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

BMC Medical Genetics

Research Article

Ilze Radovica-Spalvina¹  Davids Fridmanis¹  Ivars Silamikelis¹  Ilze Elbere¹  Janis Klovins¹  Guna Ozola²  Andrejs Erglis³  Gustavs Latkovskis³  Karlis Ventins⁴ 

[1] Latvian Biomedical Research and Study Center, Ratsupites Street 1, LV-1067, Riga, Latvia;Latvian Center of Cardiology, Pauls Stradins Clinical University Hospital, Pilsonu Street 13, LV-1002, Riga, Latvia;Latvian Center of Cardiology, Pauls Stradins Clinical University Hospital, Pilsonu Street 13, LV-1002, Riga, Latvia;Faculty of Medicine, University of Latvia, Raina Blvd. 19, LV-1586, Riga, Latvia;Research Institute of Cardiology, University of Latvia, Pilsonu Street 13, LV-1002, Riga, Latvia;Vidzemes Hospital, Jumaras Street 195, LV-4201, Valmiera, Latvia;

关键词: APOB;    Diagnostic tools;    Genetics;    LDL;    LDLR;    LDLRAP1;    Next-generation sequencing;    PCSK9;   

DOI  :  10.1186/s12881-015-0230-x

 received in 2015-02-03, accepted in 2015-09-15,  发布年份 2015

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Radovica-Spalvina et al. 2015