Background. Studying the genetic profile of patients with familial hypercholesterolemia (FH) and their phenotypic characteristics may contribute to a better understanding of the pathogenesis of the disease.Objective. Evaluation of the genetic profile of patients with severe FH phenotype and study of the phenotype of patients with variants of uncertain significance.Design and methods. The study included patients over 18 years of age with ≥ 7 points on the Dutch Lipid Clinical Network Criteria (DLCN) score from the register of the Centre for Atherosclerosis and Lipid Metabolism Disorders of the Almazov National Medical Research Centre. Clinical and anamnestic data were collected, and molecular genetic testing was performed to identify variants in candidate genes responsible for the development of FH.Results. Of 127 patients (mean age 45,2 ± 12,8 years, 61,6 % women), molecular genetic analysis identified a positive diagnosis of FH in 61,4 % with a predominant presence of pathogenic variants in the LDLR gene (90,6 %) and the most frequent type II c.1202T>A p.Leu401His. Among patients with variants of uncertain significance (18,1 %) tendon xanthomas and lipoid arc of the cornea were detected in 6,7 % and 20,0 %, respectively. The mean LDL–C level before treatment was 7,7 ± 1,7 mmol/L. Variants of uncertain significance were verified mainly in low-density lipoprotein cholesterol (35,9 %) and APOB (28,2 %) genes. Three patients from the study sample are carriers of variants in two FH genes: c.*653G>A in LDLR with c.11788+16C>T in APOB; c.1465T>A in LDLR with c.*25C>T in APOE; c.817+6C>T in LDLR with c.2068–4T>A in APOB.Conclusions. The genetic profile of patients with FH is represented by various mutation variants in a number of known genes, the presence of variants of uncertain significance in LDLR and APOB genes indicates the complex genetic nature of the disease, indicating the need for further study of their role.

Genetic analysis of patients with lipid metabolism disorders is becoming increasingly prevalent in clinical practice. In particular, researchers are directing considerable attention toward studying familial hypercholesterolemia (FH). Despite its high population frequency (heterozygous FH occurs in approximately 1 in 250–300 individuals, with even higher prevalence reported in some regions of the world), the heterogeneity of this condition presents major obstacles to its diagnosis. Owing to the advancement of molecular methods and laboratory technologies, it has become possible to establish the genetic basis of metabolic disorders. In the present study, using next-generation sequencing (NGS), a cohort of 261 patients with a confirmed clinical diagnosis of familial hypercholesterolemia was investigated. Among the 82 variants identified in FH-associated genes (LDLR, APOB, PCSK9, LDLRAP1), the most prevalent was the LDLR NP_000518.3:p.Leu401His variant, which was detected in 21 patients. The second most frequent variant in our cohort (19 patients) was APOB NP_000433.2:p.Arg3527Gln. Overall, 56.1% of patients with a DLCN score of 3–5 (possible FH) carried pathogenic variants, demonstrating the insufficient sensitivity of clinical criteria alone. The presence of early coronary heart disease in 22.73% of genotype-negative patients, together with the considerable number of individuals displaying a pronounced clinical FH phenotype despite negative genetic testing, underscores the importance of further exploring the genetic architecture of FH across different populations.