Genetic identification of sitosterolemia and ABCG5/ABCG8 variants among Taiwanese patients with familial hypercholesterolemia

Sitosterolemia (STSL) caused by biallelic ABCG5 / ABCG8 variants can mimic Familial Hypercholesterolemia (FH), whereas the clinical relevance of ABCG5 / ABCG8 variants remains incompletely defined. This study aimed to characterize ABCG5 / ABCG8 variants among Taiwanese patients with severe hypercholesterolemia. Patients enrolled in the Taiwan FH Registry underwent whole-exome sequencing (WES) for ABCG5 , ABCG8 , and FH-related genes, including LDLR , APOB , PCSK9 , and LDLRAP1 . Disease-causing ABCG5 / ABCG8 variants were classified using ClinVar annotation, in silico prediction, population allele frequency, published evidence, and genotype–phenotype compatibility. Among 42 patients (35.7% male; mean age at genetic diagnosis, 35.4±20.6 years) carrying disease-causing ABCG5 / ABCG8 variants, 9 had genetically confirmed STSL, 2 had STSL with concomitant heterozygous FH, 24 carried monoallelic ABCG5 / ABCG8 variants without FH, and 7 had monoallelic ABCG5 / ABCG8 variants with heterozygous FH. All concomitant FH involved heterozygous pathogenic LDLR variants. Patients with STSL were younger (mean age, 20.2±23.1 years) than the overall cohort and had markedly higher untreated LDL-C levels than monoallelic ABCG5 / ABCG8 carriers without FH (397.1±125.3 vs. 229.4±52.9 mg/dL; p <0.05), and xanthomas were observed exclusively in this group (55.6%). ABCG5 variants predominated over ABCG8 variants, being detected in 32 patients (76.2%). The most frequent variants in ABCG5 were c.1528C>A (p.H510N), c.1336C>T (p.R446X), and c.1166G>A (p.R389H), whereas those in ABCG8 were c.1256_1257delinsAA (p.I419K), c.55G>C (p.D19H), and c.1285A>G (p.M429V). One patient carried novel biallelic ABCG5 c.1068C>G (p.F356L) and ABCG8 c.818G>A (p.R273H) variants. ABCG5 / ABCG8 variants contribute to severe hypercholesterolemia through biallelic disease-causing effects and monoallelic phenotype-modifying effects. These findings support incorporating ABCG5 / ABCG8 into genetic testing for inherited hypercholesterolemia.