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. 2007. 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 2015; 96: 208–220 with permission from Elsevier.


American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders: DSM‐5, 5th edn edn. Arlington, VA: American Psychiatric Publishing.

Arlt MF, Wilson TE and Glover TW (2012) Replication stress and mechanisms of CNV formation. Current Opinion in Genetics & Development 22 (3): 204–210.

Carvalho CMB, Ramocki MB, Pehlivan D, et al. (2011) Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nature Genetics 43 (11): 1074–1081.

Estivill X and Armengol L (2007) Copy number variants and common disorders: filling the gaps and exploring complexity in genome‐wide association studies. PLoS Genetics 3 (10): e190.

Falco M, Amabile S and Acquaviva F (2017) RAI1 gene mutations: mechanisms of Smith–Magenis syndrome. The Application of Clinical Genetics 10: 85–94.

Falk A, Heine VM, Harwood AJ, et al. (2016) Modeling psychiatric disorders: from genomic findings to cellular phenotypes. Molecular Psychiatry 21: 1167–1179.

Feuk L, Carson AR and Scherer SW (2006) Structural variation in the human genome. Nature Reviews Genetics 7: 85–97.

Firth HV, Richards SM, Bevan AP, et al. (2009) DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. American Journal of Human Genetics 84 (4): 524–533.

Flaherty EK and Brennand KJ (1655) Using hiPSCs to model neuropsychiatric copy number variations (CNVs) has potential to reveal underlying disease mechanisms. Brain Research 2017: 283–293.

Flöttmann R, Kragesteen BK, Geuer S, et al. (2017) Noncoding copy‐number variations are associated with congenital limb malformation. Genetics in Medicine: 1–9.

Gillentine MA, Yin J, Bajic A, et al. (2017) Functional consequences of CHRNA7 copy‐number alterations in induced pluripotent stem cells and neural progenitor cells. American Journal of Human Genetics 101 (6): 874–887.

Goodier JL and Kazazian HH Jr (2008) Retrotransposons revisited: the restraint and rehabilitation of parasites. Cell 135 (1): 23–35.

Govoni A, Gagliardi D, Comi GP and Corti S (2018) Time is motor neuron: therapeutic window and its correlation with pathogenetic mechanisms in spinal muscular atrophy. Molecular Neurobiology. DOI: 10.1007/s12035-017-0831-9.

Han C, Chaineau M, Chen CX‐Q, Beitel LK and Durcan TM (2018) Open science meets stem cells: a new drug discovery approach for neurodegenerative disorders. Frontiers in Neuroscience 12: 47.

Hastings PJ, Ira G and Lupski JR (2009) A microhomology‐mediated break‐induced replication model for the origin of human copy number variation. PLoS Genetics 5. DOI: 10.1371/journal.pgen.1000327.

Horev G, Ellegood J, Lerch JP, et al. (2011) Dosage‐dependent phenotypes in models of 16p11.2 lesions found in autism. Proceedings of the National Academy of Sciences of the United States of America 108: 17076–17081.

Iacocca MA, Wang J, Dron JS, et al. (2017) Use of next‐generation sequencing to detect LDLR gene copy number variation in familial hypercholesterolemia. The Journal of Lipid Research 58 jlr.D079301.

Jacquemont S, Reymond A, Zufferey F, et al. (2011) Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature 478: 97–102.

Kloosterman WP, Tavakoli‐Yaraki M, Van Roosmalen MJ, et al. (2012) Constitutional chromothripsis rearrangements involve clustered double‐stranded DNA breaks and nonhomologous repair mechanisms. Cell Reports 1: 648–655.

Kloosterman WP and Cuppen E (2013) Chromothripsis in congenital disorders and cancer: Similarities and differences. Current Opinion in Cell Biology 25: 341–348.

Koumbaris G, Hatzisevastou‐Loukidou H, Alexandrou A, et al. (2011) FoSTeS, MMBIR and NAHR at the human proximal Xp region and the mechanisms of human Xq isochromosome formation. Human Molecular Genetics 20 (10): 1925–1936.

La Cognata V, Morello G, Agata VD, Cavallaro S and Cullin CUL (2017) Copy number variability in Parkinson's disease: assembling the puzzle through a systems biology approach. Human Genetics 136: 13–37.

Lanktree M and Hegele RA (2009) Copy number variation in metabolic phenotypes. Cytogenetic and Genome Research 123: 169–175.

Lee JA, Carvalho CM and Lupski JR (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131 (7): 1235–1247.

Li J, Yang T, Wang L, et al. (2009) Whole genome distribution and ethnic differentiation of copy number variation in Caucasian and Asian populations. PLoS One 4: 1–7.

Lieber MR (2008) The mechanism of human nonhomologous DNA end joining. Journal of Biological Chemistry 283 (1): 1–5.

Malhotra D and Sebat J (2012) CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148: 1223–1241.

Mehta D, Iwamoto K, Ueda J, et al. (2014) Comprehensive survey of CNVs influencing gene expression in the human brain and its implications for pathophysiology. Neuroscience Research 79: 22–33.

Middelkamp S, van Heesch S, Braat AK, et al. (2017) Molecular dissection of germline chromothripsis in a developmental context using patient‐derived iPS cells. Genome Medicine 9: 1–14.

Mitelman F, Johansson B and Mertens F (2007) The impact of translocations and gene fusions on cancer causation. Nature Reviews Cancer 7: 233–245.

Moir‐Meyer GL, Pearson JF, Lose F, et al. (2015) Rare germline copy number deletions of likely functional importance are implicated in endometrial cancer predisposition. Human Genetics 134: 269–278.

