Clinical Classification of Autosomal Dominant Cystoid Macular Edema and Genetic Fine Mapping of the Underlying Defect

Abstract

Purpose: : The present study was conducted to describe the clinical characteristics in a large extended pedigree with autosomal dominant cystoid macular edema (CYMD), and to identify the genetic cause of the disease.

Methods: : Seventy-one members of a large Dutch CYMD family were ophthalmically examined by visual acuity testing, slit lamp examination, Goldmann perimetry and spectral-domain optical coherence tomography (OCT). In addition, fluorescein angiography, color vision tests, electro-oculography (EOG) and electroretinography (ERG) were performed in selected cases. The CYMD locus was previously positioned to a 20-cM interval at 7p15-p21. The linkage interval was fine-mapped employing DNA of 135 family members, and the entire genomic interval was analysed for variants using next-generation sequencing.

Results: : We classified the progression of CYMD into three stages based on age and degree of vision loss. In stage 1 fundoscopic fine folding of the foveal inner limiting membrane was present. In stage 2 fundoscopic cystoid macular edema was seen and stage 3 showed atrophy of the retinal pigment epithelium and peripheral pigmentary alterations. OCT abnormalities consist of small cysts in stage 1 and progressed to retinal atrophy in stage 3. Generally, with progression in stage, EOG and ERG responses became more aberrant and visual fields showed increased central sensitivity loss and central scotoma. Genetic fine mapping enabled us to establish a shared haplotype refining the critical region to a 3.8 cM/2.0 Mb interval between the markers D7S493 and D7S673 at 7p15.3. All 17 genes within the interval were analysed by next-generation sequencing, which did not reveal a causative variant in the coding regions of these genes.

Conclusions: : Three clinical stages can be distinguished in CYMD. The genetic locus for this retinal dystrophy is refined to a 2.0 Mb interval at 7p15.3. No mutation was identified in the coding exons in this region, suggesting that the genetic defect may be located in the intronic or intergenic regions, or may involve a more complex rearrangement.

Keywords: edema • genetics