Prevalence and impact of a pathogenic CYP27A1 variant on phenotypes among patients with monogenic heterozygous familial hypercholesterolemia

Abstract

Cerebrotendinous xanthomatosis (CTX) is a rare inherited metabolic disorder caused by pathogenic variants in the cytochrome P450 family 27 subfamily A member 1 (CYP27A1) gene. It remains unclear whether such variants modify the clinical manifestations of familial hypercholesterolemia (FH) arising from defects in the low-density lipoprotein (LDL) receptor or related genes. We evaluated 2,011 individuals diagnosed as clinical FH according to the Japanese FH criteria at our hospital between April 1990 and March 2020. Of these, 848 participants without pathogenic variants in FH-related genes and 725 participants lacking phenotypic data and/or genetic analysis were excluded. In addition, six patients with homozygous or compound heterozygous FH were excluded. Ultimately, 644 participants were included in this analysis (male: 52%; female: 48%; mean age: 52 years). Baseline assessments for each participant—including medical history, physical examination, and blood tests—were reviewed. Among these individuals, 22 (3.4%) carried a pathogenic CYP27A1 variant. Patients harboring a pathogenic variant showed significantly higher median cholestanol concentrations compared with 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 2.1 μg/mL (95% confidence interval: 1.2–3.0 μg/mL, p < 0.001). Furthermore, carriers exhibited significantly greater Achilles tendon thickness than non-carriers (9.6 vs. 8.9 mm, p < 0.001). We identified a notable proportion of monogenic FH patients who carried a pathogenic CYP27A1 variant, which was associated with increased Achilles tendon thickness and elevated serum cholestanol levels.