Phenotypic Variability in Individuals With Genotype-Matched EYS - and USH2A -Associated Autosomal-Recessive Retinitis Pigmentosa

Purpose: Variable expressivity is well recognized in autosomal-dominant inherited retinal diseases (IRDs) but is increasingly observed and less well defined in recessive IRDs. Despite the traditional view of recessive IRDs as monogenic disorders with high penetrance, phenotypic differences among individuals sharing identical biallelic variants suggest additional disease modifiers. We quantified genotype-phenotype concordance in EYS- and USH2A-associated retinitis pigmentosa (RP) and characterized phenotypic variability among individuals with identical primary genotypes. Methods: Participants underwent standardized ophthalmic assessment with multimodal imaging. Longitudinal ellipsoid zone (EZ) widths were measured from optical coherence tomography (OCT) scans obtained ≥12 months apart. Baseline EZ width and age at OCT assessment were compared among individuals sharing identical primary genotypes. Genotype-matched comparisons in which younger individuals demonstrated smaller EZ widths than older counterparts were classified as age-discordant structural comparisons. Results: Ninety patients (41 EYS, 49 USH2A) were included. Recurrent variants EYS c.6416G>A (p.Cys2139Tyr) and USH2A c.2802T>G (p.Cys934Trp) were identified in 46% and 35% of probands, respectively. Females showed greater baseline EZ preservation, although differences were not statistically significant. Marked variability was observed within matched genotypes. Several genotype-matched comparisons demonstrated age-discordant structural variability, including younger individuals with substantially smaller EZ widths than older genotype-matched counterparts. In EYS-associated disease, the largest discordant comparison demonstrated 85.4% less EZ preservation in the younger individuals despite younger age, and the corresponding value in USH2A-associated disease was 81.8%. Intrafamilial discordance further supported the possibility of modifying influences beyond the primary genotype. Conclusions: Disease severity varied substantially among individuals sharing identical primary genotypes, supporting contributions from additional genetic or environmental modifiers. Translational Relevance: Recognition of variability within recessive IRDs has implications for prognosis, trial stratification, and interpretation of treatment response beyond genotype alone.