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Deletions and Duplications: A Genetic Variation on Chromosome 16 Associated with Autism

Interactive Autism Network at Kennedy Krieger Institute
Date Last Revised: 
March 8, 2011

Researchers from the Autism Consortium, an autism research collaboration involving major hospitals and universities in the Boston area, have discovered a genetic variation that is strongly associated with autism. Individuals with this genetic variation have a 100 times greater risk of developing an autism spectrum disorder than those who do not. 1

Copy-Number Variation: A Type of Genetic Difference

Scientists have been searching for a specific gene responsible for autism. Some progress has been made in this direction, but no single gene responsible for many cases of autism has been identified. Instead, new discoveries in the field of genetics have led to a different kind of investigation: a search for copy-number variations that might be associated with the disorder. 2

Instead of a gene that is harmful in and of itself, a "copy-number variation" (CNV) indicates an unusual quantity of genetic material. It was once accepted that a person should have two copies of each gene: one inherited from the father and one from the mother. Recent scientific breakthroughs have shown that this is not always the case. 3  Some people have zero, one, or three copies of an entire strand of DNA which may include less than a whole gene, a single gene, or a whole set of genes that are next to each other on the strand of DNA.

When a person has less than, or more than, two copies of a certain strand of DNA -- that is a copy-number variation.

It was once believed that copy-number variations were rare, but we now know that they are fairly common. Most are probably benign, but some can definitely do harm. Deletions of specific genes have been associated with risk of prostate cancer, for example, while duplications have been linked to Crohn's disease. 4  Neurodevelopmental, neurodegenerative, and psychiatric disorders are among the conditions suspected to be linked to copy-number variation. 5

This is actually good news. If there is too much or too little of some process occurring because of an abnormal amount of genetic material, we may be able to intervene and correct for this. Writes Dr. James Lupski of the Baylor College of Medicine:

"The demonstration of aberrations in gene dosage (the number of copies of a given gene present in a cell or nucleus) as a disease mechanism opens the way to new, more easily developed approaches to treatment in which the goal is not to correct abnormal or mutant proteins but instead to modify their abnormal dosage." 6

Copy-Number Variations on Chromosome 16 Tied to Autism

It is only very recently that scientists have investigated the possibility that it is not necessarily some heritable gene, passed down from generation to generation, that is responsible for certain cases of autism, but some other genetic variation. First, scientists at Cold Spring Harbor Laboratory -- using IAN data, among other data sets -- discovered that autism might be inherited in only a minority of cases, arising de novo most of the time. 7

(De novo means "new," and refers to changes that arise from genetic material altered in a single sperm or egg, or in the fertilized egg itself, but that were not part of the parent's overall genetic code. In such a case, the parent does not share his or her child's genetic difference.)

Second, it was discovered that there was a strong association between de novo copy-number variations and autism. 8,9 Still, there was no identification of which genetic material on which chromosomes -- when present in an irregular number of copies -- put a person at particular risk for an autism spectrum disorder (ASD).

This has now changed. In an article titled "Association Between Microdeletion and Microduplication at 16p11.2 and Autism," a team of researchers announced that it had identified a specific region of chromosome 16 that appears to be strongly associated with autism. 10  The researchers found that individuals with ASD had a far higher risk of having copy-number variations in this region than did unaffected individuals. These copy-number variations included both deletions (where a person has zero or one set of genetic material instead of two), which tended to arise de novo, and duplications (where a person has three or more sets of genetic material instead of two). In the case of duplications, however, the genetic difference usually was not de novo; that is, it was directly inherited from a parent who shared the same duplication.

The team first found this difference in the Autism Genetic Resource Exchange (AGRE) data set. (AGRE, which collects genetic information from families with more than one child with ASD, makes its gene bank available to autism researchers worldwide.) It then went on to confirm its findings in two additional data sets (see Table 1):

Table 1.

