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Updated: Aug 3, 2026
A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
Genetic Identification of Homozygous Familial Hypercholesterolemia by Long-Read Sequencing Among Patients With
Ahsen Chaudhry1, Mark Trinder1, Kristin Vesely1
1Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada (A.C., M.T., K.V., L.C., L.J., L.R.B.).
Background:
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by extremely elevated plasma 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 low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and low-density lipoprotein receptor adapter protein 1 (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 low-density lipoprotein cholesterol 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.
