Next-generation-sequencing-based identification of familial hypercholesterolemia-related mutations in subjects with increased LDL–C levels in a latvian populationReportar como inadecuado

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BMC Medical Genetics

, 16:86

First Online: 28 September 2015Received: 03 February 2015Accepted: 15 September 2015


BackgroundFamilial hypercholesterolemia FH is one of the commonest monogenic disorders, predominantly inherited as an autosomal dominant trait. When untreated, it results in early coronary heart disease. The vast majority of FH remains undiagnosed in Latvia. The identification and early treatment of affected individuals remain a challenge worldwide. Most cases of FH are caused by mutations in one of four genes, APOB, LDLR, PCSK9, or LDLRAP1. The spectrum of disease-causing variants is very diverse and the variation detection panels usually used in its diagnosis cover only a minority of the disease-causing gene variants. However, DNA-based tests may provide an FH diagnosis for FH patients with no physical symptoms and with no known family history of the disease. Here, we evaluate the use of targeted next-generation sequencing NGS to identify cases of FH in a cohort of patients with coronary artery disease CAD and individuals with abnormal low-density lipoprotein–cholesterol LDL–C levels.

MethodsWe used targeted amplification of the coding regions of LDLR, APOB, PCSK9, and LDLRAP1, followed by NGS, in 42 CAD patients LDL–C, 4.1–7.2 mmol-L and 50 individuals from a population-based cohort LDL–C, 5.1–9.7 mmol-L.

ResultsIn total, 22 synonymous and 31 nonsynonymous variants, eight variants in close proximity 10 bp to intron–exon boundaries, and 50 other variants were found. We identified four pathogenic mutations p.Arg3527Gln in APOB, and p.Gly20Arg, p.Arg350*, and c.1706–10G > A in LDLR in seven patients 7.6 %. Three possible pathogenic variants were also found in four patients.

ConclusionNGS-based methods can be used to detect FH in high-risk individuals when they do not meet the defined clinical criteria.

KeywordsAPOB Diagnostic tools Genetics LDL LDLR LDLRAP1 Next-generation sequencing PCSK9 AbbreviationsAPOBApolipoprotein B gene

APOBApolipoprotein B

CADCoronary artery disease

FDBFamilial defective apolipoprotein B

FHFamilial hypercholesterolemia

FHVDThe Familial Hypercholesterolemia Variant Database

HDL–CHigh-density lipoprotein–cholesterol

HGMDThe Human Gene Mutation Database

LDL–CLow-density lipoprotein–cholesterol

LDLRLow-density lipoprotein receptor

LDLRAP1Low-density lipoprotein receptor adapter protein 1

LGDBThe Genome Database of the Latvian Population

NGSNext-generation sequencing

PCSK9Proprotein convertase subtilisin-kexin type 9

SNPSingle-nucleotide polymorphism

TCTotal cholesterol

Electronic supplementary materialThe online version of this article doi:10.1186-s12881-015-0230-x contains supplementary material, which is available to authorized users.

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Autor: Ilze Radovica-Spalvina - Gustavs Latkovskis - Ivars Silamikelis - Davids Fridmanis - Ilze Elbere - Karlis Ventins - Guna Oz


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