A nationwide genetic and phenotypic spectrum of 63 probands of homozygous familial hypercholesterolemia in Taiwan

BACKGROUND The genetic and phenotypic spectrum of homozygous familial hypercholesterolemia (HoFH) in Han Chinese populations remains insufficiently defined. OBJECTIVE To delineate the nationwide genetic and clinical features of HoFH in Taiwan, including true HoFH, double heterozygous FH (HeFH), and compound HeFH. METHODS Patients with clinically diagnosed probable or definite FH enrolled in the Taiwan FH Registry who underwent genetic testing between 2006 and 2025 were analyzed. A comprehensive workflow integrating microarray assay, mass spectrometry, targeted next-generation sequencing, and multiplex ligation-dependent probe amplification was implemented. Variants were classified using American College of Medical Genetics and Genomics guidelines. RESULTS Of 1479 screened individuals, 63 were genetically confirmed to have HoFH (mean age, 32.8 ± 22.7 years), including 28.6% with atherosclerotic vascular disease. The cohort comprised 14 true HoFH (including homozygous APOB variants), 6 double HeFH, and 43 compound HeFH. The highest documented low-density lipoprotein cholesterol (LDL-C) levels were 357.3 ± 123.5 mg/dL in true HoFH, 347.3 ± 39.2 mg/dL in double HeFH, and 443.5 ± 170.9 mg/dL in compound HeFH. The most frequent genotypes were LDLR IVS2+4A>T;IVS2+4A>T in true HoFH, APOB p.R3527W;LDLR IVS2+4A>T and APOB p.R3527W;LDLR p.D90N in double HeFH, and LDLR p.D90N;p.C329Y in compound HeFH. Patients with double HeFH had lower LDL-C levels and fewer xanthomas than those with LDLR homozygosity or compound mutations, while individuals with homozygous LDLR exon deletions/duplications had the highest LDL-C levels. CONCLUSION This nationwide study provides the first comprehensive genetic and clinical characterization of HoFH in Taiwan. Our findings highlight the importance of precise genetic diagnosis and early detection strategies in improving outcomes for this high-risk population.