Frizzled 4 Gene (FZD4) Mutations in Patients with Familial Exudative Vitreoretinopathy with Variable Expressivity

Abstract

Abstract: : Purpose: To search for mutations in the frizzled 4 (FZD4) gene in patients with familial exudative vitreoretinopathy (FEVR) and to delineate the defective-gene-associated clinical features. Methods: Direct sequencing following polymerase chain reaction of exons of FZD4 was performed for 24 probands with FEVR (18 familial and six sporadic), and some of their families. Clinical symptoms among individuals with mutations were assessed. Results: We identified five novel sequence changes in four patients with familial and two with sporadic FEVR. Four of these mutations were missense (Met105Val, Arg417Gly, Gly488Asp, and His69Tyr) and one was a nonsense change (Trp319Ter). Met105Val, Arg417Gly, and Gly488Asp co-segregated with the disease. A double mutation, Gly488Asp and His69Tyr, was found in one patient with familial FEVR, for whom compound heterozygosity was demonstrated. None of these sequence changes were found among 50 healthy volunteers except His69Tyr, which was found on two putatively healthy chromosomes. The severity of vitreoretinopathy in the individuals involved in this study varied, but no patient exhibited rhegmatogenous retinal detachment. Conclusions: FZD4 gene mutations were found in some cases of autosomal dominant and sporadic FEVR. FZD4 mutations were responsible for FEVR with variable clinical manifestations. However, these do not explain most cases of the disease, which are associated with rhegmatogenous retinal detachment.

Keywords: clinical laboratory testing • genetics • retinal detachment