Early onset high myopia and severe anisometropia associated with familial exudative vitreoretinopathy of irregular dominant inheritance in 12 Chinese families：analysis of refraction features and pathogenic variations

Abstract Purpose Familial exudative vitreoretinopathy (FEVR) is a hereditary blinding vitreoretinopathy characterized by anomalous retinal vascularization. In the early stages, patients are mostly asymptomatic and prone to missed diagnosis because the lesion is located in the peripheral part of the retina. Early-onset high myopia and severe anisometropia are often the earliest reasons for ophthalmologic consultation in FEVR patients. However, there are few studies on 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 12 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 constructed with alphfold, and mutant proteins were visualized and analyzed with pymol software. The pathogenicity of the variants was determined in accordance with the guidelines of the American College of Medical Genetics and Genomics (ACMG). The protein-protein interaction (PPIs) network analysis with STRING and k mean clustering was applied for detecting the interacting of genes in the candidate genes and the ClusPro Server was used for protein-protein docking. Results A total of 12 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, VCAN, and FZD4 known to be associated with FEVR in 7 probands. FFA examination found that FEVR patients in all families showed the onset of the disease earlier than the previous generation, and the disease gradually worsened. It should be noted that the FEVR probands in all families showed an earlier age of onset than the previous generation and a more severely fundus abnormalities in the fundus examination and fluorescin angiography. Among them, 3 probands had severe anisometropia and asymmetric fundus changes in both eyes and showed the higher the degree of myopia, the worse the best corrected visual acuity and the more serious the degree of FEVR. Cluster analysis show 13 eoHM related gene blong to 3 cluster, which belong to collagen-containing extracellular matrix cellular component, endosome lumen and Wnt signaling pathway respectively. Among the 13 eoHM related genes, FZD4 and LRP2 encode protein can dock by together analyzed by ClusPro software, the same to VCAN and FBN1 encoding protein. The complex protein, FZD4-LRP2 and VCAN-FBN1 play a bridge role among eoHM related gene according to PPI network analysis. Conclusion In this study, the FEVR families showed the phenomenon of irregular dominant inheritance. The asymmetric FEVR manifested as severe anisometropia and the eye with the higher myopia tends to have a more heavily staged FEVR and more pronounced fundus changes. PPIs network analysis revealed important modules of gene interacting and FZD4-LRP2 and VCAN-FBN1 complex protein were 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 comprehensive examination of the peripheral fundus and early genetic testing.