org/10.1074/jbc.M009423200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11076954">Knouff et al. (2001)</a> concluded that moderate and controlled overexpression of LDLR completely ameliorates the type III HLP phenotype of APOE2 homozygous mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11076954" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#65" class="mim-tip-reference" title="Hasty, A. H., Shimano, H., Osuga, J., Namatame, I., Takahashi, A., Yahagi, N., Perrey, S., Iizuka, Y., Tamura, Y., Amemiya-Kudo, M., Yoshikawa, T., Okazaki, H., Ohashi, K., Harada, K., Matsuzaka, T., Sone, H., Gotoda, T., Nagai, R., Ishibashi, S., Yamada, N. <strong>Severe hypercholesterolemia, hypertriglyceridemia, and atherosclerosis in mice lacking both leptin and the low density lipoprotein receptor.</strong> J. Biol. Chem. 276: 37402-37408, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11445560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11445560</a>] [<a href="https://doi.org/10.1074/jbc.M010176200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11445560">Hasty et al. (2001)</a> generated mice deficient in both the low density lipoprotein receptor and leptin (ob/ob). These doubly mutant mice exhibited striking elevations in both total plasma cholesterol and triglyceride levels and had extensive atherosclerotic lesions throughout the aorta by 6 months of age. Although fasting, diet restriction, and low-level leptin treatment significantly lowered total plasma triglyceride levels, they caused only slight changes in total plasma cholesterol levels. Hepatic cholesterol and triglyceride contents as well as mRNA levels of cholesterologenic and lipogenic enzymes suggested that leptin deficiency increased production of hepatic triglycerides, but not cholesterol, in the ob/ob mice regardless of their Ldlr genotype. These data provided evidence that the hypertriglyceridemia and hypercholesterolemia in the doubly mutant mice were caused by distinct mechanisms, suggesting that leptin might have some impact on plasma cholesterol metabolism, possibly through an LDLR-independent pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11445560" 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>Much of the early nosologic work that established the hyperlipoproteinemia phenotype (<a href="#47" class="mim-tip-reference" title="Fredrickson, D. S., Levy, R. I., Lees, R. S. <strong>Fat transport in lipoproteins-an integrated approach to mechanisms and disorders.</strong> New Eng. J. Med. 276: 215-225, 1967.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5333808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5333808</a>] [<a href="https://doi.org/10.1056/NEJM196701262760406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5333808">Fredrickson et al., 1967</a>) and suggested familial occurrence (<a href="#77" class="mim-tip-reference" title="Hould, F., Leclerc, R., Marcoux, J. <strong>Essential familial hypercholesterolemia with xanthomatosis.</strong> Pediatrics 43: 455-459, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5775198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5775198</a>]" pmid="5775198">Hould et al., 1969</a>; <a href="#126" class="mim-tip-reference" title="Schrott, H. G., Goldstein, J. L., Hazzard, W. R., McGoodwin, M. M., Motulsky, A. G. <strong>Familial hypercholesterolemia in a large kindred: evidence for a monogenic mechanism.</strong> Ann. Intern. Med. 76: 711-720, 1972.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5025321/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5025321</a>] [<a href="https://doi.org/10.7326/0003-4819-76-5-711" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="5025321">Schrott et al., 1972</a>; <a href="#95" class="mim-tip-reference" title="Kwiterovich, P. O., Jr., Fredrickson, D. S., Levy, R. I. <strong>Familial hypercholesterolemia (one form of familial type II hyperlipoproteinemia): a study of its biochemical, genetic, and clinical presentation in childhood.</strong> J. Clin. Invest. 53: 1237-1249, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4363406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4363406</a>] [<a href="https://doi.org/10.1172/JCI107670" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4363406">Kwiterovich et al., 1974</a>) was done before the extensive genetic heterogeneity of the phenotype was defined. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=5025321+4363406+5775198+5333808" 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="#Allen1980" class="mim-tip-reference" title="Allen, J. M., Thompson, G. R., Myant, N. B., Steiner, R., Oakley, C. M. <strong>Cardiovascular complications of homozygous familial hypercholesterolaemia.</strong> Brit. Heart J. 44: 361-368, 1980.">Allen et al. (1980)</a>; <a href="#Armston1988" class="mim-tip-reference" title="Armston, A. E., Iversen, S. A., Burke, J. F. <strong>Diagnosis of familial hypercholesterolaemia using DNA probes for the low-density lipoprotein (LDL) receptor gene.</strong> Ann. Clin. Biochem. 25: 142-149, 1988.">Armston et al. (1988)</a>; <a href="#Berg1978" class="mim-tip-reference" title="Berg, K., Heiberg, A. <strong>Linkage between familial hypercholesterolemia with xanthomatosis and C3 polymorphism confirmed.</strong> Cytogenet. Cell Genet. 22: 621-623, 1978.">Berg and Heiberg (1978)</a>; <a href="#Berg1979" class="mim-tip-reference" title="Berg, K., Heiberg, A. <strong>Is the locus for familial hypercholesterolemia with xanthomatosis on chromosome 6? (Abstract)</strong> Cytogenet. Cell Genet. 25: 136-137, 1979.">Berg and Heiberg (1979)</a>; <a href="#Berger1978" class="mim-tip-reference" title="Berger, G. M. B., Miller, J. L., Bonnici, F., Joffee, H. S., Dubovsky, D. W. <strong>Continuous flow plasma exchange in the treatment of homozygous familial hypercholesterolemia.</strong> Am. J. Med. 65: 243-251, 1978.">Berger et al. (1978)</a>; <a href="#Bilheimer1985" class="mim-tip-reference" title="Bilheimer, D. W., East, C., Grundy, S. M., Nora, J. J. <strong>II. Clinical studies in a kindred with a kinetic LDL receptor mutation causing familial hypercholesterolemia.</strong> Am. J. Med. Genet. 22: 593-598, 1985.">Bilheimer et al.
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(1985)</a>; <a href="#Bilheimer1983" class="mim-tip-reference" title="Bilheimer, D. W., Grundy, S. M., Brown, M. S., Goldstein, J. L. <strong>Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes.</strong> Proc. Nat. Acad. Sci. 80: 4124-4128, 1983.">Bilheimer et al. (1983)</a>; <a href="#Bilheimer1978" class="mim-tip-reference" title="Bilheimer, D. W., Ho, Y. K., Brown, M. S., Anderson, R. G. W., Goldstein, J. L. <strong>Genetics of the low density lipoprotein receptor: diminished receptor activity in lymphocytes from heterozygotes with familial hypercholesterolemia.</strong> J. Clin. Invest. 61: 678-696, 1978.">Bilheimer et al. (1978)</a>; <a href="#Brink1987" class="mim-tip-reference" title="Brink, P. A., Steyn, L. T., Coetzee, G. A., van der Westhuyzen, D. R. <strong>Familial hypercholesterolemia in South African Afrikaners: PvuII and StuI DNA polymorphisms in the LDL-receptor gene consistent with a predominating founder gene effect.</strong> Hum. Genet. 77: 32-35, 1987.">Brink et
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al. (1987)</a>; <a href="#Brown1975" class="mim-tip-reference" title="Brown, M. S., Goldstein, J. L. <strong>Familial hypercholesterolemia: genetic, biochemical, and pathophysiological considerations.</strong> Adv. Intern. Med. 20: 273-296, 1975.">Brown and Goldstein (1975)</a>; <a href="#Brown1976" class="mim-tip-reference" title="Brown, M. S., Goldstein, J. L. <strong>Receptor-mediated control of cholesterol metabolism.</strong> Science 191: 150-154, 1976.">Brown and Goldstein (1976)</a>; <a href="#Brown1976" class="mim-tip-reference" title="Brown, M. S., Goldstein, J. L. <strong>Receptor-mediated control of cholesterol metabolism.</strong> Science 191: 150-154, 1976.">Brown and Goldstein (1976)</a>; <a href="#Brown1986" class="mim-tip-reference" title="Brown, M. S., Goldstein, J. L. <strong>A receptor-mediated pathway for cholesterol homeostasis.</strong> Science 232: 34-47, 1986.">Brown and Goldstein (1986)</a>; <a href="#Brown1981" class="mim-tip-reference" title="Brown, M. S., Kovanen, P. T., Goldstein, J. L. <strong>Regulation of plasma cholesterol by lipoprotein receptors.</strong> Science 212: 628-635, 1981.">Brown et al.
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(1981)</a>; <a href="#Buja1979" class="mim-tip-reference" title="Buja, L. M., Kovanen, P. T., Bilheimer, D. W. <strong>Cellular pathology of homozygous familial hypercholesterolemia.</strong> Am. J. Path. 97: 327-357, 1979.">Buja et al. (1979)</a>; <a href="#Cai1985" class="mim-tip-reference" title="Cai, H., Fan, L., Huang, M., Chen, X., Liu, G., Chen, Q. <strong>Homozygous familial hypercholesterolemic patients in China.</strong> Atherosclerosis 57: 303-312, 1985.">Cai et al. (1985)</a>; <a href="#Cuthbert1986" class="mim-tip-reference" title="Cuthbert, J. A., East, C. A., Bilheimer, D. W., Lipsky, P. E. <strong>Detection of familial hypercholesterolemia by assaying functional low-density-lipoprotein receptors on lymphocytes.</strong> New Eng. J. Med. 314: 879-883, 1986.">Cuthbert et al.
