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Chromosome 15 duplications common in autism

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Emily Singer
30 August 2012

Common copies: With dropping costs, genetic testing is becoming more common, and reveals that duplication of 15q11-13 is the second most common chromosomal alteration in autism.

About 1 in 500 children referred for genetic testing for undefined developmental delay, intellectual disability or autism have duplications of the 15q11-13 chromosomal region, according to a new analysis.

The findings suggest that duplications of 15q11-13 are the second most common large genetic alteration linked to autism after deletions or duplications of the 16p11.2 region. David Ledbetter, executive vice president and chief scientific officer of Geisinger Health System in Danville, Pennsylvania, described the findings 9 August at a conference organized by the Dup15qAlliance in Boston.

Extrapolating to the general population, Ledbetter estimates that the overall prevalence of this duplication is 1 in 12,000. Lots of families out there,” he says.

Ledbetter’s findings, which are in press at Molecular Psychiatry1 are based on a total of 31,516 cases from two large published datasets2, 3Signature Genomics, a commercial clinical genomics lab, and the International Standards for Cytogenomic Arrays Consortium, a group of clinical cytogenetics and molecular genetics laboratories. The latter includes data from three autism repositories: the Autism Genetic Resource Exchange, the Autism Genome Project and the Simons Simplex Collection, which is funded by SFARI.org’s parent organization.  According to Ledbetter’s analysis, the 15q duplication is rarely found in controls.

There are two types of 15q duplications linked to autism — an interstitial duplication within the chromosome, and an isodicentric form, in which a duplication of the region makes up an extra chromosome. 

Most research into the duplication syndrome has been focused on the isodicentric form, probably because these children have more severe symptoms and their parents are more likely to seek out specialist care.

But it appears that there may be a larger pool of children with the duplication, especially those who have the interstitial form, than researchers knew. Preliminary research on eight children with the interstitial form suggests that they have milder symptoms, including near-normal intelligence quotients, according to findings presented at the conference by Lawrence Reiter, associate professor of neurology at the University of Tennessee Health Science Center in Memphis.

Untapped population:

Reiter said at the conference that he is surprised by the prevalence of the duplication given the difficulties he has had recruiting people for his studies.

It’s possible that many children who have the interstitial form don’t show up at clinics — or join research studies — because their symptoms are not severe enough for parents to persist through the 12-month waiting period often required to see a genetic specialist, said Ledbetter.

The numbers may also reflect the dropping costs and growing use of genetic tests among non-geneticists, especially for testing children with mild symptoms.

Based on the figures, the Dup15q Alliance aims to reach out to this untapped population and encourage them to participate in research. The nonprofit advocacy group is based in Fayetteville, New York, and was founded by families of children with the duplication.

Last year, the alliance launched a patient registry that now houses data from 243 families. Parents upload results of genetic tests, which are verified by a genetic counselor, and answer 143 questions about other symptoms, such as attention deficit disorder, heart and sleep problems.

About 41 percent of children in the registry have an autism diagnosis and 17 percent have pervasive developmental disorder-not otherwise specified, according to Kadi Luchsinger, executive director of the alliance.

Roughly half of the children have seizures, many experience frequent ear infections, and perhaps most curiously, 83 percent have an unusually high pain tolerance as reported by their parents.

The registry includes a researcher portal, which the organizers announced at the conference, in which scientists can explore the data collected to date. Researchers at the conference were intrigued by the pain tolerance, a characteristic that can be tested in mouse models relatively easily.

For more reports from the 2012 Dup15q Scientific Meeting, please click here.


References:

1: Moreno-De-Luca D. et al. Mol. Psychiatry In press.

