Clustering of functionally-related genes impacts significantly on CNV-mediated disease

Abstract

Clusters of functionally-related genes can be disrupted by a single copy-number variant (CNV). We demonstrate that the simultaneous disruption of multiple functionally-related genes is a frequent and significant characteristic of de novo CNVs in patients with developmental disorders (p = 1 x10-3). Using three different functional networks, we identified unexpectedly large numbers of functionally-related genes within de novo CNVs from two large independent cohorts of individuals with developmental disorders. The presence of multiple functionally-related genes was a significant predictor of a CNV's pathogenicity when compared to CNVs from apparently healthy individuals, and a better predictor than the presence of known disease or haplo-insufficient genes for larger CNVs. The functionally-related genes found in the de novo CNVs belonged to 70% of all clusters of functionally related genes found across the genome. De novo CNVs were more likely to affect functional clusters and affect them to a greater extent than benign CNVs (p = 6 x 10-4). Furthermore, such clusters of functionally-related genes are phenotypically-informative: different patients possessing CNVs that affect the same cluster of functionally-related genes exhibit more similar phenotypes than expected (p < 0.05). The spanning of multiple functionally-similar genes by single CNVs contributes substantially to how these variants exert their pathogenic effects.