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 LDL-C (low-density lipoprotein cholesterol) and accelerated atherosclerosis. Accurate identification of patients with HoFH is essential as they may be eligible for specialized treatments. We hypothesized that a subset of patients with clinically diagnosed heterozygous FH (HeFH) may in fact have HoFH, and this could be identified by genetic diagnosis. Methods: We recruited patients with a clinical diagnosis of HeFH based on 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, followed by long-read sequencing of the LDLR gene in patients with >1 pathogenic LDLR variant. We examined lipid levels and cardiovascular events. Results: Among 705 patients with clinically diagnosed HeFH, we identified a single pathogenic variant in 300 (42.6%) and >1 pathogenic variant in the LDLR gene in 11 patients (1.6%). We established a genetic diagnosis of HoFH in 6 (0.9%) patients (3 true homozygotes and 3 compound heterozygotes). The mean baseline LDL-C and prevalence of premature cardiovascular disease of patients with genetically identified HoFH was significantly higher than patients with HeFH. Conclusions: In a cohort of patients with clinically diagnosed HeFH, genetic testing including long-read sequencing revealed that 0.9% had HoFH. These patients tended to have a more severe clinical phenotype. Genetic testing of patients with clinical FH may identify patients with HoFH that had eluded clinical diagnosis.

Phenotypic homozygous familial hypercholesterolemia successfully treated with proprotein convertase subtilisin/kexin type 9 inhibitors

“… 11 , 12 Genetic testing for FH is not mandatory; it can make the diagnosis of FH more definitive, and if the originator has been genetically tested, the diagnosis of FH in the family is also assured. 13 , 14 There are several methods of genetic testing. NGS is renowned for its ability to sequence millions to billions of DNA strands simultaneously.…”

Clinical impact of genetic testing for lipid disorders

“…Thus, the question remains what proportion of patients with clinically diagnosed HeFH actually have HoFH proven by genetic diagnosis. Performing genetic testing including long-read sequencing in a cohort of 705 patients with clinically diagnosed HeFH, Chaudhry et al [49 ▪ ] reported 0.9% of them having HoFH and requiring more aggressive LLT.…”