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/β-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/β-catenin genes, the , , , and 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/β-catenin genes.

Main Outcome Measures: The phenotype associated with or without pathogenic variants of the Norrin/β-catenin genes.

Results: One-hundred eight probands (38.4%) had 88 different pathogenic or likely pathogenic variants in the genes: 24 with the , 42 with the , 10 with the , and 12 with the gene. Compared with the 173 probands without pathogenic variants, the 108 variant-positive probands had characteristics of familial predisposition (63.9% vs. 37.6%, < 0.0001), progression during infancy (75.0% vs. 53.8%,  = 0.0004), asymmetrical severity between the 2 eyes (50.0% vs. 37.6%,  = 0.0472), and nonsyndromic characteristics (10.2% vs. 17.3%,  = 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%,  < 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%,  = 0.0346). Nine probands with variants had features different from probands with typical Norrin/β-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/β-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.

Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.