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The combination of exome sequencing and bioinformatics analyses of large expression datasets can be highly effective in prioritization of candidate genes. In a young adult male with congenital cataract, retinal degeneration, epilepsy and leukodystrophy, routine studies were not informative. Exome sequencing of gDNA identified over 30 de novo heterozygous variants. To identify candidates for ocular phenotypes, we used the iSyTE database which provides meta-analysis of expression profiles of photoreceptor and lens datasets. iSyTE identified EZR (Ezrin) and NR2E3 (Nuclear Receptor Subfamily 2, Group E, Member 3) as top candidate genes in the lens and photoreceptors respectively. Expression of Ezr is enriched in the mouse lens pre and postnatally as well as the adult mouse retinal pigment epithelium, and is the best candidate to explain a congenital cataract phenotype. EZR functions asa protein-tyrosine kinase substrate in microvilli and plays a key role in cell surface structure adhesion, migration and organization. Recently, a few EZR variants in individuals with age related cataract and epilepsy had been reported. Nr2e3 is only expressed in the lens postnatally, but it has high expression in photoreceptors, and defects in NR2E3 (a nuclear transcription factor) cause retinitis pigmentosa as well as the enhanced S cone syndrome. The two de novo heterozygous variants found in this individual are predicted to be deleterious.The enriched expression of EZR in the developing lens and of NR2E3 in retinal photoreceptors, together with the reported human phenotypes, suggest that mutations in these two genes caused cataract and retinal degeneration in this individual.

Cataract; Retinal Degeneration; Exome; Leukodystrophy, Epilepsy, iSYTE; Mutation