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(1986)</a>; <a href="#Davis1986" class="mim-tip-reference" title="Davis, C. G., Lehrman, M. A., Russell, D. W., Anderson, R. G. W., Brown, M. S., Goldstein, J. L. <strong>The J.D. mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors.</strong> Cell 45: 15-24, 1986.">Davis et al. (1986)</a>; <a href="#Deckelbaum1977" class="mim-tip-reference" title="Deckelbaum, R. J., Lees, R. S., Small, D. M., Hedberg, S. E., Grundy, S. M. <strong>Failure of complete bile diversion and oral bile acid therapy in the treatment of homozygous familial hypercholesterolemia.</strong> New Eng. J. Med. 296: 465-470, 1977.">Deckelbaum et al. (1977)</a>; <a href="#Edwards1978" class="mim-tip-reference" title="Edwards, J. A., Bernhardt, B., Schnatz, J. D. <strong>Hyperlipidemia in a Lebanese community: difficulties in definition, diagnosis and decision on when to treat.</strong> J. Med. 9: 157-182, 1978.">Edwards et al.
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1177/000456328802500203" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000130606" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9343(78)90815-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(78)91977-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320220318" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.80.13.4124" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI108980" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.atherosclerosis.2007.01.034" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa061189" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198604033141404" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1159/000153992" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197703032960901" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1469-1809.1975.tb00109.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9343(59)90325-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/(SICI)1096-8628(19961016)65:2<149::AID-AJMG14>3.0.CO;2-Q" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.81.9.2826" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0888-7543(89)90037-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM196701262760406" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00280546" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2006-2567" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.78.9.5695" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0092-8674(77)90263-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.70.10.2804" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9343(75)90563-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1146/annurev.ge.13.120179.001355" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.cir.76.3.504" target="_blank">Full Text</a>]
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<strong>Genetic heterogeneity in familial hypercholesterolemia: evidence for two different mutations affecting functions of low-density lipoprotein receptor.</strong>
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[<a href="https://doi.org/10.1073/pnas.72.3.1092" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198308043090507" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI107332" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2004-1541" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.1380010602" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.3344433" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.80.19.6096" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1432-1033.1987.tb10995.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.24.3.144" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3924410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3924410</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3924410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(85)80054-4" target="_blank">Full Text</a>]
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<strong>A DNA probe for the LDL receptor gene is tightly linked to hypercholesterolemia in a pedigree with early coronary disease.</strong>
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[<a href="https://doi.org/10.1172/JCI112579" target="_blank">Full Text</a>]
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<strong>Human genes involved in cholesterol metabolism: chromosomal mapping of the loci for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A reductase with cDNA probes.</strong>
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[<a href="https://doi.org/10.1073/pnas.82.24.8567" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa1816454" target="_blank">Full Text</a>]
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<strong>Genetics of the low density lipoprotein receptor: I. Low density lipoprotein receptor activity in cultured fibroblasts from subjects with or without familial hypercholesterolemia.</strong>
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<strong>Data from hybrid cell lines raise the possibility that factors controlling the low density lipoprotein receptor activity may reside on human chromosome 21, 5 or both. (Abstract)</strong>
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[<a href="https://doi.org/10.1056/NEJM198108273050902" target="_blank">Full Text</a>]
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<strong>Coronary ectasia in a homozygous patient with familial hypercholesterolemia.</strong>
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[<a href="https://doi.org/10.1016/0021-9150(86)90031-6" target="_blank">Full Text</a>]
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<strong>Reduction of serum cholesterol in heterozygous patients with familial hypercholesterolemia: additive effects of compactin and cholestyramine.</strong>
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[<a href="https://doi.org/10.1056/NEJM198303173081101" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0002-9343(78)90822-7" target="_blank">Full Text</a>]
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<strong>Genetics of the low density lipoprotein receptor: II. Genetic control of variation in cell membrane low density lipoprotein receptor activity in cultured fibroblasts.</strong>
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<strong>Treatment of familial hypercholesterolemia by portacaval anastomosis: effect on cholesterol metabolism and pool sizes.</strong>
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[<a href="https://doi.org/10.1073/pnas.80.2.564" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(83)92802-7" target="_blank">Full Text</a>]
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<strong>Analysis of a recycling-impaired mutant of low density lipoprotein receptor in familial hypercholesterolemia.</strong>
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<strong>Homozygous familial hypercholesterolemia mutant with a defect in internalization of low density lipoprotein.</strong>
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[<a href="https://doi.org/10.1073/pnas.78.8.5151" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.5.1.9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5201360" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.1320220317" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa1913805" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa2004215" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa1912387" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJMoa2019910" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00214181" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.7326/0003-4819-76-5-711" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00288276" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(84)91876-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.26.1.32" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(81)91213-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/01.cir.98.6.509" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.20172" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(78)92216-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0092-8674(82)90276-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0092-8674(83)90079-x" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8757561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8757561</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8757561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(96)70188-9" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6118572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6118572</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6118572" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(81)91330-1" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0140-6736(00)03587-X" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2007.00915.x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1089/hum.1992.3.2-179" target="_blank">Full Text</a>]
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Yamamoto, T., Bishop, R. W., Brown, M. S., Goldstein, J. L., Russell, D. W.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3010466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3010466</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=3010466[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=3010466" 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.3010466" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Ada Hamosh - updated : 09/17/2024
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Ada Hamosh - updated : 01/06/2021<br>Ada Hamosh - updated : 06/04/2020<br>Ada Hamosh - updated : 12/05/2019<br>Ada Hamosh - updated : 03/11/2015<br>Marla J. F. O'Neill - updated : 2/9/2012<br>Marla J. F. O'Neill - updated : 5/7/2009<br>John A. Phillips, III - updated : 3/9/2009<br>John A. Phillips, III - updated : 3/25/2008<br>Marla J. F. O'Neill - updated : 3/20/2008<br>Victor A. McKusick - updated : 5/31/2007<br>John A. Phillips, III - updated : 7/31/2006<br>Cassandra L. Kniffin - updated : 10/5/2005<br>Victor A. McKusick - updated : 4/26/2005<br>Cassandra L. Kniffin - updated : 3/1/2005<br>Marla J. F. O'Neill - updated : 5/14/2004<br>Marla J. F. O'Neill - updated : 2/19/2004<br>Victor A. McKusick - updated : 12/23/2003<br>Jane Kelly - updated : 8/29/2003<br>Cassandra L. Kniffin - reorganized : 6/5/2002<br>Cassandra L. Kniffin - updated : 6/5/2002<br>John A. Phillips, III - updated : 2/20/2002<br>Victor A. McKusick - updated : 10/11/2001<br>Victor A. McKusick - updated : 9/20/2001<br>Victor A. McKusick - updated : 8/3/2001<br>Victor A. McKusick - updated : 8/2/2001<br>Michael J. Wright - updated : 7/24/2001<br>Stylianos E. Antonarakis - updated : 6/19/2001<br>Victor A. McKusick - updated : 6/5/2001<br>Paul J. Converse - updated : 5/18/2001<br>Victor A. McKusick - updated : 7/26/2000<br>Carol A. Bocchini - updated : 6/9/2000<br>Victor A. McKusick - updated : 6/2/2000<br>Paul Brennan - updated : 3/8/2000<br>Victor A. McKusick - updated : 2/11/2000<br>Victor A. McKusick - updated : 11/10/1999<br>Victor A. McKusick - updated : 9/24/1999<br>Wilson H. Y. Lo - updated : 8/30/1999<br>Michael J. Wright - updated : 2/11/1999<br>Victor A. McKusick - updated : 1/25/1999<br>Victor A. McKusick -updated : 11/4/1998<br>John A. Phillips, III - updated : 10/1/1998<br>Victor A. McKusick - updated : 9/18/1998<br>Victor A. McKusick - updated : 8/17/1998<br>Victor A. McKusick - updated : 12/19/1997<br>Victor A. McKusick - updated : 8/26/1997<br>Victor A. McKusick - updated : 6/18/1997<br>Victor A. McKusick - updated : 3/21/1997<br>Iosif W. Lurie - updated : 1/8/1997<br>Cynthia K. Ewing - updated : 9/23/1996
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 6/4/1986
