Genetic architecture of reciprocal CNVs

Abstract

Copy number variants (CNVs) represent a frequent type of lesion in human genetic disorders that typically affects numerous genes simultaneously. This has raised the challenge of understanding which genes within a CNV drive clinical phenotypes. Although CNVs can arise by multiple mechanisms, a subset is driven by local genomic architecture permissive to recombination events that can lead to both deletions and duplications. Phenotypic analyses of patients with such reciprocal CNVs have revealed instances in which the phenotype is either identical or mirrored; strikingly, molecular studies have shown that such phenotypes are often driven by reciprocal dosage defects of the same transcript. Here we explore how these observations can help the dissection of CNVs and inform the genetic architecture of CNV-induced disorders.

Figure 1. Theoretical models to explain penetrance and phenotypic variability of reciprocal CNVs

Schematic representation of a genomic segment encompassing five genes (Gene A-E) flanked by low-copy repeats (LCRs). LCRs are depicted as blue arrows with the orientation indicated by the direction of the arrowheads. Recombination between LCRs results in reciprocal deletions and duplications. The “single gene” model posits that a single primary gene is the major driver of the phenotype; the single primary driver accounts for 100% of the expressivity and penetrance. Conversely, the cis-epistasis models posit that one or multiple genes are necessary and sufficient to cause phenotypes but epistasis interactions modulate the expressivity and penetrance of the phenotype(s). Two models arise: 1) A single primary driver or 2) Multiple primary drivers are sufficient to cause independent or same phenotypes. The other genes within the CNV modulate the penetrance and/or expressivity of the phenotype(s) primarily driven by the major driver(s).