Purpose: The purpose of this study was to define genotypic-phenotypic correlations related to PRPH2-associated retinopathies in an observational longitudinal cohort and to improve diagnostic accuracy.
Methods: Individuals with PRPH2 variants were identified by genetic sequencing of 263 individuals (including 59 families). Ocular examinations with multimodal imaging were evaluated.
Results: Two pathogenic/likely pathogenic PRPH2 variants were identified in 22 individuals with retinopathies, low genetic susceptibility to age-related macular degeneration (AMD) and younger age of onset. The mean follow-up was 14 years. One family and 4 independent cases (n = 7) were heterozygous for the variant rs121918563 L185P (p.Leu185Pro). The individuals developed retinopathy compatible with autosomal dominant pattern dystrophy (PD), including adult-onset vitelliform macular dystrophy and butterfly macular dystrophy in their fourth to fifth decades of life, evolving to retinal pigment epithelial (RPE) irregularities and central macular atrophy 20 years later. Two families and an independent case (n = 15) had the rs281865373 splice-site variant c.828+3A>T (IVS2+3A>T) presenting as retinal flecks consistent with adult-onset fundus flavimaculatus with macular dystrophy and diffuse RPE atrophy consistent with central areolar chorioretinal dystrophy (CACD) in the fifth decade of life progressing to extensive atrophy in the sixth to eighth decades. The L185P variant was associated with better visual acuity (VA) during follow-up versus c.828+3A>T variant. Some individuals were initially misdiagnosed with geographic atrophy secondary to AMD.
Conclusions: Individuals with the L185P variant had less severe disease with clinical manifestation typical of PD and better VA. More advanced disease with CACD and worse VA were associated with the c.828+3A>T variant. Results contribute to knowledge about genotypic-phenotypic associations of PRPH2 retinopathies and inform clinical and therapeutic end points.