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Tero-Pekka Alastalo, Kati Kämpjärvi, Lucia Guidugli, Johanna Känsäkoski, Kirsty Wells, Hanna Västinsalo, Laura Sarantaus, Pertteli Salmenperä, Samuel Myllykangas, Eeva-Marja Kaarina Sankila, Juha Koskenvuo, Sari Tuupanen; Prevalence and genetic characteristics of RPE65-associated retinal disease. Invest. Ophthalmol. Vis. Sci. 2019;60(9):400.
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© ARVO (1962-2015); The Authors (2016-present)
Variants in RPE65 gene are associated with severe retinal diseases including Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Recent advancements in targeted therapy have incentivised genetic diagnostics and the efforts to identify RPE65 patients eligible for therapy have increased. Our goal was to evaluate the prevalence of RPE65 variants and variant characteristics in an inherited retinal dystrophy cohort of 2240 patients by using modern next-generation sequencing (NGS) technologies.
The analysis included patients tested at a CLIA certified laboratory during 2016 and 2018 and the eligibility criteria were as follow: LCA, RP, rod-cone dystrophy and early onset retinal dystrophies. Sequencing analysis was done by using in-house developed and validated NGS, bioinformatics and clinical interpretation
There were a total of 18 patients (0.8%) with RPE65-related disease: seven (38.8%) had LCA, four (22.2%) had RP, 6 (33.3%) were defined as affected with severe early onset retinal dystrophy, and one (5.5%) patient had congenital stationary night blindness (CSNB). The median age was 13 years and ranged from one to 60 years at the moment of molecular diagnosis. Altogether the patients carried 35 disease-associated RPE65 variants, of which 18 (51%) were missense, 10 (29%) protein truncating (nonsense, frameshift, start codon), five (13%) splice site variants, and 2 (5.7%) copy number variants (CNVs). Notably, two (11.1%) of the patients carried a CNV: one patient had a single exon deletion of RPE65, while the other patient had a deletion of the whole RPE65 gene. Altogether, 12 (67%) patients had at least one loss-of-function variant (protein truncating, splice site or CNV). One patient had the c.1430A>G, p.(Asp477Gly) variant associated with the autosomal dominant form of RPE65-mediated disease and was affected with an atypical form of RP.
Our study indicates that RPE65 has a major role in LCA and is important also in differential diagnostics of retinal dystrophies. These results also highlight the importance of CNVs in RPE65-mediated disease and further supports the need of high-quality genetic diagnostics that covers both sequence variants and CNVs for optimized diagnosis and clinical care.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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