Relevance of Copy Number Variation to Human Genetic Disease


Genomic rearrangements leading to the appearance of copy number variations (CNVs) are frequent and widespread events, mostly as a consequence of the inherent repeat architecture of the human genome. It is currently accepted that these structural variants represent a major genetic component underlying our phenotypic diversity and also play an important role in human disease. CNVs can lead to disease by means of gene dosage effect, gene disruption, gene fusion and other effects on gene function, including position effect mechanisms. Recurrent CNVs with common breakpoints define genomic disorders that frequently involve the contribution of multiple genes and are associated with a particular phenotype, although most of them exhibit variable expressivity and incomplete penetrance. These rearrangements are presently unavoidable elements when studying the genetic basis of syndromes and complex diseases, such as cancer, metabolism disorders, neurodegenerative and neurodevelopmental disorders.

Key Concepts

  • The detection and identification of recurrent CNVs has allowed the definition of previously unidentified genomic disorders.
  • Many CNV‐associated disorders show incomplete penetrance and variable expressivity.
  • An adequate estimation of CNV‐associated odds ratio of disease is of utmost relevance for genetic counselling.
  • These disorders usually affect multiple genes, and even though in some cases there is a key gene recognised as the main contributor to the disease features, others are contiguous gene syndromes, that is result from the contribution of dosage changes in multiple genes.
  • Animal/hiPSC models are helping to understand the pathogenic mechanisms by which CNVs cause disease.
  • hiPSC models are also being used for drug discovery and development.

Keywords: genomic rearrangements; CNVs; genomic disorders; aCGH; MPS

Figure 1. Structural rearrangements – schematic representation: (a) most common type of CNVs, comprising deletions, duplications and inversions. Adapted from Estivill, X., and Armengol, L. . Copy Number Variants and Common Disorders: Filling the Gaps and Exploring Complexity in Genome‐Wide Association Studies. PLoS Genetics, 3(10), e190. (b) Schematic representation of a chromothripsis event. Adapted with permission from Springer Nature from Tubio JMC, Estivill X. Nature 2011; 470: 476–477. Structural rearrangements may lead to altered gene expression, gene fusions, disruption of regulatory elements such as enhancers and boundaries of topologically associated domains (TADs) and/or unmasking of recessive mutations in the unaffected allele. Middelkamp S et al. Genome Med 2017; 9: 1–14.
Figure 2. Outcomes for duplication CNVs: region B can be duplicated in direct or inverted orientation or can be inserted at another locus (not shown). Arrows represent genes, dashed lines represent duplication breakpoints. 1 – Intragenic: Duplication in direct or inverted orientation; 2 – Gene fusion: can be created by intergenic duplications with breakpoints in two different genes; 3 – Genes intact: direct intergenic duplications can generate a nonfunctional gene at the breakpoint junction while maintaining intact genes at the edges of the duplication; 4 – Haploinsufficiency: may arise by loss of one gene copy through inverted duplication; 5 – Haploinsufficiency, gene fusion: inverted intergenic duplications can create a fusion gene at the junction and will mutate one gene without retaining an intact copy at the locus. Haploinsufficiency may arise by loss of one gene copy. Adapted from Newman S et al. Am J Hum Genet ; 96: 208–220 with permission from Elsevier.


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Further Reading

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Torres, Fátima, Lopes, Fátima, and Maciel, Patrícia(Jul 2018) Relevance of Copy Number Variation to Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0020226.pub2]