Establishing the Mutational Spectrum of Hungarian Patients with Familial Hypercholesterolemia

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.

Genetic Testing for Familial Hypercholesterolemia in a Pediatric Group: A Romanian Showcase

“…To initiate appropriate treatment, it is important to know whether the patient has a heterozygous, compound heterozygous or homozygous genotype. In addition, by cascade testing, the affected yet asymptomatic family members can be identified, leading to correct and timely treatment [ 56 ].…”

“…The LDLR c.1618G>A, p.(Ala540Thr) missense variant, detected in one index patient, is also a commonly occurring variant among Romanian patients and has been described in several European, Latin American and even Chinese populations [ 56 , 60 , 61 , 62 ]. It is located in the epidermal growth factor (EGF)-precursor homology domain.…”

“…It is located in the epidermal growth factor (EGF)-precursor homology domain. Its pathogenicity is demonstrated by the fact that homozygous patients present with severe clinical symptoms at a young age, e.g., premature coronary heart disease, tendon xanthomas or high total cholesterol level [ 56 ]. The phenotype of our patient was similar to the literature-reported clinical presentation in terms of high cholesterol level, but he did not show any other clinical signs.…”

“…This variant was associated with a strong founder effect in a Greek region, where it was present in almost one-third of the patients examined and detected in a homozygous form in several cases [ 63 ]. According to the literature data, the cholesterol-elevating effect does not associate with its zygosity [ 56 ]. In addition, nonsense variations have been previously described as FH-causing pathogenic variants.…”

Clinical Aspects of Genetic and Non-Genetic Cardiovascular Risk Factors in Familial Hypercholesterolemia

“…Interestingly, no mutational hotspots have been identified in the LDLR gene; the genetic variants are widely spread from the promoter region to the very last exon of the gene. However, pathogenic variants occur more frequently in some regions, such as the ligand-binding domain and the epidermal growth factor-like domain [ 6 ].…”