Genetic Study of Familial Exudative Vitreoretinopathy

Abstract

Abstract: : Purpose: Familial exudative vitreoretinopathy (FEVR) is an autosomal dominant retinal dystrophy characterized by premature arrest of normal retinal angiogenesis and incomplete vascularization of the peripheral retina. Vitreous hemorrhage and tractional retinal detachments are two severe complications of FEVR. FEVR is genetically heterogeneous, with three loci mapped and two genes identified. Two mutations on chromosome 11q, the LRP5 and FZD4 mutations, have been shown to be associated with FEVR. We and other have shown that the Wnt signaling pathway plays an important role in retinal angiogenesis. The purpose of this study was to characterize clinical features and screening for mutations in a panel of 115 FEVR patients. Methods: Fundus photographs and fluorescein angiograms (FA) were performed to assess the retinal vasculature. Genomic DNA was PCR–amplified with primers corresponding to the coding sequence of FZD4 and LRP5. The PCR products were screened for mutations by direct sequencing. Results: Affected patients presented with a variety of fundus and FA features including macular folds, temporal macular dragging, macular edema and lipid exudation, peripheral non–perfusion, peripheral vascular mass, traction retinal detachment, vitreous hemorrhage. There is a marked intra and inter familial expression of the clinical phenotype. Mutation analysis revealed 5 mutations in FEVR, one in LRP5. Conclusions: There is a marked intra and inter familial expression of the clinical phenotype, suggesting a genetic modifier effect. Mutations in FZD4 and LRP5 may only represent a small fraction of the underlying genetic cause of FEVR. We have established a FEVR research consortium (American FEVR Research Consortium, http://fevr.genetics.utah.edu) with a world–wide referral network to facilitate clinical care and research participation of FEVR patients. Our clinical and genetic studies will aid better classification and treatment of FEVR.

Keywords: retinal degenerations: hereditary • gene mapping