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 09/17/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 09/17/2024<br>carol : 08/11/2023<br>alopez : 05/28/2021<br>alopez : 01/06/2021<br>alopez : 01/06/2021<br>alopez : 06/04/2020<br>alopez : 12/05/2019<br>carol : 06/20/2019<br>carol : 06/19/2019<br>carol : 06/12/2019<br>carol : 12/14/2017<br>carol : 11/01/2017<br>carol : 10/31/2017<br>carol : 10/31/2017<br>alopez : 03/11/2015<br>carol : 9/30/2014<br>carol : 2/15/2012<br>carol : 2/13/2012<br>terry : 2/9/2012<br>terry : 10/26/2011<br>joanna : 9/1/2011<br>carol : 2/9/2011<br>terry : 6/3/2009<br>wwang : 5/18/2009<br>terry : 5/7/2009<br>alopez : 3/9/2009<br>terry : 1/29/2009<br>terry : 1/27/2009<br>terry : 1/21/2009<br>carol : 3/25/2008<br>carol : 3/25/2008<br>terry : 3/20/2008<br>alopez : 6/4/2007<br>terry : 5/31/2007<br>alopez : 7/31/2006<br>wwang : 10/18/2005<br>wwang : 10/12/2005<br>ckniffin : 10/5/2005<br>tkritzer : 4/28/2005<br>terry : 4/26/2005<br>tkritzer : 3/9/2005<br>ckniffin : 3/1/2005<br>carol : 5/18/2004<br>terry : 5/14/2004<br>alopez : 4/7/2004<br>alopez : 4/7/2004<br>tkritzer : 2/24/2004<br>terry : 2/19/2004<br>tkritzer : 12/29/2003<br>terry : 12/23/2003<br>carol : 8/29/2003<br>alopez : 5/29/2003<br>alopez : 5/16/2003<br>alopez : 5/14/2003<br>tkritzer : 11/19/2002<br>carol : 6/5/2002<br>carol : 6/5/2002<br>ckniffin : 6/5/2002<br>ckniffin : 6/3/2002<br>ckniffin : 5/17/2002<br>ckniffin : 5/17/2002<br>mgross : 4/8/2002<br>alopez : 2/20/2002<br>cwells : 10/29/2001<br>carol : 10/25/2001<br>mcapotos : 10/11/2001<br>mcapotos : 10/8/2001<br>mcapotos : 10/1/2001<br>terry : 9/20/2001<br>mcapotos : 8/15/2001<br>mcapotos : 8/13/2001<br>terry : 8/3/2001<br>terry : 8/2/2001<br>terry : 7/24/2001<br>mgross : 6/19/2001<br>cwells : 6/13/2001<br>cwells : 6/8/2001<br>terry : 6/5/2001<br>cwells : 5/18/2001<br>cwells : 5/14/2001<br>mcapotos : 7/26/2000<br>mcapotos : 7/26/2000<br>terry : 6/9/2000<br>carol : 6/9/2000<br>terry : 6/2/2000<br>carol : 4/27/2000<br>alopez : 3/8/2000<br>mgross : 2/23/2000<br>terry : 2/11/2000<br>carol : 11/17/1999<br>carol : 11/16/1999<br>carol : 11/16/1999<br>terry : 11/10/1999<br>mgross : 10/1/1999<br>terry : 9/24/1999<br>carol : 9/8/1999<br>carol : 8/31/1999<br>carol : 8/30/1999<br>terry : 4/30/1999<br>carol : 4/20/1999<br>mgross : 3/16/1999<br>mgross : 2/22/1999<br>mgross : 2/17/1999<br>terry : 2/11/1999<br>carol : 2/8/1999<br>terry : 1/25/1999<br>carol : 11/12/1998<br>terry : 11/4/1998<br>carol : 10/1/1998<br>dkim : 9/23/1998<br>terry : 9/18/1998<br>carol : 8/20/1998<br>terry : 8/17/1998<br>alopez : 8/7/1998<br>dkim : 6/30/1998<br>terry : 6/18/1998<br>terry : 5/29/1998<br>alopez : 5/14/1998<br>carol : 3/28/1998<br>mark : 1/10/1998<br>terry : 12/19/1997<br>terry : 12/19/1997<br>mark : 11/11/1997<br>terry : 11/10/1997<br>mark : 10/19/1997<br>terry : 9/15/1997<br>jenny : 9/5/1997<br>terry : 8/26/1997<br>alopez : 7/29/1997<br>alopez : 7/28/1997<br>terry : 7/7/1997<br>joanna : 7/7/1997<br>mark : 7/1/1997<br>mark : 6/30/1997<br>mark : 6/30/1997<br>mark : 6/30/1997<br>jenny : 6/27/1997<br>alopez : 6/25/1997<br>jenny : 6/23/1997<br>mark : 6/18/1997<br>terry : 3/21/1997<br>terry : 3/17/1997<br>terry : 3/6/1997<br>terry : 3/6/1997<br>terry : 3/6/1997<br>jenny : 3/4/1997<br>jenny : 2/24/1997<br>jenny : 1/21/1997<br>jenny : 1/8/1997<br>mark : 9/23/1996<br>terry : 11/17/1995<br>mark : 10/2/1995<br>pfoster : 4/7/1995<br>mimadm : 4/19/1994<br>warfield : 4/8/1994<br>carol : 2/24/1994
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 143890
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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HYPERCHOLESTEROLEMIA, FAMILIAL, 1; FHCL1
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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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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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FHC; FH<br />
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HYPERLIPOPROTEINEMIA, TYPE II<br />
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HYPERLIPOPROTEINEMIA, TYPE IIA<br />
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HYPER-LOW-DENSITY-LIPOPROTEINEMIA<br />
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HYPERCHOLESTEROLEMIC XANTHOMATOSIS, FAMILIAL<br />
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LDL RECEPTOR DISORDER
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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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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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LOW DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 2, INCLUDED; LDLCQ2, INCLUDED
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</span>
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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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 397915002;
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<strong>ICD10CM:</strong> E78.00;
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<strong>ORPHA:</strong> 391665;
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<strong>DO:</strong> 13810;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
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</span>
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</h4>
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
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</th>
|
|
<th>
|
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Phenotype
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</th>
|
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<th>
|
|
Phenotype <br /> MIM number
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</th>
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<th>
|
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Inheritance
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
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<th>
|
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Gene/Locus
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</th>
|
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<th>
|
|
Gene/Locus <br /> MIM number
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</th>
|
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</tr>
|
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</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
1q23.3
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
{Hypercholesterolemia, familial, modifier of}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
143890
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Autosomal recessive
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
APOA2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
107670
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
5p13.1-p12
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Hypercholesterolemia, familial, modifier of}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
143890
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
GHR
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
600946
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
7p14.3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Hypercholesterolemia, susceptibility to}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
143890
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
GSBS
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
604088
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
8p21.2-p21.1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Hypercholesterolemia, familial, due to LDLR defect, modifier of}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
143890
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
EPHX2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
132811
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
19p13.2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
LDL cholesterol level QTL2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
143890
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
LDLR
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
606945
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
19p13.2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hypercholesterolemia, familial, 1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
143890
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
LDLR
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
606945
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
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|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
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|
|
<div>
|
|
|
|
<h4>
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<p>A number sign (#) is used with this entry because familial hypercholesterolemia-1 (FHCL1) can be caused by heterozygous, compound heterozygous, or homozygous mutation in the low density lipoprotein receptor gene (LDLR; 606945) on chromosome 19p13.</p>
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<strong>Description</strong>
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<p>Familial hypercholesterolemia is characterized by elevation of serum cholesterol bound to low density lipoprotein (LDL), which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis). The disorder occurs in 2 clinical forms: homozygous and heterozygous (Hobbs et al., 1992). </p><p>The FHCL1 phenotype can be modified by mutation in other genes. For example, in individuals with the LDLR mutation IVS14+1G-A (606945.0063), the phenotype can be altered by a SNP in the APOA2 gene (107670.0002), a SNP in the EPHX2 gene (132811.0001), or a SNP in the GHR gene (600946.0028).</p><p><strong><em>Genetic Heterogeneity of Familial Hypercholesterolemia</em></strong></p><p>
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Other forms of monogenic familial hypercholesterolemia include FHCL2 (144010), caused by mutation in the APOB gene (107730); FHCL3 (603776), caused by mutation in the PCSK9 gene (607786); and FHCL4 (603813), caused by mutation in the LDLRAP1 gene (605747).</p>
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<strong>Clinical Features</strong>
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<p>Individuals with heterozygous familial hypercholesterolemia develop tendinous xanthomas, corneal arcus, and coronary artery disease; the last usually becomes evident in the fourth or fifth decade. Homozygous individuals have a more severe clinical picture with earlier presentation, usually in the first 2 decades of life (Hobbs et al., 1992). </p><p>The ranges of serum cholesterol and LDL-cholesterol are, in mg per dl, 250-450 and 200-400 in heterozygotes, greater than 500 and greater than 450 in homozygous affecteds, and 150-250 and 75-175 in homozygous unaffecteds, with some positive correlation with age (Khachadurian, 1964; Kwiterovich et al., 1974). </p><p>In homozygous familial hypercholesterolemia, the aortic root is prone to develop atherosclerotic plaque at an early age. Such plaques can accumulate in unusual sites, such as the ascending aorta and around the coronary ostia. Summers et al. (1998) evaluated the aortic root using MRI imaging in a blinded, prospective study of 17 homozygous FH patients and 12 healthy controls. When patient age and body mass index were taken into account, 53% of patients with homozygous FH had increased aortic wall thickness compared to controls; this was thought to result from a combination of medial hyperplasia and plaque formation. Supravalvular aortic stenosis was seen in 41% of patients. </p><p>Houlston et al. (1988) studied the relationship of lipoprotein(a) (152200) levels and coronary heart disease in patients with familial hypercholesterolemia. Individuals with coronary artery disease had a significantly higher mean lipoprotein(a) concentration than those without coronary heart disease, suggesting that lipoprotein(a) measurements may help predict the risk of coronary heart disease in individuals with familial hypercholesterolemia. </p><p>Deramo et al. (2003) investigated the relationship between nonarteritic ischemic optic neuropathy (NAION; 258660) and serum lipid levels in 37 consecutive patients diagnosed with NAION at or below age 50 years and 74 age- and gender-matched controls. They found that hypercholesterolemia was a risk factor in these patients and suggested that NAION might be the first manifestation of a previously unrecognized lipid disorder. The patients had experienced a focal, microvascular central nervous system ischemic event at a relatively young age. Deramo et al. (2003) suggested that aggressive treatment of lipid abnormalities might be warranted in these patients. </p>
