Nationwide genotypic and phenotypic characterisation of homozygous familial hypercholesterolemia

Background Homozygous familial hypercholesterolemia (HoFH) represents the most severe form of inherited hypercholesterolemia, characterized by extreme low-density lipoprotein cholesterol (LDL-C) elevation and premature atherosclerotic cardiovascular disease. However, the genetic architecture and phenotypic heterogeneity of HoFH in Han Chinese populations remain incompletely defined. Purpose To delineate the nationwide genetic spectrum, clinical characteristics, and genotype–phenotype correlations of HoFH in Taiwan. Methods Patients with clinically probable or definite familial hypercholesterolemia enrolled in the Taiwan FH Registry between 2006 and 2025 who underwent comprehensive genetic testing were analyzed. A multi-platform workflow incorporating microarray analysis, mass spectrometry, targeted next-generation sequencing, and multiplex ligation-dependent probe amplification was employed. Variants were interpreted according to American College of Medical Genetics and Genomics criteria. Genetically confirmed HoFH included true homozygous FH, double heterozygous FH, and compound heterozygous FH. Results Among 1,479 screened individuals, 63 probands were genetically confirmed as HoFH (mean age 32.8±22.7 years), with 28.6% exhibiting atherosclerotic vascular disease. The cohort comprised 14 true HoFH, 6 double heterozygous FH, and 43 compound heterozygous FH. Peak documented LDL-C levels differed by genotype, averaging 357.3±123.5 mg/dL in true HoFH, 347.3±39.2 mg/dL in double heterozygous FH, and 443.5±170.9 mg/dL in compound heterozygous FH. The most prevalent genotypes included 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 heterozygotes, and LDLR [p.D90N];[p.C329Y] in compound heterozygotes. Double heterozygous individuals exhibited comparatively lower LDL-C levels and fewer xanthomas, whereas homozygous LDLR exon deletions or duplications were associated with the most extreme LDL-C elevations. Conclusions This nationwide analysis provides the first comprehensive delineation of the genetic and clinical spectrum of HoFH in Taiwan. Marked genotype-dependent variability underscores the necessity of precise molecular diagnosis for risk stratification, early detection, and individualized therapeutic planning in this ultra–high-risk population.