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J.M. Robitaille, M.L. MacDonald, D.L. Guernsey, B. Zheng, L.S. Siebert, A. Hoskin-Mott, M.J. Beis, M.R. Hayden, Y.P. Goldberg, M.E. Samuels; Mutant Frizzled-4 (FZD4) Causes Autosomal Dominant Familial Exudative Vitreoretinopathy (FEVR) With Variable Intrafamilial Phenotype . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1477.
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Purpose: Familial exudative vitreoretinopathy (FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization inducing neovascularization that may result in retinal detachment and blindness. There are three identified FEVR loci, at 11q (EVR1), Xp (EVR2) and 11p (EVR3). The aim of this study was to identify a gene for autosomal dominant FEVR and describe the phenotype. Methods: We ascertained a large multigenerational Canadian family segregating FEVR. Clinical examinations were done for all participants as well as a chart review for each affected family member. Blood samples were collected to refine the disease locus and investigate candidate genes within the region. Results: We confirmed linkage to the EVR1 locus in this family and further refined the disease locus to a small genomic region spanning about 1.5 Mb. Investigating candidate genes within the region, we found a novel deletion of two amino acids in FZD4, a member of the Wnt receptors, which segregated completely with affected individuals in the family. This mutation was not observed in 153 control chromosomes. 30 members of the family were identified with FEVR and presented a variable phenotype ranging from asymptomatic to complete blindness (no light perception) in both eyes. The age of onset of legal blindness (visual acuity < 20/200) occurred as early as 2 months of age, but delayed onset was also a feature in some affected members. Conclusion: The range of clinical manifestations of FEVR in this family will be presented. The identification of FZD4 as causative of FEVR establishes the role of a Wnt receptor in retinal angiogenesis and a single mutation found in this family causes a variable phenotype.
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