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<strong>Pathogenesis</strong>
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<p>By studies of cultured fibroblasts from homozygotes, Goldstein and Brown (1973) and Brown and Goldstein (1974) showed that the basic defect concerns the cell membrane receptor for LDL. Normally, LDL is bound at the cell membrane and taken into the cell ending up in lysosomes where the protein is degraded and the cholesterol is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. In familial hypercholesterolemia, there is a binding defect due to a dysfunctional receptor. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Harders-Spengel et al. (1982) presented evidence that the receptor defect is present on liver membranes. </p><p>To determine the influences of intrauterine and genetic factors on atherogenic lipid profiles in later life, Ijzerman et al. (2001) investigated 53 dizygotic and 61 monozygotic adolescent twin pairs. They found an association between low birth weight and high levels of total cholesterol, LDL cholesterol, and apolipoprotein B that persisted in the intrapair analysis in dizygotic twin pairs but was reversed within monozygotic twin pairs. Furthermore, they found that the association between low birth weight and low levels of HDL cholesterol tended to persist in the intrapair analysis in both dizygotic and monozygotic twins. These data suggested that genetic factors may account for the association of low birth weight with high levels of total cholesterol, LDL cholesterol, and apolipoprotein B, whereas intrauterine factors possibly play a role in the association of low birth weight with low levels of HDL cholesterol. </p><p>Garcia-Otin et al. (2007) determined serum noncholesterol sterols in normolipidemic control subjects and in well-phenotyped patients with dyslipidemias, including autosomal dominant hypercholesterolemia (ADH) with and without known genetic defects and familial combined hyperlipidemia (FCHL; 144250). Intestinal cholesterol absorption was highest in ADH without known defect, followed by ADH with known defect, then controls, and then FCHL. Garcia-Otin et al. (2007) concluded that intestinal cholesterol absorption might play a role in the lipid abnormalities of patients with autosomal dominant hypercholesterolemia without identified genetic defects. They suggested that serum noncholesterol sterols are a useful tool for the differential diagnosis of genetic hypercholesterolemias. </p>
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<strong>Diagnosis</strong>
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<p>Humphries et al. (1985) found a RFLP of the LDL receptor gene using the restriction enzyme PvuII. About 30% of persons are heterozygous for the polymorphism which is, therefore, useful in family studies and early diagnosis of FHC. Schuster et al. (1989) also used RFLPs of the LDLR gene in the diagnosis of FH. </p><p>Bhatnagar et al. (2000) reported a case-finding experience in the UK among relatives of patients with familial hypercholesterolemia by a nurse-led genetic register. By performing cholesterol tests on 200 relatives, 121 new patients with familial hypercholesterolemia were discovered. The newly diagnosed patients were younger than the probands and were generally detected before they had clinically overt atherosclerosis. A case was made for organizing a genetic register approach, linking lipid clinics nationally. </p><p>Umans-Eckenhausen et al. (2001) found that in the Netherlands targeted family screening with DNA analysis proved to be highly effective in identifying patients with hypercholesterolemia. Most of the identified patients sought treatment and were successfully started on cholesterol-lowering treatment to lower the risk of premature cardiovascular disease. </p><p>Newson and Humphries (2005) discussed cascade testing in familial hypercholesterolemia. They questioned whether and how family members should be contacted for testing. The implications of the test results for life planning, employment, or ability to obtain life insurance are concerns. The pros and cons of cascade testing were reviewed by de Wert (2005). </p><p><strong><em>Prenatal Diagnosis</em></strong></p><p>
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Vergotine et al. (2001) demonstrated the feasibility of prenatal diagnosis of homozygous familial hypercholesterolemia in the Afrikaner population. </p>
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<strong>Clinical Management</strong>
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<p>Starzl et al. (1984) performed both heart transplant and liver transplant in a 6.75-year-old girl with homozygous familial hypercholesterolemia. </p><p>Tonstad et al. (1996) conducted a double-blind placebo-controlled trial over 1 year using 8 grams of cholestyramine in prepubertal children (aged 6-11 years) with familial hypercholesterolemia. After 1 year of a low-fat, low-cholesterol diet, children with a family history of premature cardiovascular disease had LDL cholesterol levels at or greater than 4.9 mmol/liter, while children without such a family history had LDL cholesterol levels at or greater than 4.1 mmol/liter. The LDL cholesterol levels in the test group lowered by 16.9% (95% confidence interval), compared with a 1.4% increase in the placebo group. Growth velocity was not adversely affected in the treatment group, although folate and 25-hydroxyvitamin D deficiency were noted among a small number of treated children. Additionally, a boy who had an appendectomy 3 months before the study required surgery for intestinal obstruction after he had taken the first 2 cholestyramine doses. Given the number of gastrointestinal side effects, Tonstad et al. (1996) recommended caution in starting cholestyramine after abdominal surgery in children. </p><p>Cuchel et al. (2007) treated 6 patients with homozygous familial hypercholesterolemia with an inhibitor of microsomal triglyceride transfer protein (157147). A reduction of LDL cholesterol levels was observed, owing to reduced production of apolipoprotein B. However, the therapy was associated with elevated liver aminotransferase levels and hepatic fat accumulation. </p><p><strong><em>Statin Therapy</em></strong></p><p>
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The 'statin' drugs are potent competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme-A reductase and have proven useful in the treatment of hypercholesterolemia (Betteridge et al., 1978; Goldstein and Brown, 1987; Hoeg and Brewer, 1987). Brorholt-Petersen et al. (2001) tested the hypothesis that the cholesterol lowering effect of statin therapy is a function of the particular type of LDLR mutation. They studied the response to treatment with fluvastatin in 28 patients with heterozygous FH as a result of a receptor-negative mutation (trp23 to ter; 606945.0060) and in 30 patients with a receptor-binding defective mutation (trp66 to gly; 606945.0003). They found no statistically significant differences. A tabulation of the results of this and earlier studies suggested that differences in treatment response as an apparent function of LDLR gene mutation type occur mainly in populations with recent genetic admixture. The authors suggested that in such populations persons with the same mutation in the LDLR gene are also more likely to share other but undetermined genetic variations affecting the pharmacology of statins. </p><p>Chaves et al. (2001) examined the presence of mutations in the LDLR gene among subjects clinically diagnosed with FH and analyzed whether the molecular diagnosis helped to predict the response to simvastatin treatment in their FH population. They conducted a randomized clinical trial with simvastatin in 42 genetically diagnosed subjects with FH, with 22 classified as carriers of null mutations and 20 with defective mutations. A mutation causing FH was identified in 46 probands (84%). In 41 of them (89%), a total of 28 point mutations were detected, 13 of which had not been previously described. FH with null mutations showed a poor response to simvastatin treatment. The mean percentage reduction of plasma total and LDL cholesterol levels in these subjects was significantly lower than in subjects with defective mutations. Subjects with FH with null mutations (class I) showed lower plasma HDL cholesterol values and a poor LDL cholesterol response to simvastatin treatment. </p><p>Hedman et al. (2005) studied the efficacy and safety for up to 2 years of pravastatin treatment in 19 girls and 11 boys with autosomal dominant familial hypercholesterolemia. Pravastatin was started at 10 mg/d, with a forced titration by 10 mg at 2, 4, 6, and 12 months until the target cholesterol level of less than 194 mg/dl was reached. By 2, 4, 6, 12, and 24 months of treatment, the total cholesterol levels had, respectively, decreased by 19, 20, 23, 27 and 26%, and the LDL cholesterol levels had decreased by 25, 27, 29, 33, and 32% compared with the dietary baseline values. The side effects were mild, and no clinically significant elevations in alanine aminotransferase, creatine kinase, or creatinine were seen. The authors concluded that the efficacy in children with slight or moderate hypercholesterolemia was satisfactory, but in children with severe hypercholesterolemia it was insufficient. </p><p>Luirink et al. (2019) reported a 20-year follow-up study of statin therapy in children with familial hypercholesterolemia. A total of 214 patients with familial hypercholesterolemia, genetically confirmed in 98% as due to mutations in either LDLR or APOB (see FHCL2, 144010), who were previously participants in a placebo-controlled trial evaluating the 2-year efficacy and safety of pravastatin, were invited for follow-up, together with their 95 unaffected sibs. The incidence of cardiovascular disease among the patients with familial hypercholesterolemia was compared with that among their 156 affected parents. The mean LDL cholesterol level in the patients had decreased from 237.3 to 160.7 mg per deciliter, a decrease of 32% from the baseline level; treatment goal of LDL cholesterol less than 100 mg per deciliter was achieved in 37 patients (20%). Mean progression of carotid intima-media thickness over the entire follow-up period was 0.0056 mm per year in patients with familial hypercholesterolemia and 0.0057 mm per year in sibs (mean difference adjusted for sex, -0.0001 mm per year). The cumulative incidence of cardiovascular events and of death from cardiovascular causes at 39 years of age was lower among the patients with familial hypercholesterolemia than among their affected parents (1% vs 26% and 0% vs 7%, respectively). Luirink et al. (2019) concluded that initiation of statin therapy during childhood in patients with familial hypercholesterolemia slowed the progression of carotid intima-media thickness and reduced the risk of cardiovascular disease in adulthood. </p><p><strong><em>Inclisiran</em></strong></p><p>
