Conclusions: Our analysis estimates BCD prevalence and revealed large differences among various populations. Moreover, it highlights advantages and limitations of the gnomAD database.
Methods: CYP4V2 gnomAD data and reported mutations were used to calculate carrier frequency of each variant. An evolutionary-based sliding window analysis was used to detect conserved protein regions. Potential exonic splicing enhancers (ESEs) were identified using ESEfinder.
Purpose: Bietti crystalline dystrophy (BCD) is a rare monogenic autosomal recessive (AR) chorioretinal degenerative disease caused by biallelic mutations in CYP4V2. The aim of the current study was to perform an in-depth calculation of worldwide carrier frequency and genetic prevalence of BCD using gnomAD data and comprehensive literature CYP4V2 analysis.
Results: We identified 1171 CYP4V2 variants, 156 of which were considered pathogenic, including 108 reported in patients with BCD. Carrier frequency and genetic prevalence calculations confirmed that BCD is more common in the East Asian population, with ∼19 million healthy carriers and 52,000 individuals who carry biallelic CYP4V2 mutations and are expected to be affected. Additionally, we generated BCD prevalence estimates of other populations, including African, European, Finnish, Latino, and South Asian. Worldwide, the estimated overall carrier frequency of CYP4V2 mutation is 1:210, and therefore, ∼37 million individuals are expected to be healthy carriers of a CYP4V2 mutation. The estimated genetic prevalence of BCD is about 1:116,000, and we predict that ∼67,000 individuals are affected with BCD worldwide.
Translational relevance: This analysis is likely to have important implications for genetic counseling in each studied population and for developing clinical trials for potential BCD treatments.