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Purpose: To identify the genetic defect in the FZD4 gene responsible for familial exudative vitreoretinopathy (FEVR) in a Japanese family., Design: Interventional case report., Methods: Complete ophthalmologic examinations were performed, and the FZD4 gene was analyzed by direct genomic sequencing., Results: Fundus examination of a 13-year-old Japanese girl who had had esotropia and exudative retinal detachment at 3 years exhibited peripheral avascular areas bilaterally, a dragged disk, and retinal holes unilaterally. In contrast, her asymptomatic father had only bilateral avascular areas in the peripheral retina. Molecular genetic analysis revealed that both the proband and her father had a heterozygous missense mutation of A to G at 1026 bp of the FZD4 gene (Met342Val)., Conclusions: A novel mutation in the FZD4 gene was identified in Japanese patients with FEVR. Our observations support the hypothesis that the FZD4-associated FEVR might represent a milder form than that associated with other genetic origins.

Background: Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder characterized by impaired vascularization of parts of the peripheral retina. Autosomal dominant FEVR (adFEVR), a major form of FEVR and assigned to chromosome 11q13-23 (EVR1) locus, is caused by deletion mutations in the C- terminal region of the frizzled-4 (FZD4) gene. This paper describes the clinical phenotype of adFEVR in two Japanese families with two different mutations in the FZD4 gene., Methods: We encountered three Japanese patients with adFEVR and studied them using mutation analysis of the FZD4 gene with PCR, sequencing, and a restriction enzyme digestion., Results: Two previously unreported missense mutations, p.H69Y and p.C181R, were identified in the N-terminal extra- cellular region of two of the patients. This region was highly conserved among other vertebrate species and FZD family members, unlike the C-terminal region. Co-segregation analysis revealed that all affected individuals carried one of these mutations, while unaffected individuals did not. The mutations were not detected in normal individuals (n=120). The affected individuals had mild to severe retinal abnormalities., Conclusions: FZD4 mutations in either the N- or C-terminal region underlie adFEVR, which indicates that FZD4 plays an important role in retinal angiogenesis. Analysis of FZD4 mutations in families with adFEVR is useful for genetic counseling and for early diagnosis