Abstract 13821: Genetic Identification of Homozygous Familial Hypercholesterolemia by Long-Read Sequencing Among Patients With Clinically Diagnosed Heterozygous Familial Hypercholesterolemia

Abstract

Background: Homozygous Familial Hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma low-density lipoprotein cholesterol (LDL-C) and accelerated atherosclerosis. Accurate identification of patients with HoFH is essential as they may be eligible for specialized treatments. The objective of this study was to identify and characterize patients with HoFH among patients with clinically diagnosed heterozygous FH (HeFH). Methods: We studied patients from the British Columbia FH Registry with a Dutch Lipid Clinic Network score ≥6 and no secondary cause of hypercholesterolemia. We performed targeted next-generation sequencing of the LDLR , APOB , PCSK9 and LDLRAP1 genes. Long-read sequencing of the LDLR gene was subsequently done for patients with >1 pathogenic LDLR variant to determine haplotypes. We examined lipid levels and cardiovascular events (unstable angina, myocardial infarction and coronary revascularization). Results: Among 705 patients with clinically diagnosed HeFH, we identified a single pathogenic variant in 300 (42.6%) patients and >1 pathogenic variant in the LDLR gene in 11 (1.6%) patients. We established a genetic diagnosis of HoFH in 6 (0.9%) patients (3 true homozygous and 3 compound heterozygous in trans). The mean baseline LDL-C of genetically identified HoFH patients was significantly higher than those with 1 variant. The prevalence of premature cardiovascular disease was numerically greater in the genetically identified HoFH group (29.4% vs 18.0%, p=0.2). Conclusions: In a cohort of patients with clinically diagnosed HeFH, genetic testing by long-read sequencing revealed that 0.9% had HoFH. These patients tended to have a more severe phenotype. Genetic testing of patients with clinical FH may identify patients with HoFH that had eluded clinical diagnosis.