Genotype–phenotype correlations in RPGRIP1-associated retinal dystrophy in a nationwide Japanese cohort

PURPOSE: To investigate genotype-phenotype correlations in a nationwide Japanese cohort of patients with RPGRIP1-associated retinal dystrophy. DESIGN: Retrospective, multicenter cohort study. METHODS: Japanese patients with biallelic pathogenic RPGRIP1 variants diagnosed with Leber congenital amaurosis (LCA) or achromatopsia (ACHM) were recruited from university hospitals throughout Japan. Genetic analyses included polymerase chain reaction for detection of the exon 18 deletion variant (exon 18-DEL), whole-exome sequencing, and whole-genome sequencing. Ophthalmic evaluations comprised best-corrected visual acuity (BCVA), visual field testing, full-field electroretinography (ERG), and multimodal retinal imaging. RESULTS: Thirty-four patients from 26 families [23 (18 families) with ACHM and 11 (8 families) with LCA] were included. Fourteen distinct RPGRIP1 variants were identified, with exon 18-DEL being the most prevalent (43 of 68 alleles, 63.2%). In ACHM, variants were predominantly clustered around exon 18, whereas LCA showed more diverse variant combinations. BCVA was significantly worse in LCA than in ACHM, although the rate of BCVA decline did not differ between phenotypes. Multimodal imaging demonstrated relatively preserved macular structure even in older patients with LCA, while ACHM showed age-dependent progressive outer retinal degeneration. ERG revealed near-complete loss of rod and cone function in early infancy in LCA, whereas rod function was initially preserved in ACHM but gradually deteriorated. CONCLUSIONS: RPGRIP1 variants cause two distinct clinical phenotypes, LCA and ACHM, with clear genotype-phenotype correlations. The exon 18-DEL, observed in both phenotypes, likely represents a founder variant in the Japanese population. These findings expand the clinical spectrum of RPGRIP1-associated retinal dystrophy and have implications for molecular diagnosis, prognostic counseling, and future therapeutic development.