Mutation analysis in 36 unrelated Spanish subjects with familial hypercholesterolemia: Identification of 3 novel mutations in the LDL receptor gene

Mozas, Pilar; Cenarro, Ana; Civeira, Fernando; Castillo, Sergio; Ros, Emilio; Pocovı́, Miguel

doi:10.1002/(sici)1098-1004(200005)15:5<483::aid-humu19>3.0.co;2-q

Cited by 35 publications

(29 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Both variants have been reported as disease-causing in HGMD. 38,49 Here, we only identified both variants in the index patients of family 7080 and 8985 and not in the two other affected family members. Both index patients have markedly elevated LDLC levels of 310 and 204 mg/dl, respectively.…”

Section: Ldlr Gene Variantsmentioning

confidence: 82%

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

et al. 2015

View full text Add to dashboard Cite

Familial hypercholesterolemia (FH) is an oligogenic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDLC) levels. Variants in four genes have been reported to cause the classical autosomal-dominant form of the disease. FH is largely under-diagnosed in European countries. As FH increases the risk for coronary artery disease (CAD) and myocardial infarction (MI), it might be specifically overlooked in the large number of such patients. Here, we systematically examined the frequency of potential FH-causing variants by exome sequencing in 255 German patients with premature MI and a positive family history for CAD. We further performed co-segregation analyses in an average of 5.5 family members per MI patient. In total, we identified 11 potential disease-causing variants that co-segregate within the families, that is, 5% of patients with premature MI and positive CAD family history had FH. Eight variants were previously reported as disease-causing and three are novel (LDLR.c.811G4A p.(V271I)), PCSK9.c.610G4A (p. (D204N)) and STAP1.c.139A4G (p. (T47A))). Co-segregation analyses identified multiple additional family members carrying one of these FH variants and the clinical phenotype of either FH (n = 2) or FH and premature CAD (n = 15). However, exome sequencing also revealed that some variants in FH genes, which have been reported to cause FH, do not co-segregate with FH. The data reveal that a large proportion of FH patients escape the diagnosis, even when they have premature MI. Hence, systematic molecular-genetic screening for FH in such patients may reveal a substantial number of cases and thereby allow a timely LDLC-lowering in both FH/MI patients as well as their variantcarrying family members.

show abstract

Section: Ldlr Gene Variantsmentioning

confidence: 82%

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Interestingly only four mutations were found in common with the Spanish FH population, namely M-21L [15], S156L [16], D200G [17], and G322S [18] and this last one also with the Brazilian population [19]. From the available literature it seems that not enough FH patients have been studied in these three countries for results in the populations to be compared.…”

Section: Discussionmentioning

confidence: 97%

Familial hypercholesterolaemia in Portugal

Bourbon

Alves²,

Medeiros³

et al. 2008

Atherosclerosis

View full text Add to dashboard Cite

Familial hypercholesterolaemia (FH) is characterised clinically by an increased level of circulating LDL cholesterol that leads to lipid accumulation in tendons and arteries, premature atherosclerosis and increased risk of coronary heart disease (CHD). Although Portugal should have about 20,000 cases, this disease is severely under-diagnosed in our country, this being the first presentation of Portuguese data on FH. A total of 602 blood samples were collected from 184 index patients and 418 relatives from several centres throughout Portugal. Fifty-three different mutations were found in 83 index patients, 79 heterozygous and 4 with two defective LDLR alleles. Additionally, 4 putative alterations were found in 8 patients but were not considered mutations causing disease, mainly because they did not co-segregate with hypercholesterolaemia in the families. Three unrelated patients were found to be heterozygous for the APOB 3500 mutation and two unrelated patients were found to be heterozygous for a novel mutation in PCSK9, predicted to cause a single amino acid substitution, D374H. Cascade screening increased the number of FH patients identified genetically to 204. The newly identified FH patients are now receiving counselling and treatment based on the genetic diagnosis. The early identification of FH patients can increase their life expectancy and quality of life by preventing the development of premature CHD if patients receive appropriate pharmacological treatment.

show abstract

“…Previous literature (Jensen et al 1996;Heath et al 2000;Mozas et al 2000) had indicated significant linkage disequilibrium with mutation T705I in exon 15. Our direct tests for T705I in subjects positive for 1061-8T→C were all positive, whereas other subjects tested were negative.…”

Section: Specific Comments On Sequence Variants Identified From Cohormentioning

confidence: 91%

“…Sequencing of exon 15 was undertaken for samples positive for 1061-8T→C in exon 8 since it was suspected (Jensen et al 1996;Heath et al 2000;Mozas et al 2000) that mutation T705I and i7-8 would co-occur. Residual genomic DNA in the respective meltMADGE exon 8 PCR products was used as template and primers both for exon 15 PCR and subsequent sequencing were 5Ј-AGGCGCACACCTATGAGAAG-3Ј (sense) and 5Ј-GTGAGGACGACACCTGGACT-3Ј (antisense).…”

Section: Generation Of Artificial Positive Controls For Ldlr Ampliconsmentioning

confidence: 99%

Mutation scanning by meltMADGE: Validations usingBRCA1andLDLR, and demonstration of the potential to identify severe, moderate, silent, rare, and paucimorphic mutations in the general population

Alharbi¹,

Aldahmesh²,

Spanakis³

et al. 2005

Genome Res.

View full text Add to dashboard Cite

We have developed a mutation-scanning approach suitable for whole population screening for unknown mutations. The method, meltMADGE, combines thermal ramp electrophoresis with MADGE to achieve suitable cost efficiency and throughput. The sensitivity was tested in blind trials using 54 amplicons representing the BRCA1 coding region and a panel of 94 unrelated family breast cancer risk consultands previously screened in a clinical diagnostic laboratory. All 10 common polymorphisms, 15/15 previously identified disease-causing mutations, and three previously untested single base changes were identified. Assays of LDLR exons 3 and 8 were validated in 460 familial hypercholesteremics and detected 8/9 known variants. We then applied the exon 3 assay in several DNA banks representing ∼8000 subjects with known cholesterol values and applied both assays in one DNA bank (n = 3600). In exon 3 we identified one previously reported moderate mutation, P84S (n = 1), also associated with moderate hypercholesteremia in this subject; an unreported silent variant, N76N (n = 1); and known severe hypercholesteremia splice mutation 313+1G→A (n = 2). Around exon 8 we identified a paucimorphism (n = 35) at the splice site 1061-8T→C (known to be in complete linkage disequilibrium with T705I) and unreported sequence variants 1186+11G→A (n = 1) and D335N G→A (n = 1). The cholesterol value for D335N was on the 96.2 percentile and for T705I, 2/35 carriers were above the 99th percentile. Thus, variants with predicted severe, moderate, and no effect were identified at the population level. In contrast with case collections, CpG mutations predominated. MeltMADGE will enable definition of the full population spectrum of rare, paucimorphic, severe, moderate (forme fruste), and silent mutations and effects.

show abstract

Mutation analysis in 36 unrelated Spanish subjects with familial hypercholesterolemia: Identification of 3 novel mutations in the LDL receptor gene

Cited by 35 publications

References 20 publications

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction

Familial hypercholesterolaemia in Portugal

Mutation scanning by meltMADGE: Validations usingBRCA1andLDLR, and demonstration of the potential to identify severe, moderate, silent, rare, and paucimorphic mutations in the general population

Contact Info

Product

Resources

About