Background: Familial exudative vitreoretinopathy (FEVR, OMIM 133780) is a severe inherited eye disease characterized by abnormal development of the retinal vasculature. Variants in the reported genes account for ∼50% of total FEVR cases. However, the pathogenesis of the other 50% of FEVR cases remains unclear. Therefore, it is crucial to identify novel variants responsible for the pathogenesis of FEVR. Aims: To find causative variants responsible for FEVR in two Han Chinese families. Materials and Methods: We recruited two families with FEVR patients and applied exome sequencing on the genomic DNA samples from the probands. Sanger sequencing was performed for variant validation. Western blot analysis and luciferase assays were performed to test the expression levels and activity of the mutant proteins. Results: We identified two novel missense variants in the LRP5 gene (NM_002335), c.1176 C > A (p.Asp392Glu) and c.2435 A>C (p.Asp812Ala), both inherited in an autosomal dominant manner. Both variants significantly reduced Norrin/β-catenin signaling activity without affecting the expression of the LRP5 protein. Conclusion: This study expands the variant spectrum of the LRP5 gene for FEVR, providing valuable information for prenatal counseling and molecular diagnosis of FEVR.
Keywords: FEVR; LRP5 variants; Wnt signaling; exome sequencing.