Investigation of the genetic background of familial hypercholesterolemia in a Turkish cohort and its clinical implications.

Abstract

Objective: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated plasma cholesterol and an increased risk of early-onset coronary artery disease (CAD). FH has a complex genetic basis. Advances in molecular genetic techniques have deepened our understanding of FH, which is critical for accurate classification, CAD risk assessment, and optimized treatment strategies. This study aimed to evaluate the monogenic etiologies of FH and polygenic background as a possible cause of clinical FH phenotype and their relationship to clinical outcomes in a Turkish cohort.

Methods: Patients were selected based on the Simon Broome Criteria. Various molecular techniques were employed, including Sanger sequencing, multiplex-ligation dependent probe amplification (MLPA), next-generation sequencing (NGS) panel analysis, and RNA-based studies. For the first time in a Turkish FH cohort, we calculated 6-single nucleotide polymorphism (SNP) and 12-SNP scores and compared them with a control group.

Results: Multiple variants were identified, including 2 novel variants and a synonymous splice region variant in LDLR, which was shown to disrupt splicing through RNA analysis. The 6-SNP and 12-SNP scores displayed patterns consistent with other populations.

Conclusion: Our findings suggest subtle differences in the monogenic etiology of FH in the Turkish population, with variant negative patients predominantly exhibiting polygenic background. Additionally, polygenic factors appear to influence the phenotype even in variant-positive individuals.