Prevalence and Impact of a Pathogenic CYP27A1 Variant on the Phenotypes Among Patients with Monogenic Heterozygous Familial Hypercholesterolemia.

OBJECTIVE: Cerebrotendinous xanthomatosis (CTX) is a rare inherited metabolic disorder caused by pathogenic variants of cytochrome P450 family 27 subfamily A member 1 (CYP27A1). It remains unclear whether such variants modify the clinical manifestations of familial hypercholesterolemia (FH) caused by defects in the low-density lipoprotein (LDL) receptor or other related genes. We aimed to clarify the impact of the pathogenic variants of CYP27A1 on the clinical phenotypes of patients with FH. METHODS: We analyzed clinical data from 644 patients with a clinical diagnosis of monogenic FH who underwent genotyping for CYP27A1 and phenotypic assessment, including the serum sterol levels. Multivariate linear regression analyses, adjusted for age and sex, were conducted to assess the impact of pathogenic CYP27A1 variants on the serum cholestanol levels. RESULTS: Among these individuals, 22 (3.4%) carried pathogenic CYP27A1 variants. Patients harboring a pathogenic variant showed significantly higher median cholestanol concentrations than non-carriers (3.7 vs. 2.3 μg/mL, p ＜0.001). A single pathogenic CYP27A1 variant was associated with an increase in serum cholestanol of 2.3 μg/mL (95% confidence interval: 1.4-3.2 μg/mL, p ＜0.001) and an Achilles tendon thickness of 0.4 mm (95% confidence interval: 0.1-0.7 mm, p = 0.02). Furthermore, carriers exhibited significantly greater Achilles tendon thickness than non-carriers (9.6 vs. 8.9 mm, p ＜0.001). CONCLUSIONS: We identified a substantial number of patients with pathogenic CYP27A1 variants among the patients with monogenic FH, which influenced their Achilles tendon thickness and serum cholestanol levels.