Spectrum of DNA Variants in Southwestern Ontario Patients with Familial Hypercholesterolemia

Heterozygous familial hypercholesterolemia (HeFH) is the most prevalent inherited dyslipidemia, and it predisposes individuals to premature atherosclerotic cardiovascular disease. Genetic testing can provide a definitive diagnosis. The spectrum of causal DNA variants in Ontario patients with hypercholesterolemia is not fully defined.

In Southwestern Ontario patients with a clinical diagnosis of HeFH, we performed targeted next-generation DNA sequencing and bioinformatic analysis to determine the qualitative and quantitative spectrum of pathogenic and likely pathogenic (P/LP) variants.

We observed 101 unique P/LP variants in 254 patients, of which 6 were novel LDLR pathogenic variants. We observed 23 variants of uncertain significance among 30 patients. Phenotypic severity followed a descending biochemical gradient for the LDLR P/LP variant, the APOB variant, and the variants of uncertain significance subgroups. The 3 most commonly observed P/LP variants were APOB p.R3527Q, LDLR 15.8 kb French Canadian deletion, and LDLR p.C681X Middle Eastern variant, seen in 15.4%, 7.1%, and 3.1% of patients, respectively. About three-quarters of variants originated in Europe, with others from Asia, Africa, and the Middle East.

This study provides a comprehensive overview of the clinical and genetic spectrum of HeFH in Southwestern Ontario. The P/LP variant diversity reflects historical colonization and later migration patterns both from across the world and interprovincially from Quebec.