Variants of uncertain significance in the genetic diagnosis of heterozygous familial hypercholesterolemia

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.