FZD4 in a Large Chinese Population With Familial Exudative Vitreoretinopathy: Molecular Characteristics and Clinical Manifestations

Abstract

Purpose The purpose of this study was to establish a genotype-phenotype correlation of familial exudative vitreoretinopathy (FEVR) caused by FZD4 gene mutations. Methods Six hundred fifty-one probands and their family members were recruited based on a clinical diagnosis of FEVR between 2015 and 2021 at Zhongshan Ophthalmic Center. Ocular examinations were performed in all participants. Targeted gene panel sequencing and whole-exome sequencing were performed in the probands, and Sanger sequencing was used to verify the mutations and segregation analysis was performed in the family members. Results Fifty-one FZD4 mutations (24 novels and 27 known) were detected in 84 families. Of these 168 eyes with FEVR, the eyes at stages 1, 2, 3, 4, and 5 were 29 (17.3%), 15 (8.9%), 19 (11.3%), 55 (32.7%), and 12 (7.1%), respectively. Exact stage of 38 (22.6%) eyes could not be determined. The FEVR phenotypes were more severe in the probands than the phenotypes in the family members ( P < 0.001). The families were divided into two groups, probands that inherited the variant from the mother, and probands that inherited the variant from the father. In addition, the FEVR stage differences between these two groups were different ( P < 0.05). Despite the mutations being located in different domains of FZD4 , no significant differences were identified among the domains in terms of FEVR staging, retinal folds, retinal detachment, temporal midperipheral vitreoretinal interface abnormality, and foveal hypoplasia. Conclusions The FZD4 probands had severer phenotype than the family members, and the FEVR stage difference was greater between the probands and mothers than that between the probands and fathers.

Decrease of FZD4 exon 1 methylation in probands from FZD4-associated FEVR family of phenotypic heterogeneity

“…The FZD4 gene encodes a 537-amino acid protein, which functions as a receptor of the Wnt signaling pathway (42). According to our previous work, more than half (51.43%) in the FZD4 group were identified asymmetry, suggesting FZD4 mutations might initiate the most diverse and asymmetric phenotypes (22). Previous study suggested epigenetic modifications might involve in the developing fetal retina which caused high asymmetric FZD4 gene expression (43).…”

“…FEVR is a rare disease featured by peripheral retinal vascular abnormalities ( 19 , 34 ). It is clinically characterized by phenotypic heterogeneity, suggesting that non-genetic factors are involved in disease etiology ( 2 , 22 , 23 ). Comparing the epigenetic features among FEVR family members with or without mutation would provide important information regarding epigenetic factors which could contribute to phenotypic heterogeneity.…”

“…The inheritance patterns of FEVR include autosomal dominant (AD), autosomal recessive (AR), and X-linked recessive (XL), with AD being the most common mode. Despite clear definition of causative genes, mutations of the same gene often manifest with drastic phenotypic heterogeneity in carriers ( 2 , 22 , 23 ). First-degree relatives of index patients with severe FEVR are often asymptomatic despite carrying the same mutation ( 24 ).…”

Familial Exudative Vitreoretinopathy and Systemic Abnormalities in Patients With CTNNB1 Mutations

“…Family members with different phenotype severity is a common occurrence in CTNNB1 -associated FEVR, 24 and has also been observed in FEVR associated with other genes, such as FZD4. 28 The reason for this is unknown, and thus further study is needed to determine the mechanism.…”

“…All probands and their family members underwent complete ophthalmic examinations, as described in our previous study. 28 Patients who could not cooperate with the examination were examined while under sedation. The anterior segment was examined using a handheld slit lamp (Keeler, Malvern, PA, USA), and the fundus was examined via RetCam wide-field fundoscopy (Clarity Medical Systems, Pleasanton, CA, USA).…”