Establishing the Mutational Spectrum of Hungarian Patients with Familial Hypercholesterolemia.

László Madar,Lóránt Kerkovits,Lilla Juhász,Mariann Harangi,István Balogh,Zsuzsanna Szűcs

doi:10.3390/genes13010153

László Madar, Lóránt Kerkovits + Show 4 more

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https://doi.org/10.3390/genes13010153

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Abstract

Familial hypercholesterolemia (FH) is one of the most common autosomal, dominantly inherited diseases affecting cholesterol metabolism, which, in the absence of treatment, leads to the development of cardiovascular complications. The disease is still underdiagnosed, even though an early diagnosis would be of great importance for the patient to receive proper treatment and to prevent further complications. No studies are available describing the genetic background of Hungarian FH patients. In this work, we present the clinical and molecular data of 44 unrelated individuals with suspected FH. Sequencing of five FH-causing genes (LDLR, APOB, PCSK9, LDLRAP1 and STAP1) has been performed by next-generation sequencing (NGS). In cases where a copy number variation (CNV) has been detected by NGS, confirmation by multiplex ligation-dependent probe amplification (MLPA) has also been performed. We identified 47 causal or potentially causal (including variants of uncertain significance) LDLR and APOB variants in 44 index patients. The most common variant in the APOB gene was the c.10580G>A p.(Arg3527Gln) missense alteration, this being in accordance with literature data. Several missense variants in the LDLR gene were detected in more than one index patient. LDLR variants in the Hungarian population largely overlap with variants detected in neighboring countries.

Highlights

Familial hypercholesterolemia (FH, MIM#143890) is one of the most common autosomal, dominantly inherited diseases; it is a disorder of the cholesterol metabolism and one of the major risk factors for early arteriosclerosis and cardiovascular complications.Disease prevalence is 1:200–250
We identified a total of 47 variants related to familial hypercholesterolemia in 44 unrelated Hungarian index patients with suspected FH
Patients clinically diagnosed with FH were examined with a next-generation sequencing method that detects the small-scale variants but large-scale deletions and insertions as well

Summary

Introduction

Familial hypercholesterolemia (FH, MIM#143890) is one of the most common autosomal, dominantly inherited diseases; it is a disorder of the cholesterol metabolism and one of the major risk factors for early arteriosclerosis and cardiovascular complications.Disease prevalence is 1:200–250. A FH score calculation system has been set up based on the recommendations of the European Society of Atherosclerosis [2] This scoring system is known as the Dutch Lipid Clinic Network (DLCN), based on which it can be decided if the patient’s diagnosis of FH is unlikely, possible, probable, or definite. Pathogenic variants of the LDLR and APOB genes are responsible for familial hypercholesterolemia, and sometimes alterations in the PCSK9 gene, but more FH-related genes have been described, such as the LDLRAP1 and STAP1 genes. Variants in these genes have a negative effect on the proper elimination of low-density lipoproteins (LDL)

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