Abstract
Purpose: :
Copy number variations (CNVs) in the human genome cover deletions or gains of single or multiple genes. When annotating genes reported in CNV studies of brain disorders against retinal disorders, we noted an overlap of loci (e.g. WFS1). Consequently, we generated a list of retinal disease genes (RDGs) and screened in silico for overlapping loci in CNV studies of brain disorders and controls.
Methods: :
For this in silico study, n=368 RDGs were retrieved from NEIBank (Eye Disease Genes, View by Tissue). The Cooper-database for CNVs contains large rearrangements for 19K human genes in n=8,329 controls and n=15,767 cases with developmental delay, mostly related to brain disorders (Cooper et al., Nature Genetics, 2011). Overlapping loci were determined, by setting the threshold at n=3 CNV per RDG. Deletions and duplications were analyzed separately. For replication, gene lists from CNV studies in psychiatric disorders were screened for RDGs.
Results: :
N=114 RDGs (30%) were found to match the Cooper-dataset, i.e. n=91 RDGs in deletions (causing haploinsufficiency), n=63 RDGs in duplications, and n=40 RDGs in both; these numbers are in the random range with the threshold set at n=3 CNVs. 15/91 RDGs were in deletions and 13/63 in duplications of genomic disorders that were annotated in the database as previously described. Retinal involvement was part of complex syndromes for most of the other matched genes (OMIM). No enrichment for cases was evident. N=41 of matched genes were listed in RetNet, i.e. n=28 as autosomal recessive forms, n=6 as autosomal dominant, and n=7 as both. N=8/12 RDGs found in CNV datasets for psychiatric disorders also matched the Cooper-dataset, indicating good replication.
Conclusions: :
Using a data-mining approach, a subset of about 30% of known RDGs was compiled that is overlapping with large scale sequence rearrangements. This dataset can now guide ophthalmic investigations to find out whether retinal dysfunction or dystrophy is part of the complex phenotype associated with new CNVs. These findings may also stimulate the investigation of CNVs for loci of retinal disorders in which the causative gene remains to be identified.
Keywords: genetics • degenerations/dystrophies • retina