Geographic and Phenotypic Variability in RHO-Associated Retinopathy: Evidence From a Chinese Cohort and Global Literature.

Abstract

To investigate the genotype-phenotype correlation in RHO-associated retinopathy, with a focus on delineating an ethnic-specific variant spectrum and comparing clinical severity across biological classes and common variants. Retrospective cohort study and literature review. We systematically reviewed all published cases of RHO-associated retinal diseases (2196 patients, 1278 probands) and analyzed clinical, genetic, and imaging data from our institutional cohort (80 probands). Variants were categorized by type and by biological class (Class 1-7), and phenotypes were compared across different biological classes and three common variants. A marked geographic divergence was observed: P23H was common in North America but rare in other populations, whereas P347L and R135W were major common variants in European and Asian populations. Genotype-phenotype analysis revealed that Class 2 variants were associated with later onset and slower visual decline, whereas Class 1 and Class 3 variants correlated with earlier onset (P < .0001) and more aggressive phenotypes. Notably, R135W (Class 3) emerged as an under-recognized but highly aggressive variant, with earlier onset (P < .01) and potentially earlier macular involvement. Our study represents the largest study integrating ethnic, genotypic, and clinical data in RHO-associated retinopathy. The findings highlight substantial inter-ethnic differences in common variants and underscore the clinical relevance of biological classification in predicting disease course. In particular, R135W and P347L warrants closer clinical attention due to their aggressive trajectory, which may inform prioritization in gene therapy trials and individualized patient management.