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Ray et al. (2020) reported the results of 2 phase 3 trials of inclisiran, a small interfering RNA that reduces hepatic synthesis of PCSK9 (607786). Ray et al. (2020) enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540. A total of 1,561 and 1,617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (+/- SD) LDL cholesterol levels at baseline were 104.7 +/- 38.3 mg per deciliter and 105.5 +/- 39.1 mg per deciliter, respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% in the ORION-10 trial and by 49.9% in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% and 49.2% (p less than 0.001 for all comparisons vs placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo. Nevertheless such reactions were generally mild, and none were severe or persistent. </p><p>Raal et al. (2020) performed a phase 3, double-blind clinical trial of inclisiran in which 482 adults with heterozygous familial hypercholesterolemia were randomly assigned in a 1:1 ratio to receive either subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. The patients included 15 LDLR (606945) homozygotes, 131 patients with LDLR variants, 11 patients with APOB (107730) variants, and 91 patients who either did not have detectable variants or had no genetic testing done. The 2 primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% in the inclisiran group and an increase of 8.2% in the placebo group, for a between-group difference of minus 47.9 percentage points. The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% in the inclisiran group and an increase of 6.2% in the placebo group. There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. </p><p><strong><em>Evinacumab</em></strong></p><p>
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Dewey et al. (2017) tested the effects of a human monoclonal antibody, evinacumab, against Angptl3 in dyslipidemic mice and against ANGPTL3 in healthy human volunteers with elevated levels of triglycerides or LDL cholesterol. In dyslipidemic mice, inhibition of Angptl3 with evinacumab resulted in a greater decrease in atherosclerotic lesion area and necrotic content than a control antibody. In humans, evinacumab caused a dose-dependent placebo-adjusted reduction in fasting triglyceride levels of up to 76% and LDL cholesterol levels of up to 23%. </p><p>Raal et al. (2020) performed a double-blind, placebo-controlled, phase 3 trial in which 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy were randomly assigned in a 2:1 ratio to receive an intravenous infusion of evinacumab, a monoclonal antibody against ANGPTL3, at a dose of 15 mg per kg of body weight every 4 weeks or placebo. Patients with homozygous or compound heterozygous LDLR (606945) mutations were most frequent, but those with biallelic APOB (107730) or PCSK9 (607786) variants were also eligible. Only two-thirds of patients were genotyped. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24. The mean baseline LDL cholesterol level in the 2 groups was 255.1 mg per dL, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points; the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per dL. The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null-null variants in LDLR (-43.4% vs +16.2%) and in those with non-null variants (-49.1% vs -3.8%). Adverse events were similar in the 2 groups. </p><p><strong><em>Evolocumab</em></strong></p><p>
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Santos et al. (2020) studied evolocumab, a human monoclonal antibody directed against PCSK9 (607786), in a 24-week, randomized, double-blind, placebo-controlled trial in 157 pediatric patients aged 10 to 17 years with heterozygous familial hypercholesterolemia. The patients had received stable lipid-lowering treatment for at least 4 weeks before screening and had an LDL cholesterol level of 130 mg per deciliter or more and a triglyceride level of 400 mg per deciliter or less. At week 24, the mean percent change from baseline in LDL cholesterol level was -44.5% in the evolocumab group (104 patients) and -6.2% in the placebo group (53 patients), for a difference of -38.3 percentage points (p less than 0.001). The absolute change in the LDL cholesterol level was -77.5 mg per deciliter (-2.0 mmol per liter) in the evolocumab group and -9.0 mg per deciliter (-0.2 mmol per liter) in the placebo group, for a difference of -68.6 mg per deciliter. Results for all secondary lipid variables were significantly better with evolocumab than with placebo, and the incidence of adverse events that occurred during the treatment period was similar in both groups. </p>
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<p>Wilson et al. (1992) presented a detailed clinical protocol for the ex vivo gene therapy of familial hypercholesterolemia. The approach, which they proposed to use to treat homozygous FH patients with symptomatic coronary artery disease who have a relatively poor prognosis but can tolerate a noncardiac surgical procedure with acceptable risks, involves recovery of hepatocytes from the patient and reimplanting them after genetic correction by a retrovirus-mediated gene transfer. Not only were the technical details of vectors and viruses, transduction and delivery of hepatocytes, evaluation of engraftment and rejection, etc., discussed, but also assessment of risks versus benefits and informed consent for both adult and child patients. </p><p>Grossman et al. (1994) reported a 29-year-old woman with FH caused by mutation in the LDLR gene (606945.0003) who underwent hepatocyte-directed ex vivo gene therapy with LDLR-expressing retroviruses. She tolerated the procedures well, liver biopsy after 4 months showed engraftment of the transgene, and there was no clinical or pathologic evidence for autoimmune hepatitis. The patient showed an improvement in serum lipids up to 18 months after the treatment. </p>
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<p>Three independent linkage studies, by Ott et al. (1974), Berg and Heiberg (1976), and Elston et al. (1976), strongly suggested loose linkage between familial hypercholesterolemia and the third component of complement; C3 (120700) has been mapped to chromosome 19 by somatic cell hybridization. Donald et al. (1984) presented further data on HC-C3 linkage, bringing the combined male-female lod score to a maximum of 3.79 at theta 0.25. C3 and FHC are about 20 cM apart; APOE (107741) and C3 are about 15 cM apart. FHC is not closely linked to APOE, suggesting that these 2 loci are on opposite sides of C3. The LDLR gene was regionalized to 19p13.1-p13.3 by in situ hybridization (Lindgren et al., 1985). Judging by the sequence of loci suggested by linkage data (pter--FHC--C3--APOE/APOC2), the location of FHC (LDLR) is probably 19p13.2-p13.12 and of C3, 19p13.2-p13.11. </p><p>Leppert et al. (1986) found tight linkage between a RFLP of the LDL receptor gene and dominantly inherited hypercholesterolemia; specifically, no exception to cosegregation was found between high-LDL cholesterol phenotype and a unique allele at the LDLR locus. The maximum lod score was 7.52 at theta = 0. </p><p>In 3 adult Dutch, Swedish, and Australian twin samples totaling 410 dizygotic twin pairs, Beekman et al. (2003) found consistent evidence for linkage between chromosome 19 and LDL cholesterol levels, with maximum lod scores of 4.5, 1.7, and 2.1, respectively. No linkage was observed in an adolescent Dutch twin sample of 83 dizygotic twin pairs. Combined analysis of the adult samples increased the maximum lod to 5.7 at 60 cM from pter. Beekman et al. (2003) concluded that there is strong evidence for the presence of a QTL on chromosome 19 with a major effect on LDL cholesterol levels. </p>
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<p>Horsthemke et al. (1987) analyzed DNA from 70 patients in the UK with heterozygous familial hypercholesterolemia. In most, the restriction fragment pattern of the LDLR gene was indistinguishable from the normal; however, 3 patients were found to have a deletion of about 1 kb in the central portion of the gene. In 2 patients, the deletion included all or part of exon 5 (606945.0027); in the third, the deletion included exon 7 (606945.0033). Including a previously described patient with a deletion in the 3-prime part of the gene, these results indicated that 4 of 70 patients, or 6%, have deletions. </p><p>Hobbs et al. (1990) reviewed the many mutations found in the LDLR gene as the cause of familial hypercholesterolemia. </p><p>Varret et al. (2008) reviewed 17 published studies of autosomal dominant hypercholesterolemia and evaluated the contribution of mutations in the LDLR, APOB, and PCSK9 genes. They noted that the proportion of subjects without an identified mutation ranged from 12% to 72%, suggesting the existence of further genetic heterogeneity. </p><p>In a patient diagnosed with probable heterozygous FH, Bourbon et al. (2007) analyzed the LDLR gene and identified a novel variant initially assumed to be a silent polymorphism (R385R; 606945.0065); however, analysis of mRNA from the patient's cells showed that the mutation introduces a new splice site predicted to cause premature termination of the protein. The R385R mutation was also found in a Chinese homozygous FH patient. </p><p>Defesche et al. (2008) analyzed the LDLR gene in 1,350 patients clinically diagnosed with familial hypercholesterolemia who were negative for functional DNA variation in the LDLR, APOB (107730), and PCSK9 (607786) genes. The authors examined the effects of 128 seemingly neutral exonic and intronic DNA variants and identified 2 synonymous variants in LDLR, R385R and G186G (606945.0066), that clearly affected splice sites and segregated with hypercholesterolemia in all families examined. The R385R variant was found in 2 probands of Chinese origin, whereas G186G was found in 35 Dutch probands, 2 of whom were homozygous for the variant and had a more severe phenotype, with myocardial infarction occurring in both before the age of 20 years. </p><p>Kulseth et al. (2010) performed RNA analysis in 30 unrelated patients with clinically defined hypercholesterolemia but without any LDLR mutations detected by standard DNA analysis; sequencing of RT-PCR products from an index patient revealed an insertion of 81 bp from the 5-prime end of intron 14 of LDLR, and DNA sequencing of exons 13 and 14 detected an splice site mutation in intron 14 (606945.0067). Twelve of 23 family members tested were heterozygous for the mutation, and carriers had significantly increased total cholesterol levels compared to noncarriers. Kulseth et al. (2010) analyzed an additional 550 index patients and identified the same splice site mutation in 3 more probands. In 1 proband's family, the mutation was found in 6 of 7 tested family members, who all had LDL cholesterol levels above the 97th percentile. </p><p>Do et al. (2015) sequenced the protein-coding regions of 9,793 genomes from patients with myocardial infarction (MI) at an early age (50 years or younger in males and 60 years or younger in females) along with MI-free controls. They identified 2 genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exomewide significance: LDLR (606945) and APOA5 (606368). Carriers of rare nonsynonymous mutations in LDLR were at 4.2-fold increased risk for MI, while carriers of null alleles in LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbor a rare, damaging mutation in LDLR; this estimate is similar to one made by Goldstein et al. (1973) using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol greater than 190 mg/dl. Carriers of rare nonsynonymous mutations in APOA5 were at 2.2-fold increased risk for MI. When compared with noncarriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides (see 145750). Evidence has connected MI risk with coding-sequence mutations at 2 genes functionally related to APOA5, namely lipoprotein lipase (LPL; 609708) and apolipoprotein C-III (APOC3; 107720). Do et al. (2015) concluded that LDL cholesterol as well as disordered metabolism of triglyceride-rich lipoproteins contributes to myocardial infarction risk. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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A SNP in the promoter region of the G-substrate gene (GSBS; 604088.0001) correlated with elevated plasma total cholesterol levels.</p><p>A SNP in intron 17 of the ITIH4 gene (600564.0001) was associated with hypercholesterolemia susceptibility in a Japanese population.