The clustering of functionally related genes contributes to 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 × 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.

Characterization of chromosomal abnormalities in pregnancy losses reveals critical genes and loci for human early development

“…In addition to HOX genes, we found that developmental genes were also clustered in the genome regardless of gene family, which led to the identification of 31 genomic loci containing at least four predicted developmental genes each. Our finding is consistent with a recent study showing the clustering of functionally related genes in the genome (Andrews et al., ). Since CNVs detected in products of conception could affect multiple clusters of developmental genes, which eventually led to the pregnancy loss or severe congenital malformations, we further examined the clinical phenotypes caused by CNVs affecting each genomic loci with clustered developmental genes.…”

The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease

“…Compared with single-nucleotide variants (SNVs), CNVs are responsible for more than ten times the heritable sequence differences in general populations (Pang et al 2010), and their genome-wide map has been comprehensively studied (Zarrei et al 2015). Likewise, they are involved in the pathogenesis of both sporadic Mendelian disorders and complex multifactorial disease (Andrews et al 2015; Stankiewicz and Lupski 2010; Weischenfeldt et al 2013). It is noteworthy that common CNVs and SNPs in relatively nearby regions have been associated with an increased likelihood of causing the same phenotype, such as Crohn disease (McCarroll et al 2008a), rheumatoid arthritis and type 1 diabetes etc.…”

Integrative Variation Analysis Reveals that a Complex Genotype May Specify Phenotype in Siblings with Syndromic Autism Spectrum Disorder

“…Adding exome genes to the network of each sibling showed that, as stated by Andrews et al [30], the more connected the genes were, the more severe was the clinical presentation. The male sibling had a network that was more well connected, and, with the inclusion of the exome, more genes from the translocation were included.…”

“…However, recurrent CNVs have been associated with an increased risk of other neurodevelopmental disorders, such as schizophrenia and epilepsy [28]. Various authors have attempted to improve the understanding of the nature of CNVs and to elucidate their contribution to specific phenotypes [29,30]. In patients with developmental disorders, Andrews et al [30] found that, if protein-protein interactions are taken into account, patients with genic (especially de novo ) CNVs, disrupting the same cluster of functionally related genes, present phenotypes that are more similar than would be expected.…”

“…Various authors have attempted to improve the understanding of the nature of CNVs and to elucidate their contribution to specific phenotypes [29,30]. In patients with developmental disorders, Andrews et al [30] found that, if protein-protein interactions are taken into account, patients with genic (especially de novo ) CNVs, disrupting the same cluster of functionally related genes, present phenotypes that are more similar than would be expected. Whole-exome sequencing studies have reported that de novo non-synonymous single nucleotide variants (SNVs) and small insertions and deletions (indels) are strongly associated with ASD [31–34].…”