Data Set

Individuals with ASD

Control Group

Autism Genetic Resource Exchange (AGRE)

751 families containing 1441 individuals with ASD

1420 AGRE parents and 2814 individuals with bipolar disorder, or National Institute of Mental Health controls

Children's Hospital Boston
(member of
Autism Consortium)

512 children with diagnosis of developmental delay, mental retardation, or ASD

434 children referred for issues other than developmental delay, mental retardation, or ASD

Icelandic Population

299 individuals with ASD

18,834 unaffected individuals

Overall, the team found that individuals with a copy-number variation in a specific region of chromosome 16 -- namely 16p11.2 -- were 100 times more likely to develop autism than people without this genetic difference.

It is interesting to note that, in the massive Icelandic sample, individuals with this same type of copy-number variation on chromosome 16 were also 10 times more likely than people without it to have a non-ASD psychiatric or language disorder, such as schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, panic disorder, anxiety, or depression.

A Partial Answer, a Crucial Clue

Researchers sought to find genetic differences associated with autism, using the latest technologies and techniques available. Because they found no frequent genetic difference other than the copy-number variations on chromosome 16, they say it is likely that "large de novo copy-number mutations may explain only a fraction of familial idiopathic autism." 11

Nevertheless, these findings offer essential clues to the mystery of autism. They establish that a specific genetic difference -- copy-number variation on chromosome 16 -- is strongly associated with autism. In the future, genetic tests may help families discover whether their child has such a copy-number variation on chromosome 16, and whether it arose de novo. If it did, the risk of the same parents having another child with autism would be the same as anyone else's (1 in 100), because the child did not inherit the genetic difference from a parent who could pass it on to other offspring. In addition, because we know that several genes in the identified region of chromosome 16 are involved in brain function or neurodevelopment, this new information may help researchers identify the biological mechanisms that play a part in autism.

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  1. Weiss, L. A., Shen, Y., Korn, J. M., Arking, D. E., Miller, D. T., Fossdal, R., et al. (2008). Association between microdeletion and microduplication at 16p11.2 and autism. The New England journal of medicine, 358(7), 667-75.  View Abstract
  2. Freeman, J. L., Perry, G. H., Feuk, L., Redon, R., McCarroll, S. A., Altshuler, D. M., et al. (2006). Copy number variation: New insights in genome diversity. Genome research, 16(8), 949-961. View Abstract
  3. Redon, R., Ishikawa, S., Fitch, K. R., Feuk, L., Perry, G. H., Andrews, T. D., et al. (2006). Global variation in copy number in the human genome. Nature, 444(7118), 444-454.  View Abstract
  4. Human Genome Structural Variation Working Group, Eichler, E. E., Nickerson, D. A., Altshuler, D., Bowcock, A. M., Brooks, L. D., et al. (2007). Completing the map of human genetic variation. Nature, 447(7141), 161-165.  View Abstract
  5. Lee, J. A., & Lupski, J. R. (2006). Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron, 52(1), 103-121.  View Abstract
  6. Lupski, J. R. (2007). Structural variation in the human genome. The New England journal of medicine, 356(11), 1169-1171.  View Abstract
  7. Zhao, X., Leotta, A., Kustanovich, V., Lajonchere, C., Geschwind, D. H., Law, K., et al. (2007). A unified genetic theory for sporadic and inherited autism. Proceedings of the National Academy of Sciences of the United States of America, 104(31), 12831-12836.  View Abstract
  8. Jacquemont, M. L., Sanlaville, D., Redon, R., Raoul, O., Cormier-Daire, V., Lyonnet, S., et al. (2006). Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. Journal of medical genetics, 43(11), 843-849.  View Abstract
  9. Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., et al. (2007). Strong association of de novo copy number mutations with autism. Science (New York, N.Y.), 316(5823), 445-449.  View Abstract
  10. Weiss, L. A., Shen, Y., Korn, J. M., Arking, D. E., Miller, D. T., Fossdal, R., et al. (2008). Association between microdeletion and microduplication at 16p11.2 and autism. The New England journal of medicine, 358(7), 667-75.  View Abstract
  11. Weiss, L. A., Shen, Y., Korn, J. M., Arking, D. E., Miller, D. T., Fossdal, R., et al. (2008). Association between microdeletion and microduplication at 16p11.2 and autism. The New England journal of medicine, 358(7), 667-75.  View Abstract