Targeted CYP27A1 gene analysis for early identification of cerebrotendinous xanthomatosis in juvenile cataract patients: report of a novel variant

Cerebrotendinous xanthomatosis (CTX) is a rare yet treatable neurometabolic disorder caused by pathogenic variants in the CYP27A1 gene. Juvenile-onset cataracts may precede systemic signs, allowing for early diagnosis. This study evaluated the prevalence of CYP27A1 variants in patients with bilateral juvenile cataracts and described related clinical findings. This single-center retrospective study was conducted between May 2022 and April 2025 at Başakşehir Çam and Sakura City Hospital, Istanbul. Patients aged 6 months to 21 years with bilateral juvenile cataracts of undetermined etiology were included. Those with congenital, traumatic, or defined metabolic cataracts were excluded. All underwent ophthalmic evaluation and targeted CYP27A1 sequencing (exons 1–9, exon–intron boundaries) with confirmatory Sanger sequencing. Variants were classified per ACMG/AMP guidelines using ClinVar, HGMD, VarSome, and Franklin databases. Among 128 patients (42.2% male, 57.8% female; mean age 10.9 ± 9.4 years), two (1.5%, 95% CI: 0.2–5.4) carried a novel homozygous CYP27A1 c.398G > A (p.W133*) pathogenic variant, and three (2.4%, 95% CI: 0.5–6.9) had a heterozygous c.884 C > T (p.A295V) variant of uncertain significance. Both families had parental consanguinity. Both patients with homozygous pathogenic variants presented with bilateral cerulean cataracts. The absence of systemic symptoms at diagnosis highlights the feasibility of ophthalmology-based genetic screening for CTX. Identifying affected individuals before neurological onset enables timely initiation of oral chenodeoxycholic acid replacement therapy, which may reduce cholestanol and bile alcohol accumulation and help prevent irreversible complications. Incorporating CYP27A1 sequencing into the evaluation of bilateral juvenile cataracts may facilitate earlier detection of CTX and timely referral for appropriate management, especially in high-consanguinity regions.