Genetic Spectrum of Lithuanian Familial Hypercholesterolemia Patients.

Background and aims: Although familial hypercholesterolemia (FH) is a common congenital cause of elevated low-density lipoprotein cholesterol (LDL-C), it remains underdiagnosed and undertreated worldwide due to its inherent genetic heterogeneity. This study aimed to determine the prevalence of genetic variants in a Lithuanian patient cohort with clinically diagnosed FH and evaluate their possible clinical implications.

Methods: A total of 172 patients were included in the retrospective analysis. The study population comprised males and females ranging from 0 to 85 years of age, with LDL-C levels exceeding 4.9 mmol/L in adults and 3.9 mmol/L in children. The subjects were divided into four groups according to the Dutch Lipid Clinic Network (DLCN) criteria (definite, probable, possible, and unlikely). Children were analyzed separately. Next-generation sequencing (NGS) has been chosen as the most appropriate technique for genetic testing. All identified variants were categorized into three groups: (1) pathogenic, (2) likely pathogenic, and (3) variants of uncertain significance. Subjects without detected variants were classified into group (4) No mutation.

Results: Women were diagnosed with FH significantly later than men (p = 0.033). Genetic testing identified FH-causing variants in 41.86% of subjects, with 20.93% carrying pathogenic variants, 9.88% likely pathogenic, and 11.05% variants of uncertain significance (VUS). Frequently identified pathogenic variants were c.654_656del p.(Gly219del) in LDLR and c.10580G>A p.(Arg3527Gln) in APOB, which are both linked to the founder effect. Genetic testing led to a reassessment of Dutch Lipid Clinic Network scores, increasing the number of individuals classified as "Definite FH" by 86.2%.

Conclusions: The increasing use of NGS in FH has enhanced diagnostic capabilities and suggests population-specific genetic patterns. However, it also increases VUS detection, for which reclassification rates are still low and require strenuous efforts. Moreover, despite the benefits of genetic testing, significant gender disparities remain and require further attention.