Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Clinical Validity: Biallelic variants in RPE65 are a well‐established cause of autosomal recessive retinitis pigmentosa (retinitis pigmentosa). The association is supported by reports of compound heterozygous and homozygous loss-of-function mutations in >30 unrelated RP probands, segregation in multiple families, and concordant functional data in animal and cellular models. Given the accumulation of genetic and experimental concordance over >20 years, the gene–disease relationship is classified as Definitive.
RPE65-related RP is inherited in an autosomal recessive manner, with complete penetrance and early onset in childhood. Compound heterozygous frameshift and splice donor site mutations, such as c.1207_1210dup (p.Glu404AlafsTer4) in trans with c.1338+1G>A, were identified in two affected brothers presenting with arteriolar attenuation, peripheral pigmentary changes, waxy pallor and foveal thinning (PMID:32367544). A separate case reclassified the VUS c.1580A>G (p.His527Arg) as pathogenic based on trans segregation with c.499G>T (p.Asp167Tyr) in a 10-year-old boy with nyctalopia and complete peripheral autofluorescence loss (PMID:35904185). Large‐scale studies have confirmed biallelic RPE65 variants in early‐onset RP, accounting for up to 6% of cases in heterogeneous cohorts and 3.6% in an Indian series of 220 patients (PMID:34281261; PMID:38323530).
Over 100 unique RPE65 variants have been reported in RP, including missense, nonsense, frameshift, and splice site defects. Common recurrent alleles include IVS1+5g>a, R91W, and p.Asp167Tyr, which together account for >20% of disease alleles in some populations (PMID:11095629). The spectrum underscores the importance of comprehensive sequencing and copy-number analysis in diagnostic workflows.
RPE65 encodes the essential isomerohydrolase that converts all-trans-retinyl esters to 11-cis-retinol in the visual cycle. Biochemical assays confirmed its enzymatic activity in vitro (PMID:16116091), and Rpe65−/− mice recapitulate key features of RP with loss of rod‐mediated ERG responses (PMID:11528395). Lentiviral or AAV-mediated Rpe65 gene transfer in mouse and canine models restores cone survival and retinal function, supporting a loss-of-function mechanism and informing gene therapy strategies (PMID:17032058).
The combination of robust genetic segregation, a broad spectrum of biallelic LoF variants, mechanistic in vitro and in vivo data, and successful rescue by gene augmentation firmly establishes RPE65 as a definitive RP gene. Molecular diagnosis enables eligibility for voretigene neparvovec therapy and guides patient management. Key take-home: RPE65 genetic testing is essential for early diagnosis of autosomal recessive RP and direct therapeutic intervention.
Gene–Disease AssociationDefinitiveBiallelic RPE65 variants reported in >30 unrelated RP probands, segregation in multiple pedigrees, and concordant functional rescue in animal models Genetic EvidenceStrongAutosomal recessive inheritance with >30 probands carrying LoF/splice RPE65 variants including c.1207_1210dup (p.Glu404AlafsTer4) and c.1338+1G>A (PMID:32367544) and segregation across families Functional EvidenceModerateDemonstration of RPE65 isomerohydrolase activity in vitro, Recapitulation of RP phenotype in Rpe65−/− mice and restoration of cone function by gene therapy (PMID:16116091; PMID:17032058) |