Analysis of Rare Variants in Genes Related to Lipid Metabolism in Patients with Familial Hypercholesterolemia in Western Siberia (Russia)

Abstract

The aim of this work was to identify genetic variants potentially involved in familial hypercholesterolemia in 43 genes associated with lipid metabolism disorders. Targeted high-throughput sequencing of lipid metabolism genes was performed (80 subjects with a familial-hypercholesterolemia phenotype). For patients without functionally significant substitutions in the above genes, multiplex ligation-dependent probe amplification was conducted to determine bigger mutations (deletions and/or duplications) in the LDLR promoter and exons. A clinically significant variant in some gene associated with familial hypercholesterolemia was identified in 47.5% of the subjects. Clinically significant variants in the LDLR gene were identified in 19 probands (73.1% of all variants identified in probands); in three probands (11.5%), pathogenic variants were found in the APOB gene; and in four probands (15.4%), rare, clinically significant variants were identified in genes LPL, SREBF1, APOC3, and ABCG5. In 12 (85.7%) of 14 children of the probands, clinically significant variants were detectable in genes associated with familial hypercholesterolemia. The use of clinical criteria, targeted sequencing, and multiplex ligation-dependent probe amplification makes it possible to identify carriers of rare clinically significant variants in a wide range of lipid metabolism genes and to investigate their influence on phenotypic manifestations of familial hypercholesterolemia.

Diagnosis of Familial Hypercholesterolemia in Children and Young Adults

“…In our previous study, the frequency of detected pathogenic and likely pathogenic variants was 47.5% among the examined adult probands (age 46 ± 13.9 years, range: 20–73 years) with an FH phenotype from Western Siberia (Russia) and 85.7% among the children of the probands [ 19 ]. As in other articles, this finding confirms the effectiveness of the cascade genetic screening strategy for diagnosing FH in the children and relatives of patients with FH.…”

The Genetic Spectrum of Familial Hypertriglyceridemia in Oman

“…A higher density of disease-causing mutation mainly exists in the middle of the LPL gene. The majority of loss-of-function mutations are located in exons 5 and 6 of the LPL gene since these exons encode important functional domains of the enzyme ( Murthy et al, 1996 ; Shakhtshneider et al, 2021 ; Wu et al, 2021 ). Up to date, there is no study conducted on common genes associated with F-HTG in the Arabian region, with the exception of a case report from Israel on an Arab decent child with a mutation in the LPL gene (p.Arg270His) and p.Ser286Arg in a Moroccan patient ( Bouabdellah et al, 2015 ; Dron and Hegele, 2017 ).…”

Basic Research in Atherosclerosis: Technologies of Personalized Medicine

“…Shakhtshneider et al [ 9 ] focused on the genetic variants potentially involved in familial hypercholesterolemia in 43 genes associated with lipid metabolism disorders. Targeted high-throughput sequencing of lipid metabolism genes was performed (80 subjects with a familial-hypercholesterolemia phenotype).…”