Update and Analysis of the University College London Low Density Lipoprotein Receptor Familial Hypercholesterolemia Database

Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, The Rayne Building, Royal Free and University College London Medical School, London WC1E 6JJ, UK.
Annals of Human Genetics (Impact Factor: 2.21). 08/2008; 72(Pt 4):485-98. DOI: 10.1111/j.1469-1809.2008.00436.x
Source: PubMed


Familial hypercholesterolemia (FH) (OMIM 143890) is most commonly caused by variations in the LDLR gene which encodes the receptor for Low Density Lipoprotein (LDL) cholesterol particles. We have updated the University College London (UCL) LDLR FH database ( by adding variants reported in the literature since 2001, converting existing entries to standard nomenclature, and transferring the database to the Leiden Open Source Variation Database (LOVD) platform. As of July 2007 the database listed 1066 unique LDLR gene events. Sixty five percent (n = 689) of the variants are DNA substitutions, 24% (n = 260) small DNA rearrangements (<100bp) and 11% (n = 117) large DNA rearrangements (>100bp), proportions which are similar to those reported in the 2001 database (n = 683, 62%, 24% and 14% respectively). The DNA substitutions and small rearrangements occur along the length of the gene, with 24 in the promoter region, 86 in intronic sequences and 839 in the exons (93 nonsense variants, 499 missense variants and 247 small rearrangements). These occur in all exons, with the highest proportion (20%) in exon 4 (186/949); this exon is the largest and codes for the critical ligand binding region, where any missense variant is likely to be pathogenic. Using the PolyPhen and SIFT prediction computer programmes 87% of the missense variants are predicted to have a deleterious effect on LDLR activity, and it is probable that at least 48% of the remainder are also pathogenic, but their role in FH causation requires confirmation by in vitro or family studies.

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Available from: Christina S. Hubbart
    • "These mutations comprise mostly of missense, nonsense or splicing substitutions (60.1%), small deletions and insertions (22.7%) and large rearrangements (17.2%) (Stenson et al. 2009). The greatest number of changes is in exon 4, which is the largest exon of LDLR (Leigh et al. 2008). Spectrum of mutations in European countries is very variable. "
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    ABSTRACT: Familial hypercholesterolemia (FH) is the world's most abundant and the most common heritable disorder of lipid metabolism. The prevalence of the disease in general population is 1:500. Therefore the approximate number of FH patients all over the world is 14 million. From the genetic point of view the disease originates as a result of mutations in genes affecting the processing of LDL particles from circulation, resulting in an increase in LDL cholesterol and hence total cholesterol. These are mutations in genes encoding LDL receptor, apolipoprotein B, proprotein convertase subtilisin/kexin 9 and LDL receptor adaptor protein 1. Cholesterol depositing in tissues and blood vessels of individuals creates tendon xanthoma, xanthelesma and arcus lipoides cornae. Due to the increased deposition of cholesterol in blood vessels, atherosclerosis process is accelerated, what leads to a significantly higher risk of premature cardiovascular diseases. Therefore, early clinical diagnosis confirmed by the DNA analysis, and effective treatment are crucial to reduce the mortality and high risk of premature atherosclerotic complications.
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    • "However, much risk remains unexplained. Genes of molecules that are involved in several physiological pathways have been investigated in the pathogenesis of ischemic stroke, such as lipid metabolism (Goldstein et al. 1973; Leigh et al. 2008), inflammatory response (Flex et al. 2004; Cvetkovic et al. 2005; Gulcher et al. 2005; Wang et al. 2009a; Markus 2011; Manso et al. 2011; Chakraborty et al. 2013), coagulation and haemostasis (Carter et al. 1997; Kin and Becker 2003), blood pressure regulation (Malard et al. 2013), and adhesion molecules (Pola et al. 2003; Li et al. 2009). Despite many hundreds of publications, results have been largely disappointing with few replicable associations identified. "
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    • "FH-causing mutations were detected in 4 out of 193 (2.1%) subjects in the high-cholesterol group and in 5 out of 232 (2.2%) subjects in the cholesterol-therapy group (Table 2). All nine mutations have been previously reported as pathogenic in FH patients [15,16]. No FH-causing mutations were detected in the 192 subjects in the normocholesterolaemic control group. "
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    ABSTRACT: Background Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia. Methods We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls. Results Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls. Conclusions We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis.
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