A novel PRPF31 variant associated with autosomal dominant retinitis pigmentosa in Japanese families.

BACKGROUND: PRPF31-associated inherited retinal dystrophy is an autosomal dominant form of retinitis pigmentosa (RP), typically caused by haploinsufficiency. Although affected individuals generally exhibit early-onset nyctalopia and progressive visual field loss, the clinical and genetic characteristics associated with individual PRPF31 variants remain incompletely defined, particularly for variants initially classified as variants of uncertain significance (VUS). METHODS: We investigated five unrelated families carrying the same heterozygous PRPF31 variant, c.613_615del (p.Tyr205del), which was previously classified as a VUS. Clinical and genetic data were systematically collected from 15 individuals carrying the variant. Segregation patterns and clinical findings were assessed in relation to the established disease mechanism. In addition, cross-sectional clinical characteristics were analyzed in 35 individuals with PRPF31-associated RP to characterize the disease phenotype and progression. RESULTS: The accumulated familial and phenotypic evidence provided additional support for the pathogenicity of p. Tyr205del, enabling its reclassification as a likely pathogenic variant. Analysis of 35 affected individuals showed that PRPF31-associated RP follows the typical progression pattern of classical RP, with rod-predominant degeneration followed by progressive deterioration of central visual function. CONCLUSIONS: Systematic accumulation of clinical and familial data across multiple cases can provide important evidence for variant interpretation, particularly for rare PRPF31 variants initially classified as VUS. Integrating genetic, segregation, and phenotypic information may improve diagnostic accuracy and facilitate the identification of patients who may benefit from future PRPF31-targeted therapies.