Parent's Corner > Risk Factors > Genetics > Importance of CNVs

What is a copy number variant, and why are they important risk factors for ASD?

For decades, scientists have known that microscopically visible chromosomal rearrangements can result in a wide range of developmental disorders. However, technological and computational advances in the past decade have enabled the development of assays capable of identifying even smaller structural changes in chromosomes that could not have been detected by traditional cytogenetic analysis.

Among the most heavily scrutinized of these submicroscopic structural variants are copy number variants, or CNVs. CNVs are submicroscopic chromosomal deletions and/or duplications that are typically defined as DNA segments 1000 basepairs or larger in size that are present in a different number of copies when compared to a reference (or standard) genome1. For example, as shown in the middle of the figure below, the pair of normal chromosomes each have sections A-B-C-D. However, the loss of section C from one of the chromosomes results in an abnormal chromosome with only sections A-B-D (left pair in the figure below); an individual with this deletion therefore now has only one copy of section C in their chromosomes.

On the other hand, the gain of an extra copy of section C on one of the chromosomes results in an abnormal chromosome with sections A-B-C-C-D (right pair in the figure below); an individual with this duplication now has three copies of section C in their chromosomes. In other words, both of these individuals (left and right in the figure below) have CNVs involving section C – one has lost a copy, the other has gained a copy, but both have a varied number of copies of C when compared to the original, reference set of chromosomes.

Like other types of genetic variation, apparently benign CNVs that cause no ill effects on the individual(s) harboring them have been observed throughout the human genome in the general population. However, there is considerable evidence from analysis of large autistic populations that CNVs at specific locations in the genome result in increased susceptibility to ASD2. It has been estimated that 10-20% of ASD cases result from the presence of one or more pathogenic CNVs in an affected individual3.  This means that CNVs are one of the most, if not the most, common genetic causes of ASD.

Click to see how copy number variants may contribute to ASD.

  1. Feuk L, Carson AR, Scherer SW (2006) Structural variation in the human genome. Nat. Rev. Genet. 7(2): 85-97. PMID: 16418744.
  2. Marshall CR, Scherer SW (2012) Detection and characterization of copy number variation in autism spectrum disorder. Methods Mol. Biol. 838: 115-135. PMID: 22228009.
  3. Miles JH, McCathren RB, Stichter J, Shinawi M. Autism Spectrum Disorders. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. 2003 Aug 27 [updated 2010 Apr 13]. PMID: 20301615.
  4. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, et al. (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459(7246): 569-73. PMID: 19404257.
  5. Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, et al.  (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466(7304): 368-372. PMID: 20531469.