Rare and Deleterious Mutations in ABCG5/ABCG8 Genes Contribute to Mimicking and Worsening of Familial Hypercholesterolemia Phenotype

Abstract

Background: A substantial proportion of patients clinically diagnosed as having familial hypercholesterolemia (FH) do not manifest causative mutation(s) in the FH genes such as LDLR, APOB, and PCSK9. We aimed to evaluate the effect of rare and deleterious mutation(s) in ABCG5/ABCG8 on hyper-low-density lipoprotein (LDL) cholesterolemia in individuals who meet the clinical criteria for FH. Methods and Results: We compared the LDL cholesterol (LDL-C) values among 487 subjects with FH; the subjects were grouped according to the presence of mutation(s) in FH and ABCG5/ABCG8 genes. We identified 276 individuals with a deleterious mutation in 1 FH gene (57%, monogenic FH), but found no causative mutations in 156 individuals (32%, mutation-negative). A total of 37 individuals had deleterious mutations in ABCG5 or ABCG8, but not in FH genes (8%, ABCG5/ABCG8 mutation carriers). Among these, 3 individuals had sitosterolemia (0.6%) with double mutations. We also identified 18 individuals with deleterious mutations in an FH gene and ABCG5 or ABCG8 (4%, ABCG5/ABCG8-oligogenic FH). Subjects without mutations had significantly higher polygenic scores than those in any other groups. LDL-C levels in oligogenic FH subjects were significantly higher than in the monogenic FH subjects. Moreover, sitosterol/lathosterol levels were significantly affected by those mutations. Conclusions: The results suggested that rare and deleterious mutations in ABCG5/ABCG8 contribute substantially to mimicking and exacerbation of the FH phenotype.