Compound heterozygous RPE65 mutations associated with an early onset autosomal recessive retinitis pigmentosa.

BACKGROUND: Retinitis pigmentosa (RP) is one of the most common form of inherited retinal dystrophies. Identification of disease-causing mutations is a prerequisite to apply targeted therapeutic approaches. The aim of this work is to identify disease-associated mutations in a large Serbian family, in which two brothers suffer from retinitis pigmentosa starting in the first decade of their lives. METHODS: The index patient and 12 additional members of a four-generation family were analyzed in this study. All participants underwent detailed ophthalmic examinations. Genomic DNA was isolated from the family members for whole exome sequencing (WES) and Sanger sequencing of the candidate genes. RESULTS: An early onset RP phenotype was presented in both ocular fundi of the index patient and his brother: arteriolar attenuation, and retinal pigmentary changes in peripheral fundus and waxy disc pallor. Both brothers showed foveal thinning. The index patient showed epiretinal membranes in both eyes and a parafoveal cystic lesion in his right eye, while the brother of the index patient showed choroid folds and vitreomacular adhesion in his left eye. We identified compound heterozygous mutations in the RPE65 gene (a novel c.1338+1G>A splice donor site mutation in addition to the frame-shifting mutation c.1207_1210dup (p.Glu404Alafs*4)) by using an in-house WES pipeline. CONCLUSIONS: Evaluation of all previously described RPE65 mutations showed that the sequence variants identified herein located to rarely altered exons and likely effect highly conserved region of the RPE65 protein. Gene augmentation therapies might be a promising treatment option for the patients described herein.