Newman S, Hermetz KE, Weckselblatt B and Rudd MK (2015) Next‐generation sequencing of duplication CNVs reveals that most are tandem and some create fusion genes at breakpoints. American Journal of Human Genetics 96: 208–220.

Nordestgaard BG and Langsted A (2016) Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. The Journal of Lipid Research 57: 1953–1975.

Potocki L, Bi W, Treadwell‐Deering D, et al. (2007) Characterization of Potocki–Lupski Syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage‐sensitive critical interval that can convey an autism phenotype. American Journal of Human Genetics 80: 633–649.

Rausch T, Jones DTW, Zapatka M, et al. (2012) Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148: 59–71.

Redon R, Ishikawa S, Fitch KR, et al. (2006) Global variation in copy number in the human genome. Nature 444: 444–454.

Rippey C, Walsh T, Gulsuner S, et al. (2013) Formation of chimeric genes by copy‐number variation as a mutational mechanism in schizophrenia. American Journal of Human Genetics 93: 697–710.

Russo CD, Di Giacomo G, Cignini P, et al. (2014) Comparative study of aCGH and next generation sequencing (NGS) for chromosomal microdeletion and microduplication screening. Journal of Prenatal Medicine 8: 57–69.

Scoto M, Finkel RS, Mercuri E and Muntoni F (2017) Therapeutic approaches for spinal muscular atrophy (SMA). Gene Therapy 24: 514–519.

Sharp AJ, Locke DP, Mcgrath SD, et al. (2005) Segmental duplications and copy‐number variation in the human genome. American Journal of Human Genetics 77: 78–88.

Shlien A, Tabori U, Marshall CR, et al. (2008) Excessive genomic DNA copy number variation in the Li‐Fraumeni cancer predisposition syndrome. Proceedings of the National Academy of Sciences of the United States of America 105: 11264–11269.

Stankiewicz P and Lupski JR (2002) Genome architecture, rearrangements and genomic disorders. Trends in Genetics 18: 74–82.

Stankiewicz P and Lupski JR (2010) Structural variation in the human genome and its role in disease. Annual Review of Medicine 61: 437–455.

Stephens PJ, Greenman CD, Fu B, et al. (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144: 27–40.

Takumi T and Tamada K (2018) CNV biology in neurodevelopmental disorders. Current Opinion in Neurology 48: 183–192.

Talseth‐Palmer BA, Holliday EG, Evans T‐J, et al. (2013) Continuing difficulties in interpreting CNV data: lessons from a genome‐wide CNV association study of Australian HNPCC/Lynch syndrome patients. BMC Medical Genomics 6: 1–13.

Torres F, Barbosa M and Maciel P (2016) Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications. Journal of Medical Genetics 53: 73–90.

Tubio JMC and Estivill X (2011) Cancer: When catastrophe strikes a cell. Nature 470 (7335): 476–477.

Vallat JM, Mathis S and Funalot B (2013) The various Charcot–Marie–Tooth diseases. Current Opinion in Neurology 26: 473–480.

Valsesia A, Macé A, Jacquemont S, Beckmann JS and Kutalik Z (2013) The growing importance of CNVs: new insights for detection and clinical interpretation. Frontiers in Genetics 4: 1–19.

Walker LC, Pearson JF, Wiggins GAR, et al. (2017) Increased genomic burden of germline copy number variants is associated with early onset breast cancer: Australian breast cancer family registry. Breast Cancer Research 19: 1–8.

Walters RG, Jacquemont S, Valsesia A, et al. (2010) A novel highly‐penetrant form of obesity due to microdeletions on chromosome 16p11.2. Nature 463: 671–675.

Watson CT, Marques‐Bonet T, Sharp AJ and Mefford HC (2014) The genetics of microdeletion and microduplication syndromes: an update. Annual Review of Genomics and Human Genetics 15: 215–244.

Wong KK, DeLeeuw RJ, Dosanjh NS, et al. (2007) A comprehensive analysis of common copy‐number variations in the human genome. American Journal of Human Genetics 80: 91–104.

Yao Y and Dai W (2014) Genomic instability and cancer. Journal of Carcinognesis & Mutagenesis 5 pii: 1000165.

Ye T, Lipska BK, Tao R, et al. (2012) Analysis of CNVs in brain DNA from patients with Schizophrenia and other psychiatric disorders. Biological Psychiatry 72: 651–654.

Young JM, Endicott RM, Parghi SS, et al. (2008) Extensive copy‐number variation of the human olfactory receptor gene family. American Journal of Human Genetics 83: 228–242.

Zhang F, Gu W, Hurles M and Lupski J (2009a) Copy number variation in human health, disease, and evolution. Annual Review of Genomics and Human Genetic 10: 451–481.

Zhang F, Khajavi M, Connolly AM, et al. (2009b) The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nature Genetics 41 (7): 849–853.

Zhang F and Lupski JR (2015) Non‐coding genetic variants in human disease. Human Molecular Genetics 24: R102–R110.

Further Reading

Corrigan‐Curay J, O'Reilly M, Kohn DB, et al. (2015) Genome editing technologies: defining a path to clinic. Molecular Therapy 23 (5): 796–806.

Girirajan S, Rosenfeld JA, Coe BP, et al. (2012) Phenotypic heterogeneity of genomic disorders and rare copy‐number variants. The New England Journal of Medicine 367 (14): 1321–1331.

Iafrate AJ, Feuk L, Rivera MN, et al. (2004) Detection of large‐scale variation in the human genome. Nature Genetics 36 (9): 949–951.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
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]