Five novel pathogenic FZD4 variants identified in familial exudative vitreoretinopathy

Abstract

Purpose

Familial exudative vitreoretinopathy (FEVR) is a genetically heterogeneous retinal vascular disorder, with nearly half of the cases attributed to mutations in genes involved in the Norrin/β-catenin signaling pathway. This study aimed to identify and functionally characterize novel FZD4 variants in patients with FEVR.

Methods

Genetic sequencing of FZD4 was performed in a cohort of FEVR families, leading to the identification of five novel variants: c.434G ​> ​A, c.610T ​> ​G, c.844T ​> ​C, c.277C ​> ​T, and c.1155delC. Bioinformatic predictions, comprehensive clinical evaluations, and dual-luciferase reporter assays were conducted to assess the functional impact and pathogenicity of these variants.

Results

All five FZD4 variants were found to significantly reduce β-catenin signaling activity compared to wild-type FZD4. Among them, two variants previously classified as variants of uncertain significance (VUS) demonstrated functional impairment and clinical segregation consistent with pathogenicity, supporting their reclassification as disease-causing mutations.

Conclusions

These findings expand the known mutational spectrum of FZD4 in FEVR and highlight the critical role of functional validation in the interpretation of novel and uncertain variants. Incorporating experimental assays can improve diagnostic accuracy and inform clinical genetic counseling.