Genotype-Phenotype of Patients with PRPH2-Associated Retinal Dystrophy: Novel Insights on Foveal Structure and Visual Outcomes

Background PRPH2 mutations cause diverse inherited retinal dystrophies (IRDs) with unclear genotype-phenotype correlations. This study aims to elucidate these correlations and characterize associated foveal structural characteristics using multimodal imaging. Methods In this retrospective case series, 34 patients (31 families) with confirmed PRPH2 variants were analyzed. Comprehensive ophthalmic examinations and multimodal imaging were reviewed to assess foveal structure and genotype-phenotype correlations. Results Four phenotypes were identified: retinitis pigmentosa (RP, 44.1%), central areolar choroidal dystrophy (CACD, 26.5%), adult-onset vitelliform macular dystrophy (AVMD, 14.7%), and pattern dystrophy (PD, 14.7%). Twenty-five mutations (9 novel) were found, clustering in the D2 loop. Most patients (65.6%, 21/32) had mild or no visual impairment, and 15.6% (5/32) being legally blind. Multimodal imaging revealed substantial outer retinal preservation (41.9% of eyes), with RP and AVMD showing the highest preservation rates (60.7% and 62.5%, respectively). Quantitative OCT demonstrated severe macular thinning in CACD (97.9 ± 66.6 µm) compared to preserved thickness in RP and AVMD. Ellipsoid zone (EZ) thickening was observed across all phenotypic groups compared to age- and sex-matched controls ( P  < 0.001). Conclusions Despite phenotypic diversity, a shared EZ thickening suggests a unified pathogenesis in PRPH2 retinopathies. The findings provide critical phenotypic and structural foundations for developing targeted therapies and underscore the value of multimodal imaging in understanding disease progression of PRPH2 -IRD.