Fig. 2.

Multiple different ways in which a CNV can have a pathogenic effect. a CNVs cause duplication and/or deletion of the enclosed genes. If one or more of those genes is dosage-sensitive then there will be a consequent phenotype, usually deleterious. b, c Alternatively, CNVs with breakpoints within a gene disrupt the gene by truncation (b) or formation of chimeras (c). Gene truncation will usually result in loss of function, but may alternatively result in a gain of function, dominant negative effect. Chimeric genes have unpredictable effects, and may be pathogenic. d Topologically associating domains (TADs) are structural units in the three-dimensional organisation of the genome and play a large role in mediating gene–enhancer interactions and other aspects of gene expression regulation. TADs are isolated from each other by TAD boundaries, which are determined by protein binding sites. CNVs encompassing TAD boundaries create new TADs. These can result in rewiring of gene enhancer interactions including the isolation of a gene from its regulator or the placement of a gene under the regulation of an inappropriate enhancer. Disruption of TADs has been associated with human disease [64,65,66, 68]