Background: Familial exudative vitreoretinopathy (FEVR, OMIM 133780) is a severe inherited retinal disorder characterized by incomplete retinal vascular development and neovascularization. At least five genes have been reported to be associated with FEVR, including NDP, LRP5, FZD4, TSPAN12, and ZNF408. Recently reported data showed that mutations in the KIF11 gene can also lead to FEVR conditions. Previous studies suggested that known mutations only explain approximately 40-60% of FEVR cases in different populations.
Purpose: To investigate the causative genetic mutations in four Indian families with FEVR.
Methods: Whole exome sequencing was carried out to analyze the genomic DNA samples from the four FEVR proband patients and Sanger sequencing was utilized to verify all identified polymorphisms. A luciferase assay was used to test the mutant protein activity.
Results: We identified four novel LRP5 missense mutations in these FEVR families: c.C1042T (p.R348W), c.G1141A (p.D381N), c.C1870T (p.R624W), and c.A4550G (p.Y1517C). The luciferase assay demonstrated that all four of these LRP5 mutations led to significant reduction of enzymatic activity with response to NORRIN, suggesting that they are pathogenic.
Conclusion: Our findings expand the mutational spectrum of FEVR in the Indian population and provide some guidelines in clinical diagnosis.