Abstract
PURPOSE: To report the variants and genotype-phenotype correlations in patients with familial exudative vitreoretinopathy (FEVR) included in the eyeGENE database. METHODS: A retrospective study was conducted in a cohort of 122 eyeGENE patients from 114 families with FEVR. Clinical details and genetic test results were provided by referring clinicians and clinical laboratories in the eyeGENE network, respectively. Genotype and phenotype information was reviewed, and reported variants were reclassified. RESULTS: Genetic test reports of 50 probands revealed 52 variants in the four genes of the Norrin/β-catenin signaling pathway: LRP5, FZD4, TSPAN12, and NDP. Following variant reclassification, 35 of the reported variants were interpreted as pathogenic or likely pathogenic (12 in LRP5, 11 in FZD4, seven in TSPAN12 and five in NDP), providing a conclusive test result for nearly one-third (32%) of the probands. Among the reported variants, 18 were novel (34.6%) and two-thirds were missense. Retinal detachment was reported less in patients with variants in TSPAN12 (P = 0.017). One-third of the patients (33.3%) with an FZD4 variant had asymmetric findings. In contrast, asymmetry was less pronounced in patients with variants in TSPAN12 (11.1%). CONCLUSIONS: This was one of the largest cohorts reviewed from North America, expanding the variant spectrum in FEVR. Among the eyeGENE FEVR patients, disease-associated variants in Norrin/β-catenin signaling pathway genes can explain one-third of the cohort. LRP5 and FZD4 variants were the most common. The genotype-phenotype correlations supported the phenotypic variability in FEVR.