Screening for RPE65 genetic variants in Egyptian children with inherited retinal disorders: a study from a tertiary eye care center in Egypt

BACKGROUND: Pathogenic variants in the RPE65 gene cause various forms of inherited retinal dystrophies (IRD), which include Leber congenital amaurosis (LCA), early childhood-onset retinal dystrophy (ECORD), and various forms of retinitis pigmentosa (RP). To date, no study has characterised the heterogeneity of RPE65 variants associated with IRD in the Egyptian population. This study aimed to identify RPE65 pathogenic variants in a cohort of Egyptian children with IRD, with implications for gene therapy eligibility. METHODS: A total of 44 patients in the paediatric age group (from birth to 18 years old), from 27 unrelated Egyptian families with non-syndromic IRD, underwent detailed ophthalmic examination, which include electroretinogram (ERG), optical coherence tomography (OCT), and fundus autofluorescence (FAF), and their DNA samples were screened for RPE65 variants using Sanger sequencing. RESULTS: Among the 44 patients studied, 8 (18.2%) harboured disease-causing pathogenic or likely pathogenic biallelic variants in the RPE65 gene. Of these, 47.7% were male and 52.3% female; in all affected individuals, symptom onset preceded the fourth birthday. Four distinct missense variants were identified: three classified as likely pathogenic and one as pathogenic. One variant (p.Phe472Ser) was novel, with no prior reports in the literature or public databases. Affected patients demonstrated visual impairment within the first decade of life. RPE65 variants were mainly associated with nystagmus and markedly reduced rod and cone function on ERG. There was bilateral thinning of outer retinal layers outside the fovea with the disruption of the ellipsoid Zzone (EZ) and retinal pigment epithelium (RPE) layers by OCT, as well as diminished normal fluorescence in fundus autofluorescence testing in patients harbouring disease-causing RPE65 genetic variants. CONCLUSION: RPE65 gene variants account for 18.2% of this selected paediatric IRD cohort and represent an important genetic cause of LCA and ECORD in the Egyptian population. Expanded access to gene therapy trials is critically needed for eligible patients.