Genetic Spectrum of Familial Hypercholesterolemia in Russian North-West Registry: Focus on Correlation Between Clinical and Genetic Diagnosis

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.