The overarching goal of this VCEP is to curate clinically relevant genes and variants associated with Leber congenital amarosis (LCA)/early-onset retinal degeneration (eoRD). Inherited retinal degenerations are a clinically and genetically heterogenous group of Mendelian conditions resulting in progressive, irreversible blindness. The incidence of IRD is estimated to be approximately 1 in 3000 in western populations. To date, pathogenic variants in more than 270 genes affecting diverse biochemical pathways have been implicated in IRD. Among these, LCA/eoRD are comprised of a spectrum of severe retinal disorders ranging from the congenital LCA to the eoRD with onset typically before age five years and segregate in autosomal dominant and recessive modes. These are the leading cause of irreversible blindness in children. About 30 genes have been reported to be associated with these phenotypes. Pathogenic variants in these genes are estimated to contribute to about 75%-80% cases of LCA/eoRD, and genetic testing is widely available for these conditions.

Availability of vectors for the efficient delivery of genes to desired cell types, advances in gene editing or correction methodologies lead to a wide range of pre-clinical and clinical studies to evaluate therapies for LCA/eoRD phenotypes. Importantly, the FDA has recently approved the first gene therapy treatments for LCA associated with the RPE65 gene and additional clinical trials are currently under way to offer sight-saving treatments for patients with other LCA/eoRD. Therefore, we plan to initially focus on the RPE65, GUCY2D, AIPL1 and CEP290 genes that have FDA approval or are in human phase I or II clinical trials, as these treatments are likely to become available for patients in the near future if approved by FDA. An U24 proposal was submitted to the National Eye Institute to help fund this initiative.