Abstract
PURPOSE: The genetic spectrum and early clinical indicators of familial exudative vitreoretinopathy (FEVR) remain incompletely defined, and few studies have investigated the genetic variants and clinical phenotypes associated with eoHM-FEVR and anisometropia-FEVR patients. The purpose of this study was to screen the pathogenic variations in 11 FEVR families and analyze the refractive status and pathogenic genes in patients with irregular dominantly inherited FEVR. METHODS: The patients with clinical diagnoses of eoHM-FEVR or anisometropia-FEVR were evaluated from October 2019 to August 2022. Comprehensive ophthalmic tests were performed on participants to confirm the phenotype. The genotype was identified using whole-exon sequencing and further verified the results among other family members by Sanger sequencing. Normal protein structures were modeled with AlphaFold, whereas mutant variants were analyzed via PyMOL. Variant pathogenicity followed the American College of Medical Genetics and Genomics (ACMG) guidelines. The protein-protein interaction (PPI) network analysis with STRING and k-means clustering was applied for detecting the interaction of genes in the candidate genes, and the ClusPro Server was used for protein-protein docking. RESULTS: A total of 11 FEVR families were included in the study, and all the probands were found to have high myopia in both eyes or one eye before the age of 7 years. The pathogenic variants were identified in the genes TSPAN12, LRP5, and FZD4 known to be associated with FEVR in six probands. Among 13 eoHM-related genes, FZD4 and LRP2 encode proteins that can dock together as analyzed by ClusPro software. CONCLUSION: This study observed dominant inheritance of an irregular pattern in FEVR families, with asymmetric FEVR presenting as severe anisometropia. The eye with higher myopia often had more advanced FEVR and pronounced fundus changes. PPI network analysis revealed important modules of gene interaction, and the FZD4-LRP2 complex protein was potentially related to high myopia development. For patients with high myopia or with obvious anisometropia in both eyes, more attention should be paid clinically to the comprehensive examination of the peripheral fundus and early genetic testing.