Putative protective role of PCSK9 variants in a multigenerational family with familial hypercholesterolemia

Abstract

Background Familial hypercholesterolemia (FH) is most frequently caused by pathogenic variants in LDLR, but phenotypic variability suggests the influence of genetic modifiers. Methods We investigated a large multigenerational family with FH, combining clinical data, lipid profiles, and genetic analysis with functional studies. LDLR and PCSK9 variants were characterized according to ACMG/ClinGen guidelines. Functional assays in CHO-ldlA7 cells assessed LDLR activity, while plasma PCSK9 levels were quantified by ELISA. Results The LDLR c.2479G > A variant was associated with the FH phenotype in the family and showed borderline functional impairment in vitro. The presence of the established loss-of-function PCSK9 c.137G>T variant, together with the rare PCSK9 c.2023del variant with a predicted deleterious effect, was identified in a normocholesterolemic carrier of the LDLR variant who showed markedly low circulating PCSK9 levels. Conclusions These findings suggest the potential relevance of investigating gene–gene interactions and variants with opposing effects on the lipid phenotype in FH. Integrating clinical, biochemical, genetic, and functional data may help explain intrafamilial variability and support more precise interpretation of inherited dyslipidemias.