Genetic Analysis and Phenotypic Staging of Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy

Abstract

Purpose: : To describe a new ADNIV pedigree, stage disease progression, perform linkage analysis, and test candidate genes.

Methods: : The phenotype of an 8-generation ADNIV pedigree was ascertained. Fine mapping with STRP markers and a 50-K SNP array was performed. High-resolution tiling arrays covering this interval were used for comparative genomic hybridization to study copy number variation. A bioinformatic analysis identified candidate genes with both expression in the eye and immune function. DNA sequencing of the coding, promoter, and intron sequences was performed for candidate genes.

Results: : 40 affected subjects were examined and categorized into five disease stages that showed progressive clinical features with photoreceptor degeneration, panuveitis, neovascularization, fibrosis, and retinal detachment. Electroretinography confirmed early selective loss of the b-wave and revealed later loss of oscillatory potentials. Analysis of this pedigree refined the linked interval to a 6 megabase region (70,181,917-76,713,571) between rs879380 and D11S1789. No gene amplifications or deletions were detected. The interval contained 87 candidate genes. DNA sequencing of the inflammation-associated genes TNFRSF19L and IL18bp and the retinal dystrophy genes BEST1 and FZD4 did not reveal any mutations.

Conclusions: : ADNIV is a progressive autosomal dominant disease with stages similar to retinitis pigmentosa, idiopathic uveitis, diabetic retinopathy, and proliferative retinopathy. Identification of the causative gene will give important insight into the mechanisms of these pathological processes.

Keywords: genetics • uveitis-clinical/animal model • retinal degenerations: hereditary