Cor Vasa 2026, 68(5):585-588 | DOI: 10.33678/cor.2026.055

Beyond the Classic Genes: Rare Variants, Phenocopies, and Polygenic Architecture in Familial Hypercholesterolemia

Kristina Zubieliene^a, Simona Berontaite^b, Diana Zaliaduonyte^b, Ieva Aleknaite^c, Vytautas Zabiela^b

^a Kaunas Hospital of the Lithuanian University of Health Sciences, Kaunas, Lithuania

^b Hospital of Lithuanian University of Health Sciences, Kaunas, Lithuania

^c Lithuanian University of Health Sciences, Kaunas, Lithuania

Familial hypercholesterolemia (FH) is a common inherited lipid disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) levels and an increased risk of premature atherosclerotic cardiovascular disease. Traditionally, FH has been considered a monogenic disorder caused by pathogenic variants in the classical genes LDLR, APOB, or PCSK9, which disrupt the LDL receptor pathway and impair hepatic clearance of LDL particles. However, a substantial proportion of patients fulfilling clinical diagnostic criteria for FH do not carry pathogenic variants in these genes, indicating a more complex genetic architecture. Recent advances in next-generation sequencing (NGS) and polygenic risk assessment have broadened the understanding of FH genetics. In mutation-negative patients, elevated LDL-C levels may result from polyge nic hypercholesterolemia, where the cumulative effect of multiple common variants contributes to the phe notype. In addition, several rare genes may cause FH-like phenotypes or act as phenocopies. These include LIPA, ABCG5/ABCG8, APOE, and LDLRAP1, which affect lipid metabolism through distinct molecular mecha nisms. The role of STAP1 remains controversial, with current evidence suggesting it is unlikely to represent a causal FH gene. This review summarizes the contribution of rare variants, phenocopies, and polygenic architecture to the clinical presentation of FH. Expanding genetic testing panels and integrating polygenic risk scores may improve diagnostic accuracy and facilitate more personalized management of patients with severe hypercholesterolemia.

Keywords: ABCG5, ABCG8 APOE Familial hypercholesterolemia Next-generation sequencing Phenocopies Polygenic hypercholesterolemia LIPA LDLRAP1 Rare genetic variants STAP1

Received: March 10, 2026; Revised: May 29, 2026; Accepted: May 30, 2026; Prepublished online: September 21, 2026; Published: October 20, 2026  Show citation