</p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Goldstein et al. (1977) found that both receptor-absent and receptor-defective mutants occur and they concluded that some of the 'homozygotes' are in fact genetic compounds. An internalization mutant of the LDL receptor binds LDL but is unable to facilitate passage of LDL to the inside of the cell. A patient was found to be a genetic compound, having inherited the internalization mutant from the father and the binding mutant from the mother. From the fact that an individual was shown by family studies to be a genetic compound and that complementation did not occur, Goldstein et al. (1977) concluded that the gene for binding of LDL and the gene for internalization of LDL are allelic mutations at the structural locus for the LDL receptor. Miyake et al. (1981) found homozygosity for the internalization defect. </p><p>The LDL receptor is synthesized as a 120-kD glycoprotein precursor that undergoes change to a 160-kD mature glycoprotein through the covalent addition of a 40-kD protein. Tolleshaug et al. (1982) reported a heterozygous child who inherited one allele from his mother which produced an abnormal 120-kD protein that could not be further processed, and one allele from his father which produced an elongated 170-kD precursor that underwent an increase in molecular weight to form an abnormally large receptor of 210 kD. </p><p>Levy et al. (1986) reported 2 brothers with a unique genetic compound form of 'homozygous' hypercholesterolemia in which the mother had typical FHC and the father and 3 of his close relatives had what they termed the HMWR (high molecular weight receptor) trait. In these persons 2 types of functional LDL receptors were found in cultured skin fibroblasts: one with molecular weight of 140,000 and one with molecular weight of 176,000. Curiously and puzzlingly, the compound heterozygotes and the regular heterozygotes for the HMWR showed increased cholesterol synthesis, which the authors suggested may play a significant role in the pathology of the disease. </p><p>Funahashi et al. (1988) studied 16 Japanese kindreds with homozygous FHC. Ten had a receptor-negative form of the disease; 5 had a receptor-defective form; and 1 represented an internalization defect. The receptor-defective group, in which residual amounts of functional receptors were produced, showed a lower tendency to coronary artery disease than the receptor-negative group. </p><p><strong><em>Modifiers</em></strong></p><p>
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Feussner et al. (1996) described a 20-year-old man with a combination of heterozygous FH caused by splice mutation (606945.0054) and type III hyperlipoproteinemia (107741). He presented with multiple xanthomas of the elbows, interphalangeal joints and interdigital webs of the hands. Active lipid-lowering therapy caused regression of the xanthomas and significant decrease of cholesterol and triglycerides. Flat xanthomas of the interdigital webs were described in 3 of 4 formerly reported patients with a combination of these disorders of lipoprotein metabolism. Feussner et al. (1996) proposed that the presence of these xanthomas should suggest compound heterozygosity (actually double heterozygosity) for FH and type III hyperlipoproteinemia. </p><p>Sass et al. (1995) described a 4-generation French-Canadian kindred with familial hypercholesterolemia in which 2 of the 8 heterozygotes for a 5-kb deletion (exons 2 and 3) in the LDLR gene were found to have normal LDL-cholesterol levels. Analyses showed that it was unlikely that variation in the genes encoding apolipoprotein B (107730), HMG-CoA reductase (HMGCR; 142910), apoAI-CIII-AIV (see APOA1; 107680), or lipoprotein lipase was responsible for the cholesterol-lowering effect. Expression of the LDL receptor, as assessed in vitro with measurements of activity and mRNA levels, was similar in normolipidemic and hyperlipidemic subjects carrying the deletion. Analysis of the apoE isoforms (107741), on the other hand, revealed that most of the E2 allele carriers in this family, including the 2 normolipidemic 5-kb deletion carriers, had LDL cholesterol levels substantially lower than subjects with the other apoE isoforms. Thus, this kindred provided evidence for the existence of a gene or genes, including the apoE2 allele, with profound effects on LDL-cholesterol levels. </p><p>Vergopoulos et al. (1997) presented findings suggesting the existence of a xanthomatosis susceptibility gene in a consanguineous Syrian kindred containing 6 individuals with homozygous FH (see 602247). Half of the homozygotes had giant xanthomas, while half did not, even though their LDL-cholesterol concentrations were elevated to similar degrees (more than 14 mmol/l). Heterozygous FH individuals in this family were also clearly distinguishable with respect to xanthoma size. By DNA analysis they identified a hitherto undescribed mutation in the LDLR gene in this family: a T-to-C transition at nucleotide 1999 in codon 646 of exon 14, resulting in an arginine for cysteine substitution. Segregation analysis suggested that a separate susceptibility gene may explain the formation of giant xanthomas. </p><p>In a 13-year-old girl with severe hypercholesterolemia, Ekstrom et al. (1999) demonstrated compound heterozygosity for a cys240-to-phe mutation (606945.0059) and a tyr167-to-ter mutation (606945.0045) in the LDLR gene. Her 2 heterozygous sibs also carried the C240F mutation, but only one of them was hypercholesterolemic. The authors concluded that there may be cholesterol-lowering mechanisms that are activated by mutations in other genes. </p><p>Knoblauch et al. (2000) studied an Arab family that carried the tyr807-to-cys substitution (606945.0019). In this family, some heterozygous persons had normal LDL levels, while some homozygous individuals had LDL levels similar to those persons with heterozygous FH. The authors presented evidence for the existence of a cholesterol-lowering gene on 13q (604595). </p><p>Takada et al. (2002) demonstrated that a SNP of the promoter of the APOA2 gene, -265T-C (107670.0002), influenced the level of total cholesterol and low density lipoprotein (LDL) cholesterol in members with the IVS14+1G-A mutation (606945.0063) in the LDLR gene causing hypercholesterolemia. Strikingly lower total cholesterol and LDL cholesterol values were observed among most of the LDLR mutation carriers who were simultaneously homozygous for the -265C allele of the APOA2 gene. </p><p>In the same large family reported by Takada et al. (2002), Takada et al. (2003) found that a SNP in the GHR gene, resulting in a L526I (600946.0028) substitution, influenced plasma levels of high density lipoprotein (HDL) cholesterol in affected family members with the IVS14+1G-A mutation. The lowest levels of plasma HDL were observed among leu/leu homozygotes, highest levels among ile/ile homozygotes, and intermediate levels among leu/ile heterozygotes. No such effect was observed among noncarriers of the LDLR mutation. </p><p>In the pedigree reported by Takada et al. (2002), Sato et al. (2004) demonstrated a significant modification of the phenotype of familial hypercholesterolemia resulting from the IVS14+1G-A mutation by the arg287 variation in the EPHX2 gene (132811.0001). </p>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In most populations the frequency of the homozygote is 1 in a million (probably a minimal estimate, being a prevalence figure rather than incidence at birth) and the frequency of heterozygotes not less than 1 in 500. Thus, heterozygous familial hypercholesterolemia is the most frequent mendelian disorder, being more frequent than either cystic fibrosis or sickle cell anemia which, in different populations, are often given that distinction. Among survivors of myocardial infarction, the frequency of heterozygotes is about 1 in 20.</p><p>Seftel et al. (1980) pointed to a high frequency of hypercholesterolemic homozygotes in South Africa. In a 7-year period, 34 homozygotes were seen in one clinic in Johannesburg. All were Afrikaners and most lived in Transvaal Province. The authors calculated the frequency of heterozygotes and homozygotes to be 1 in 100 and 1 in 30,000, respectively. The oldest of their patients was a 46-year-old woman. Of the 34, six were age 30 or older. The authors concluded that the high frequency of the gene is attributable to founder effect, as in the case of porphyria variegata (176200), lipoid proteinosis (247100), and sclerosteosis (269500). Torrington and Botha (1981) found that 20 of 26 families with FHC (77%) belonged to the Gereformeerde Kerk, whereas according to the 1970 census only 5% of the Afrikaans-speaking white population of South Africa belonged to this religious group. Again, the data were consistent with a founder effect. Using the LDLR activity of lymphocytes, Steyn et al. (1989) calculated the prevalence of heterozygous FHC in the permanent residents of a predominantly Afrikaans-speaking community in South Africa to be 1 in 71--the highest prevalence reported to date. </p><p>In the Saguenay-Lac-Saint-Jean region of Quebec Province, De Braekeleer (1991) estimated the prevalence of familial hypercholesterolemia as 1/122, compared to the usually used frequency of 1/500 for European populations. </p><p>Defesche and Kastelein (1998) stated that more than 350 different mutations had been found in patients with familial hypercholesterolemia. They tabulated the preferential geographic distribution that has been demonstrated for some of the LDL receptor mutations. For example, in the West of Scotland about half of the index cases of FH were found to have the cys163-to-tyr mutation (606945.0058). Defesche and Kastelein (1998) commented on the geographic associations of LDL receptor mutations within the Netherlands. </p><p>Deletion of gly197 (606945.0005) is the most prevalent LDL receptor mutation causing familial hypercholesterolemia in Ashkenazi Jewish individuals. Studying index cases from Israel, South Africa, Russia, the Netherlands, and the United States, Durst et al. (2001) found that all traced their ancestry to Lithuania. A highly conserved haplotype was identified in chromosomes carrying this deletion, suggesting a common founder. When 2 methods were used for analysis of linkage disequilibrium between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the deletion was found to be 20 +/- 7 generations, so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 14th century. This corresponds with the founding of the Jewish community of Lithuania (1338 A.D.), as well as with the great demographic expansion of Ashkenazi Jewish individuals in eastern Europe, which followed this settlement. Durst et al. (2001) could find no evidence supporting a selective evolutionary metabolic advantage. Therefore, the founder effect in a rapidly expanding population from a limited number of families remains a simple, parsimonious hypothesis explaining the spread of this mutation in Ashkenazi Jewish individuals. