Whole-Exome Sequencing Identified as a Candidate Gene for Familial Exudative Vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is a blinding retinal vascular disease. Clinically, FEVR is characterized by incomplete vascularization of the peripheral retina and pathological neovascularization. Only about 50% of FEVR cases can be explained by known FEVR disease gene variations. This study aimed to identify novel genes associated with the FEVR phenotype and explore their pathogenic mechanisms. Exome sequencing analyses were conducted on one Chinese family with FEVR whose affected members did not exhibit pathogenic variants in the known FEVR genes (verified using Sanger sequencing analysis). Functions of the affected proteins were evaluated using reporter assays. Western blot analysis was used to detect mutant protein expression and the genes' pathogenic mechanisms. A rare novel heterozygous variant in (c.1792A>G; p.S598G) was identified. The amino acid residues surrounding the identified variant are highly conserved among vertebrates. A luciferase reporter assay revealed that the mutant DLG1 protein DLG1 lost its ability to activate Wnt signaling. Moreover, a knockdown (KD) of in human primary retinal endothelial cells impaired tube formation. Mechanistically, KD led to a reduction in phosphorylated VEGFR2, an essential receptor for the angiogenic potency that signals the vascular endothelial growth factor molecule. The data reported here demonstrate that is a novel candidate gene for FEVR.