The clustering of functionally related genes contributes to CNV-mediated disease

Tallulah Andrews, Frantisek Honti, Rolph Pfundt, Nicole De Leeuw, Jayne Hehir-Kwa, Anneke Vulto Van Silfhout, Bert De Vries, Caleb Webber

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


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 × 10-3). 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 haploinsufficient 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= 6×10-4). 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.

Original languageEnglish
Pages (from-to)802-813
Number of pages12
JournalGenome Research
Issue number6
Publication statusPublished - 1 Jun 2015
Externally publishedYes


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