Whole Exome Sequencing of Patients with Atherosclerosis to Identify Genetic Variation of Familial Hypercholesterolemia

Abstract

Familial Hypercholesterolemia (FH) is an inherited disorder characterized by the lifelong accumulation of low-density lipoprotein cholesterol (LDL-C), which is a risk factor for premature cardiovascular disease (CVD) development. In this study, whole exome sequencing (WES) was performed on Kazakhstani patients with atherosclerosis to identify rare genetic variants in FH-associated genes (LDLR, APOB, and PCSK9). In total, 47 rare variants were identified, 10 of which have not been previously documented in global databases. The results of sex-stratified comparison of variant carriers (n=78) revealed significantly higher rates of smoking (p<0.001) and alcohol consumption (p=0.02) in men. A more favorable lipid profile was observed in women, with significantly higher levels of HDL-C (p<0.01) and Apolipoprotein A (p<0.01). Furthermore, female carriers exhibited better subclinical left ventricular function with significantly higher LVEF (p=0.02) and global longitudinal strain (GLS) (p<0.01). Among identified genetic variants, a novel 9-base-pair in-frame deletion (c.418_426del, p.Glu140_Ser142del) in the LDLR was identified. According to ACMG/AMP guidelines, this de novo deletion is classified as likely pathogenic (PM1, PM2, PM4). Computational analysis suggested that novel deletion leads to a conformational shift, destabilizing the protein and disrupting Ca2+ coordination, which is important for ligand-binding integrity. In addition, one pathogenic and two likely pathogenic LDLR mutations were identified. The carriers of deleterious LDLR mutations showed strong genotype-phenotype correlations. This study represents the first genetic characterization of FH-associated variations within the Kazakhstani population.