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Kingsley and Krieger (1984) identified 4 different types of mutant Chinese hamster ovary cells with defective LDL receptor function. One locus, called ldlA, apparently represents the structural gene for LDL receptor, whereas the others--ldlB, ldlC, and ldlD--appear to have defects involved in either regulation, synthesis, transport, recycling, or turnover of LDL receptors. </p><p>The Watanabe heritable hyperlipidemic (WHHL) rabbit has a genetic deficiency of LDL receptors and is therefore a superb experimental model (Hornick et al., 1983). Kita et al. (1987) found that probucol prevented the progression of atherosclerosis in the Watanabe rabbit by limiting oxidative LDL modification and foam cell transformation of macrophages. Probucol was originally developed as an antioxidant. Yamamoto et al. (1986) showed that the defect in the Watanabe heritable hyperlipidemic rabbit is a mutant receptor for LDL that is not transported to the cell surface at a normal rate. Cloning and sequencing of complementary cDNAs from normal and Watanabe rabbits showed that the defect arises from an in-frame deletion of 12 nucleotides that eliminates 4 amino acids from the cysteine-rich ligand binding domain of the LDL receptor. Yamamoto et al. (1986) detected a similar mutation by S1 nuclease mapping of LDL receptor mRNA from a patient with familial hypercholesterolemia whose receptor also failed to be transported to the cell surface. These findings suggested to Yamamoto et al. (1986) that animal cells may have fail-safe mechanisms that prevent surface expression of improperly folded proteins with unpaired or improperly bonded cysteine residues. </p><p>Scanu et al. (1988) investigated hypercholesterolemia due to deficiency of the LDL receptor in a family of rhesus monkeys. Hummel et al. (1990) used PCR to analyze the mutation carried by members of a family of rhesus monkeys with spontaneous hypercholesterolemia and low density lipoprotein receptor deficiency. Affected monkeys are heterozygous for a nonsense mutation in exon 6, changing codon 284 from TGG to TAG. The G-to-A transition creates a new SpeI restriction site. LDLR RNA is reduced by about 50% on quantitative analysis of RNA obtained at liver biopsy in affected animals. </p><p>Hofmann et al. (1988) found that overexpression of LDL receptors caused elimination of both apoE and apoB, the 2 ligands, from the plasma in transgenic mice derived from fertilized eggs injected with the LDLR gene under control of the mouse metallothionein-I promoter. They speculated that overexpression of other receptors, such as those for insulin (147670) or transferrin (190000), might have pathologic effects leading to a 'ligand steal' syndrome. </p><p>Chowdhury et al. (1991) used the Watanabe rabbit for the development of liver-directed gene therapy based on transplantation of autologous hepatocytes that had been genetically corrected ex vivo with recombinant retroviruses. Animals transplanted with LDLR-transduced autologous hepatocytes demonstrated a 30 to 50% decrease in total serum cholesterol that persisted for the duration of the experiment (122 days). Recombinant-derived LDLR RNA was harvested from tissues with no diminution for up to 6.5 months after transplantation. Ishibashi et al. (1993) developed a new animal model for homozygous FH through targeted disruption of the LDLR gene in mice. Homozygous LDL receptor-deficient mice showed delayed clearance of VLDL, intermediate density lipoproteins (IDL), and LDL from plasma. As a result, total plasma cholesterol level rose from 108 mg/dl in wildtype mice to 236 mg/dl in homozygous deficient mice. Adult mice did not exhibit gross evidence of xanthomatosis, however, and the extent of aortic atherosclerosis was minimal. On the other hand, Ishibashi et al. (1994) showed that in mice homozygous for the targeted disruption of the LDLR gene who were fed a diet high in cholesterol, total plasma cholesterol rose from 246 to more than 1,500 mg/dl. In wildtype littermates fed the same diet, total plasma cholesterol remained less than 160 mg/dl. After 7 months, the homozygous deficient mice developed massive xanthomatous infiltration of the skin and subcutaneous tissue. The aorta and coronary ostia exhibited gross atheromata, and the aortic valve leaflets were thickened by cholesterol-laden macrophages. </p><p>Mice homozygous for targeted replacement with human APOE2 (107741.0001), regardless of age or gender, develop type III hyperlipoproteinemia, whereas homozygosity for APOE2 results in HLP in no more than 10% in humans, predominantly in adult males. By generating mice homozygous for human APOE2 and heterozygous for human LDLR and mouse Ldlr, Knouff et al. (2001) achieved increased stability of mRNA in liver associated with a truncation of the 3-prime-UTR of LDLR. Plasma lipoprotein levels were normal in the LDLR heterozygotes. Knouff et al. (2001) concluded that moderate and controlled overexpression of LDLR completely ameliorates the type III HLP phenotype of APOE2 homozygous mice. </p><p>Hasty et al. (2001) generated mice deficient in both the low density lipoprotein receptor and leptin (ob/ob). These doubly mutant mice exhibited striking elevations in both total plasma cholesterol and triglyceride levels and had extensive atherosclerotic lesions throughout the aorta by 6 months of age. Although fasting, diet restriction, and low-level leptin treatment significantly lowered total plasma triglyceride levels, they caused only slight changes in total plasma cholesterol levels. Hepatic cholesterol and triglyceride contents as well as mRNA levels of cholesterologenic and lipogenic enzymes suggested that leptin deficiency increased production of hepatic triglycerides, but not cholesterol, in the ob/ob mice regardless of their Ldlr genotype. These data provided evidence that the hypertriglyceridemia and hypercholesterolemia in the doubly mutant mice were caused by distinct mechanisms, suggesting that leptin might have some impact on plasma cholesterol metabolism, possibly through an LDLR-independent pathway. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>History</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Much of the early nosologic work that established the hyperlipoproteinemia phenotype (Fredrickson et al., 1967) and suggested familial occurrence (Hould et al., 1969; Schrott et al., 1972; Kwiterovich et al., 1974) was done before the extensive genetic heterogeneity of the phenotype was defined. </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>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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Allen et al. (1980); Armston et al. (1988); Berg and Heiberg (1978);
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Berg and Heiberg (1979); Berger et al. (1978); Bilheimer et al.
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(1985); Bilheimer et al. (1983); Bilheimer et al. (1978); Brink et
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al. (1987); Brown and Goldstein (1975); Brown and Goldstein (1976);
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Brown and Goldstein (1976); Brown and Goldstein (1986); Brown et al.
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(1981); Buja et al. (1979); Cai et al. (1985); Cuthbert et al.
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(1986); Davis et al. (1986); Deckelbaum et al. (1977); Edwards et al.
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(1978); Elston et al. (1975); Epstein et al. (1959); Francke et al.
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(1984); Frank et al. (1989); Fredrickson (1969); Goldstein et al.
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(1981); Goldstein and Brown (1975); Goldstein and Brown (1975);
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Goldstein and Brown (1978); Goldstein and Brown (1979); Goldstein et
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al. (1975); Goldstein et al. (1983); Harlan et al. (1966); Heiberg
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(1976); Hobbs et al. (1986); Hobgood et al. (1983); Horsthemke et al.
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(1987); Iselius (1979); King et al. (1980); Knight et al. (1989);
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Komuro et al. (1987); Kotze et al. (1987); Lehrman et al. (1985);
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Leitersdorf et al. (1989); Maartmann-Moe and Berg-Johnsen (1981);
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Maartmann-Moe et al. (1981); Maartmann-Moe et al. (1982); Mabuchi et
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al. (1981); Mabuchi et al. (1986); Mabuchi et al. (1983); Mabuchi et
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al. (1978); Magnus et al. (1981); McNamara et al. (1983); Mitchell
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(1983); Miyake et al. (1989); Nevin and Slack (1968); Nora et al.
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(1985); Rose et al. (1982); Slack and Nevin (1968); Stoffel et al.
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(1981); Tikkanen et al. (1978); Tolleshaug et al. (1983)
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Allen, J. M., Thompson, G. R., Myant, N. B., Steiner, R., Oakley, C. M.
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<strong>Cardiovascular complications of homozygous familial hypercholesterolaemia.</strong>
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Brit. Heart J. 44: 361-368, 1980.
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[PubMed: 7426196]
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[Full Text: https://doi.org/10.1136/hrt.44.4.361]
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</li>
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<p class="mim-text-font">
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Armston, A. E., Iversen, S. A., Burke, J. F.
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<strong>Diagnosis of familial hypercholesterolaemia using DNA probes for the low-density lipoprotein (LDL) receptor gene.</strong>
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Ann. Clin. Biochem. 25: 142-149, 1988.
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[PubMed: 2898232]
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[Full Text: https://doi.org/10.1177/000456328802500203]
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</li>
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<li>
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<p class="mim-text-font">
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Beekman, M., Heijmans, B. T., Martin, N. G., Whitfield, J. B., Pedersen, N. L., DeFaire, U., Snieder, H., Lakenberg, N., Suchiman, H. E. D., de Knijff, P., Frants, R. R., van Ommen, G. J. B., Kluft, C., Vogler, G. P., Boomsma, D. I., Slagboom, P. E.
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<strong>Evidence for a QTL on chromosome 19 influencing LDL cholesterol levels in the general population.</strong>
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Europ. J. Hum. Genet. 11: 845-850, 2003.
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[PubMed: 14571269]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5201053]
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</li>
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<li>
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<p class="mim-text-font">
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Berg, K., Heiberg, A.
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<strong>Linkage studies on familial hyperlipoproteinemia with xanthomatosis: normal lipoprotein markers and the C3 polymorphism.</strong>
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Cytogenet. Cell Genet. 16: 266-270, 1976.
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[PubMed: 975887]
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[Full Text: https://doi.org/10.1159/000130606]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Berg, K., Heiberg, A.
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<strong>Linkage between familial hypercholesterolemia with xanthomatosis and C3 polymorphism confirmed.</strong>
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Cytogenet. Cell Genet. 22: 621-623, 1978.
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[PubMed: 752554]
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[Full Text: https://doi.org/10.1159/000131037]
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</li>
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<li>
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<p class="mim-text-font">
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Berg, K., Heiberg, A.
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<strong>Is the locus for familial hypercholesterolemia with xanthomatosis on chromosome 6? (Abstract)</strong>
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Cytogenet. Cell Genet. 25: 136-137, 1979.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Berger, G. M. B., Miller, J. L., Bonnici, F., Joffee, H. S., Dubovsky, D. W.
