Verification of Underlying Genetic Cause in a Cohort of Russian Patients with Familial Hypercholesterolemia Using Targeted Next Generation Sequencing.

Anna E Semenova,Igor V Sergienko,Lorenzo Monserrat,Anna B Popova,Diana N Nozadze,Marat V Ezhov,Diego García-Giustiniani

doi:10.3390/jcdd7020016

Abstract

Russian patients with familial hypercholesterolemia (FH) were screened for pathogenic mutations using targeted next generation sequencing. Genetic testing was performed in 52 probands with definite or probable FH based on the Dutch lipid clinic network criteria (DLCN score ≥ 6). Blood samples were studied by massive parallel sequencing (Illumina HiSeq 1500 platform) using a custom capture library related to dyslipidemia and premature atherosclerosis. Mutations considered to be responsible for monogenic FH were identified in 48% of the probands: 24 with mutations in the LDLR gene and two with a mutation in the APOB gene. There were 22 pathogenic/likely pathogenic mutations in LDLR, eight of which have not been previously described in the literature. Four patients with a clinical picture of homozygous FH had two heterozygous LDLR mutations. Although mutation-negative patients had highly elevated total cholesterol and low-density lipoprotein cholesterol levels, only half of them had a family history of hypercholesterolemia. With respect to heterozygous FH, mutation-positive patients had higher maximum total cholesterol levels (p = 0.01), more severe carotid atherosclerotic lesions, and a higher percentage of premature peripheral artery disease (p = 0.03) than mutation-negative ones. However, the number of patients who suffered from myocardial infarction was similar between the two groups.

Highlights

Familial hypercholesterolemia (FH) is a condition mostly associated with pathogenic mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes
Pathogenic/pathogenic mutations, modifying factors, and protective factors were selected among other genetic variations while analyzing the results of next generation sequencing (NGS) to prepare a clinical report for each patient
Several risk scores based on simple clinical predictors were found appropriate for CV risk assessment in patients with a genetically confirmed heterozygous FH (HeFH) [25,26] Similarities in parameters such as arterial hypertension, smoking habit, body mass index (BMI), high-density lipoprotein cholesterol (HDL-C) levels, age and gender were present between the groups of mutation-positive and mutation-negative patients in our study (Table S6)

Summary

Introduction

Familial hypercholesterolemia (FH) is a condition mostly associated with pathogenic mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. This disease is highly underdiagnosed and undertreated in the Russian Federation and its true prevalence remains unknown [1]. The recent development of Russian FH Registry is intended to bring more attention to the problem FH represents in Russia (ClinicalTrials.gov Identifier: NCT02208869) [7]. The evaluation of additional genes associated with dyslipidemia and premature atherosclerosis may help to identify additional genetic factors which could modify the phenotype [8]

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