Familial Exudative Vitreoretinopathy With and Without Pathogenic Variants of Norrin/β-Catenin Signaling Genes

Purpose: To determine the clinical characteristics of familial exudative vitreoretinopathy (FEVR) associated with or without pathogenic variants of the Norrin/beta-catenin genes. Design: This was a multicenter, cross-sectional, observational, and genetic study. Subjects: Two-hundred eighty-one probands with FEVR were studied. Methods: Whole-exome sequence and/or Sanger sequence was performed for the Norrin/beta-catenin genes, the FZD4, LRP5, TSPAN12, and NDP genes on blood collected from the probands. The clinical symptoms of the probands with or without the pathogenic variants were assessed as well as differences in the inter Norrin/beta-catenin genes. Main outcome measures: The phenotype associated with or without pathogenic variants of the Norrin/beta-catenin genes. Results: One-hundred eight probands (38.4%) had 88 different pathogenic or likely pathogenic variants in the genes: 24 with the FZD4, 42 with the LRP5, 10 with the TSPAN12, and 12 with the NDP gene. Compared with the 173 probands without pathogenic variants, the 108 variant-positive probands had characteristics of familial predisposition (63.9% vs. 37.6%, P < 0.0001), progression during infancy (75.0% vs. 53.8%, P = 0.0004), asymmetrical severity between the 2 eyes (50.0% vs. 37.6%, P = 0.0472), and nonsyndromic characteristics (10.2% vs. 17.3%, P = 0.1185). The most frequent stage at which the more severe eye conditions was present was at stage 4 in both groups (40.7% vs. 34.7%). However, the advanced stages of 3 to 5 in the more severe eye were found more frequently in probands with variants than in those without variants (83.3% vs. 58.4%, P < 0.0001). Patients with rhegmatogenous retinal detachments progressed from stage 1 or 2 were found less frequently in the variant-positive probands (8.3% vs. 17.3%, P = 0.0346). Nine probands with NDP variants had features different from probands with typical Norrin/beta-catenin gene variants including the sporadic, symmetrical, and systemic characteristics consistent with Norrie disease. Conclusions: The results showed that the clinical characteristics of FEVR of patients with variants in the Norrin/beta-catenin genes are different from those with other etiologies. We recommend that clinicians who diagnose a child with FEVR perform genetic testing so that the parents can be informed on the prognosis of the vision and general health in the child.