RPE65-related retinal dystrophy: mutational and phenotypic spectrum in 44 affected patients.

Background: Biallelic pathogenic RPE65 variants are related to a spectrum of clinically overlapping inherited retinal dystrophies (IRD). Most affected individuals show a severe progression, with 50% of patients legally blind by 20 years of age. A better knowledge of the mutational spectrum and the phenotype−genotype correlation in RPE65−related IRD is needed. Methods: Forty−five affected subjects from 27 unrelated families with a clinical diagnosis of RPE65−related IRD were included. Clinical evaluation consisted on self−reported ophthalmological history and objective ophthalmological examination. Patients9 genotype was classified accordingly to variant class (truncating or missense) or to variant location at different protein domains. Main phenotypic outcome was age at onset (AAO) of the symptomatic disease and a Kaplan−Meier analysis of disease symptom event−free survival was performed. Results: Twenty−nine different RPE65 variants were identified in our cohort, 7 of them novel. Most frequent variants were p.(Ile98Hisfs*26), p.(Pro111Ser) and p.(Gly187Glu) accounting for the 24% of the detected alleles. Patients carrying two missense alleles showed a later disease onset than those with 1 or 2 truncating variants (Log Rank test p<0.05). While the 60% of patients carrying a missense/missense genotype presented symptoms before or at the first year of life, almost all patients with at least 1 truncating allele (91%) had an AAO ≤1 year (p<0.05). Conclusion: Our findings suggest an association between the type of the RPE65 carried variant and the AAO. Thus, our results provide useful data on RPE65-associated IRD phenotypes which may help to improve clinical and therapeutic management of these patients.