Mutational and phenotypic spectrum in RPE65 patients including seven novel variants among inherited retinal dystrophies (IRD).

Researchers at the Department of Genetics & Genomics, Instituto de Investigacíon Sanitaria-Fundacíon Jiménez Díaz Madrid, have reported a recent study characterizing a mutational and phenotypic spectrum in the RPE65 gene among a cohort of IRD patients.  In their study, a total of 27 families were characterized with biallelic disease-causing RPE65 variants, indicating a prevalence for 2.6% (95% CI = 1.6–3.5%) of 1,042 non syndromic IRD families with either autosomal recessive or sporadic pattern of inheritance. Twenty-nine different RPE65 variants have been identified, 7 of which were novel.  The researchers expected that information of RPE65-associated IRD phenotypes “may help to improve clinical and therapeutic management of these patients”.


Researchers had previously described that bi-allelic pathogenic RPE65 variants are related to a spectrum of clinically overlapping inherited retinal dystrophies (IRD).  The Spanish team commented that “most affected individuals progress to severe disease, with 50% of patients becoming legally blind by 20 years of age. Deeper knowledge of the mutational spectrum and the phenotype-genotype correlation in RPE65-related IRD is needed”.  The RPE65 gene, located at chromosome 1p.31.3, comprises 14 exons and a 2.7-kb transcript encoding an enzyme crucial in regenerating the active chromophore 11-cis-retinal in the RPE through all-trans-retinyl ester isomerization. RPE65 dysfunction results in all-trans-retinyl ester accumulation and reduced or absent levels of visual pigment in photoreceptors and this leads to apoptotic cell death in the retina. Recently, the first gene replacement therapy for IRD was approved in the FDA and EMA. However, the researchers stated that “given the substantial loss of vision in patients with RPE65 biallelic mutations during the first three decades of life”, it was timely that further genetic characterization becomes crucial to the success of these novel gene therapies. Consequently, further “knowledge of specific phenotype-genotype correlations in terms of progression and severity of the RPE65-associated IRD will likely help optimize this new therapy, whose ultimate goal is to preserve functional RPE and photoreceptor cells”.


Following the review and analysis in their research report, there was twenty-nine different RPE65 variants have been identified in their cohort, 7 of which were novel and the other 7 were previously described. All novel missense variants (p.(Gly32Arg), p.(Gly48Glu) and p.(Leu447Phe)) were classified as damaging or probably pathogenic by different in silico predictors. In this study, frequency of RPE65 variants had missense mutations (59%), frameshift (14%), splicing defects (10%), nonsense (14%) and finally, null mutations (3%). These results were consistent with earlier literature the majority of which are missense (54.71%), followed by nonsense-frameshift (32.54%) and splice site variants (12%).  In summary, pathogenic variations in RPE65 were causative of different IRDs such as LCA, EORP, or cone-rod dystrophies with an autosomal pattern of heritance. The RPE65 variants explained 2.6% of the AR non-syndromic IRD families in this 1,042-family cohort is similar to the 2.1% found in a previous study of RPE65-associated IRD in European and North American populations.  These mutational and phenotypic spectrum results in the Spanish research will likely improve current and follow-up gene replacement treatments working through the clinical research trials.