Determination of the Population Frequency of Monoallelic and Biallelic Predicted Pathogenic RPE65 Variants in a...

The RPE65-associated retinopathies include biallelic Leber congenital amaurosis 2 and severe early childhood-onset RP, and monoallelic RP with choroidal involvement. The population frequencies of these diseases have previously only been estimated from epidemiological studies, but are deduced here from the number of predicted pathogenic heterozygous or carrier variants in a normal cohort using bioinformatic analyses.

RPE65 variants were downloaded from gnomAD v4.1 (n = 807,162) and annotated with ANNOVAR. The population frequency of heterozygous predicted pathogenic variants was calculated from the numbers of pathogenic structural and copy number variants, null variants, rare missense changes classified disease-causing computationally, and from founder variants not already included. The computed population frequency for biallelic disease was compared with frequencies deduced from pathogenic variants reported in ClinVar.

The population frequencies of heterozygous predicted pathogenic RPE65 variants were 1 in 408 using our strategy and 1 in 415 using ClinVar. Variants were structural in 50 people (3%), null in 793 (41%), and missense in 1,115 (57%). Predicted pathogenic variants were commonest in Admixed American (1 in 257) and African American (1 in 268) and least common in Middle Eastern (1 in 3,031) and Ashkenazi (1 in 1,851) people. A possible founder variant (p.Tyr431His) was present in 1 in 21 Amish. The variant associated with monoallelic RPE65-retinopathy (p.Asp477Gly) was present in 1 in 294,930 Europeans.

Biallelic RPE65-associated retinopathy affects at least 1 in 665,856 of the population, but is more common in Admixed Americans (1 in 264,196) and African Americans (1 in 287,296).