Purpose: To identify novel mutations in the frizzled 4 (FZD4) gene in patients with familial exudative vitreoretinopathy (FEVR) in southern China and to delineate the mutation-associated clinical manifestations.
Methods: Clinical data and genomic DNA were collected from 100 probands and their family members. The coding regions of FZD4 were screened for mutations with PCR and Sanger sequencing. Cosegregation analysis was used to verify suspected variants, and clinical symptoms in the probands were analyzed.
Results: Fourteen causative heterozygous mutations in FZD4 in 21 unrelated probands were noted, in 21.0% of the index patients (21/100). Four novel missense mutations (C45R, C45S, C53S, and C90R) and three novel deletion mutations (T326fsX356, G492fsX512, and S345_A351del) with a high possibility of pathogenicity were detected. None of these mutations were found in current online databases and 150 ethnically matched control subjects without retinopathy. The majority of the mutations in FZD4 were identified in probands with retinal folds (15/21) and ectopic macula (5/21). No mutations in FZD4 were found in probands with complete tractional retinal detachment in infancy or with mild asymptomatic FEVR in adulthood.
Conclusions: Seven novel mutations found in this study have broadened the spectrum of mutations in FZD4 known to cause FEVR, providing a deeper understanding of this disease. The results show that mutations in FZD4 are associated with the phenotypes of retinal folds or ectopic macula in FEVR but might not be associated with extreme severe bilateral FEVR during infancy, at least in southern Chinese patients.