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<strong>Continuous flow plasma exchange in the treatment of homozygous familial hypercholesterolemia.</strong>
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Am. J. Med. 65: 243-251, 1978.
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[PubMed: 210664]
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[Full Text: https://doi.org/10.1016/0002-9343(78)90815-x]
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<li>
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<p class="mim-text-font">
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Betteridge, D. J., Reckless, J. P. D., Krone, W., Galton, D. J.
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<strong>Compactin inhibits cholesterol synthesis in lymphocytes and intestinal mucosa from patients with familial hypercholesterolaemia.</strong>
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Lancet 312: 1342-1343, 1978. Note: Originally Volume II.
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[PubMed: 82843]
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[Full Text: https://doi.org/10.1016/s0140-6736(78)91977-3]
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<p class="mim-text-font">
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Bhatnagar, D., Morgan, J., Siddiq, S., Mackness, M. I., Miller, J. P., Durrington, P. N.
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<strong>Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia.</strong>
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Brit. Med. J. 321: 1497-1500, 2000.
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[PubMed: 11118175]
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[Full Text: https://doi.org/10.1136/bmj.321.7275.1497]
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</li>
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<li>
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<p class="mim-text-font">
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Bilheimer, D. W., East, C., Grundy, S. M., Nora, J. J.
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<strong>II. Clinical studies in a kindred with a kinetic LDL receptor mutation causing familial hypercholesterolemia.</strong>
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Am. J. Med. Genet. 22: 593-598, 1985.
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[PubMed: 4061492]
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[Full Text: https://doi.org/10.1002/ajmg.1320220318]
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<li>
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Ada Hamosh - updated : 09/17/2024<br>Ada Hamosh - updated : 01/06/2021<br>Ada Hamosh - updated : 06/04/2020<br>Ada Hamosh - updated : 12/05/2019<br>Ada Hamosh - updated : 03/11/2015<br>Marla J. F. O'Neill - updated : 2/9/2012<br>Marla J. F. O'Neill - updated : 5/7/2009<br>John A. Phillips, III - updated : 3/9/2009<br>John A. Phillips, III - updated : 3/25/2008<br>Marla J. F. O'Neill - updated : 3/20/2008<br>Victor A. McKusick - updated : 5/31/2007<br>John A. Phillips, III - updated : 7/31/2006<br>Cassandra L. Kniffin - updated : 10/5/2005<br>Victor A. McKusick - updated : 4/26/2005<br>Cassandra L. Kniffin - updated : 3/1/2005<br>Marla J. F. O'Neill - updated : 5/14/2004<br>Marla J. F. O'Neill - updated : 2/19/2004<br>Victor A. McKusick - updated : 12/23/2003<br>Jane Kelly - updated : 8/29/2003<br>Cassandra L. Kniffin - reorganized : 6/5/2002<br>Cassandra L. Kniffin - updated : 6/5/2002<br>John A. Phillips, III - updated : 2/20/2002<br>Victor A. McKusick - updated : 10/11/2001<br>Victor A. McKusick - updated : 9/20/2001<br>Victor A. McKusick - updated : 8/3/2001<br>Victor A. McKusick - updated : 8/2/2001<br>Michael J. Wright - updated : 7/24/2001<br>Stylianos E. Antonarakis - updated : 6/19/2001<br>Victor A. McKusick - updated : 6/5/2001<br>Paul J. Converse - updated : 5/18/2001<br>Victor A. McKusick - updated : 7/26/2000<br>Carol A. Bocchini - updated : 6/9/2000<br>Victor A. McKusick - updated : 6/2/2000<br>Paul Brennan - updated : 3/8/2000<br>Victor A. McKusick - updated : 2/11/2000<br>Victor A. McKusick - updated : 11/10/1999<br>Victor A. McKusick - updated : 9/24/1999<br>Wilson H. Y. Lo - updated : 8/30/1999<br>Michael J. Wright - updated : 2/11/1999<br>Victor A. McKusick - updated : 1/25/1999<br>Victor A. McKusick -updated : 11/4/1998<br>John A. Phillips, III - updated : 10/1/1998<br>Victor A. McKusick - updated : 9/18/1998<br>Victor A. McKusick - updated : 8/17/1998<br>Victor A. McKusick - updated : 12/19/1997<br>Victor A. McKusick - updated : 8/26/1997<br>Victor A. McKusick - updated : 6/18/1997<br>Victor A. McKusick - updated : 3/21/1997<br>Iosif W. Lurie - updated : 1/8/1997<br>Cynthia K. Ewing - updated : 9/23/1996
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Victor A. McKusick : 6/4/1986
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alopez : 09/17/2024<br>carol : 09/17/2024<br>carol : 08/11/2023<br>alopez : 05/28/2021<br>alopez : 01/06/2021<br>alopez : 01/06/2021<br>alopez : 06/04/2020<br>alopez : 12/05/2019<br>carol : 06/20/2019<br>carol : 06/19/2019<br>carol : 06/12/2019<br>carol : 12/14/2017<br>carol : 11/01/2017<br>carol : 10/31/2017<br>carol : 10/31/2017<br>alopez : 03/11/2015<br>carol : 9/30/2014<br>carol : 2/15/2012<br>carol : 2/13/2012<br>terry : 2/9/2012<br>terry : 10/26/2011<br>joanna : 9/1/2011<br>carol : 2/9/2011<br>terry : 6/3/2009<br>wwang : 5/18/2009<br>terry : 5/7/2009<br>alopez : 3/9/2009<br>terry : 1/29/2009<br>terry : 1/27/2009<br>terry : 1/21/2009<br>carol : 3/25/2008<br>carol : 3/25/2008<br>terry : 3/20/2008<br>alopez : 6/4/2007<br>terry : 5/31/2007<br>alopez : 7/31/2006<br>wwang : 10/18/2005<br>wwang : 10/12/2005<br>ckniffin : 10/5/2005<br>tkritzer : 4/28/2005<br>terry : 4/26/2005<br>tkritzer : 3/9/2005<br>ckniffin : 3/1/2005<br>carol : 5/18/2004<br>terry : 5/14/2004<br>alopez : 4/7/2004<br>alopez : 4/7/2004<br>tkritzer : 2/24/2004<br>terry : 2/19/2004<br>tkritzer : 12/29/2003<br>terry : 12/23/2003<br>carol : 8/29/2003<br>alopez : 5/29/2003<br>alopez : 5/16/2003<br>alopez : 5/14/2003<br>tkritzer : 11/19/2002<br>carol : 6/5/2002<br>carol : 6/5/2002<br>ckniffin : 6/5/2002<br>ckniffin : 6/3/2002<br>ckniffin : 5/17/2002<br>ckniffin : 5/17/2002<br>mgross : 4/8/2002<br>alopez : 2/20/2002<br>cwells : 10/29/2001<br>carol : 10/25/2001<br>mcapotos : 10/11/2001<br>mcapotos : 10/8/2001<br>mcapotos : 10/1/2001<br>terry : 9/20/2001<br>mcapotos : 8/15/2001<br>mcapotos : 8/13/2001<br>terry : 8/3/2001<br>terry : 8/2/2001<br>terry : 7/24/2001<br>mgross : 6/19/2001<br>cwells : 6/13/2001<br>cwells : 6/8/2001<br>terry : 6/5/2001<br>cwells : 5/18/2001<br>cwells : 5/14/2001<br>mcapotos : 7/26/2000<br>mcapotos : 7/26/2000<br>terry : 6/9/2000<br>carol : 6/9/2000<br>terry : 6/2/2000<br>carol : 4/27/2000<br>alopez : 3/8/2000<br>mgross : 2/23/2000<br>terry : 2/11/2000<br>carol : 11/17/1999<br>carol : 11/16/1999<br>carol : 11/16/1999<br>terry : 11/10/1999<br>mgross : 10/1/1999<br>terry : 9/24/1999<br>carol : 9/8/1999<br>carol : 8/31/1999<br>carol : 8/30/1999<br>terry : 4/30/1999<br>carol : 4/20/1999<br>mgross : 3/16/1999<br>mgross : 2/22/1999<br>mgross : 2/17/1999<br>terry : 2/11/1999<br>carol : 2/8/1999<br>terry : 1/25/1999<br>carol : 11/12/1998<br>terry : 11/4/1998<br>carol : 10/1/1998<br>dkim : 9/23/1998<br>terry : 9/18/1998<br>carol : 8/20/1998<br>terry : 8/17/1998<br>alopez : 8/7/1998<br>dkim : 6/30/1998<br>terry : 6/18/1998<br>terry : 5/29/1998<br>alopez : 5/14/1998<br>carol : 3/28/1998<br>mark : 1/10/1998<br>terry : 12/19/1997<br>terry : 12/19/1997<br>mark : 11/11/1997<br>terry : 11/10/1997<br>mark : 10/19/1997<br>terry : 9/15/1997<br>jenny : 9/5/1997<br>terry : 8/26/1997<br>alopez : 7/29/1997<br>alopez : 7/28/1997<br>terry : 7/7/1997<br>joanna : 7/7/1997<br>mark : 7/1/1997<br>mark : 6/30/1997<br>mark : 6/30/1997<br>mark : 6/30/1997<br>jenny : 6/27/1997<br>alopez : 6/25/1997<br>jenny : 6/23/1997<br>mark : 6/18/1997<br>terry : 3/21/1997<br>terry : 3/17/1997<br>terry : 3/6/1997<br>terry : 3/6/1997<br>terry : 3/6/1997<br>jenny : 3/4/1997<br>jenny : 2/24/1997<br>jenny : 1/21/1997<br>jenny : 1/8/1997<br>mark : 9/23/1996<br>terry : 11/17/1995<br>mark : 10/2/1995<br>pfoster : 4/7/1995<br>mimadm : 4/19/1994<br>warfield : 4/8/1994<br>carol : 2/24/1994
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