Abstract
Purpose :
Inherited retinal diseases (IRDs) are a large group of clinically and genetically heterogeneous conditions characterized by progressive deterioration of vision. There is a broad phenotypic and genotypic variability between the different forms. Genetic evaluation in patients with IRDs is important for clinical management, prognosis, counseling, research, and drug development. The purpose of this study is to evaluate the pathogenicity of variants in a large cohort of pediatric patients with IRDs.
Methods :
This retrospective study evaluated a cohort of 4232 patients enrolled into an IRB approved nystagmus registry between 2013 - 2023. Clinical, demographic, and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. 175 unrelated pediatric patients with a clinical diagnosis of a variety of ocular disorders were examined using next-generation sequencing (NGS) with targeted gene panels.
Results :
The most prevalent ocular disorders identified clinically were Oculocutaneous albinism (31.2%), Leber congenital amaurosis (14.8%), Achromatopsia (9.0%), Stargardt’s disease (8.2%), X-linked congenital nystagmus (6.6%), Congenital stationary night blindness (5.7%), X-linked retinitis pigmentosa (4.9%), and Cone-rod dystrophy (3.3%). Of the 175 patients with a confirmed genetic testing, 122 (70%) different likely causative variants in 53 genes were identified. The 8 most frequently mutated genes were TYP (n = 15; 12.3%), OCA2 (n =13; 10.6%) in autosomal recessive (AR) or X-linked (XL) for oculocutaneous albinism; ABCA4 (n =8; 6.5%) in autosomal dominant (AD), or AR for Stargardt disease; CNGB3 (n =8; 6.5%), CNGA3 (n=3, 2.5%) in AR for Achromatopsia, RPGR (n =6; 4.9%) in X-linked for retinitis pigmentosa. FRMD7 (n =4; 3.3%), GPR143 (n=4; 3.3%) in X-linked for congenital nystagmus. The other 45 genes had a lower contribution to IRD pathogenesis (e.g., CACNA1F 2.5%; RHD12 2.5%; EYS 2.5%; RPE65 1.6%; MYO7A 1.6%; PDE6A 0.8%; GUCY2D 0.8%).
Conclusions :
Our analysis confirms the complex genetic etiology of IRDs and reveals the high prevalence of TYR, OCA2, ABCA4, CNGB3, RPGR and FRMD7 mutations. This study also shows genetic associations with a spectrum of clinical subgroups and highlights a valuable number of cases potentially eligible for ongoing and future gene therapy trials.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.