2: Cooper G.M. et al. Nat. Genet. 43, 838-846 (2011) PubMed

3: Sanders S.J. et al. Neuron 70, 863-885 (2011) PubMed


Comments

Name: RAJensen
30 August 2012 - 2:31PM

This is from the DUP15 Alliance on the heritabilty of DUP15 mutations. Once again it has to be asked 'Where did the heritabilty go?.
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When first learning about a chromosomal condition in their child, parents often wonder about the cause. In most cases of chromosome 15q duplication syndrome, the chromosome duplication is not inherited, but occurred as a random event during the formation of reproductive cells (eggs and sperm). In an egg, it occurred while the mother was a fetus in her mother’s uterus. In sperm this occurs continuously from puberty through adult life. Parents have no control over this natural process. There are some cases where the chromosome 15q duplication has been passed through generations. A chromosome study of the parents of an affected individual can determine if the duplication is inherited or de novo.
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http://www.dup15q.org/frequent-questions.html#anchor_34

Name: Paul Whiteley
30 August 2012 - 3:27PM

Thanks for the post.

Some interesting work from the MIND Institute & partners was published recently on 15q11-q13:

Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. http://www.ncbi.nlm.nih.gov/pubmed/22930557

To quote: "These results demonstrate a novel paradigm by which specific POPs [persistent organic pollutants] may predispose to genetic copy number variation of 15q11-q13".

Food for thought.

Name: Jessica Wright
30 August 2012 - 5:25PM

Thanks so much.

You might also be interested in Janine LaSalle's Viewpoint, in which she discusses the study you mention above.

https://sfari.org/news-and-opinion/viewpoint/2012/genes-and-environment-are-two-way-street-in-autism-risk

Name: Paul Whiteley
30 August 2012 - 7:47PM

Many thanks. I am just this evening reading Prof LaSalle's study.

Name: RAJensen
31 August 2012 - 11:52AM

Paul;
You might find a recent discovery by McCAuliffe and Colleagues even more enlightening. They found that increased levels of exposure to PCB and DDT congeners produced increased production of XY sperm in sub fertile males. Klenefelter Symdrpme is associated with increased autism risk. Klinefelter Syndrome is always caused by an extra X chromosome. Half the cases (53%) are caused by an XY sperm mutation and half is caused by an XX egg mutation.

McAuliffe ME, Williams PL, Korrick SA, Altshul LM, Perry MJ. (2012). Environmental Exposure to Polychlorinated Biphenyls and p,p´-DDE and Sperm Sex-Chromosome Disomy. Environ Health Perspect. 2012 April; 120(4): 535–540.

http://ehp03.niehs.nih.gov/article/fetchArticle.action?articleURI=info%3Adoi%2F10.1289%2Fehp.1104017

Name: Paul Whiteley
4 September 2012 - 2:58PM

Many thanks for the study details and link.

Name: Center for Autism and Related Disorders
31 August 2012 - 4:18PM

The more and more we unravel the mystery that is autism, the more complex and intricate of a problem we see it is. We hope that these strides in research will continue, and in the future bring about a remedy. http://www.centerforautism.com/

Name: RAJensen
1 September 2012 - 10:17AM

Since 15q11-13 duplications are rarely inherited just how common are duplications in the 15q11-13 chromosomal region in the sperm of healthy males? The answer is that all males generate duplicate 15q11-13 sperm mutations. Molina’s laboratory in Spain recruited 10 healthy male sperm donors and examined 10,000 sperm per sample for each donor. 15q11-13 duplications were found in all 10 donors (see Table 2). The frequency of 15q11-13 duplications range from a low of 0.12% (Donor 6) to a high of 0.53% (donor 10). The appearance in a family of a child with a 15q11-13 duplication appears to be a random event that can strike any family at any time and no family is exempt from the risk no matter how small. There are groups that just beginning to investigate how specific environmental pathogens may be associated with specific sperm mutations in syndromes where most cases are caused by de novo gene mutations. The researchers and families involved in the Dup15 Alliance ought to consider seeking alliances with research groups conducting this type of important research. The families deserve an answer as to why this has happened in their families.

Molina et al (2011). Sperm rates of 7q11.23, 15q11q13 and 22q11.2 deletions
and duplications: a FISH approach. Hum Genet (2011) 129:35–44 DOI 10.1007/s00439-010-0894-4

http://www.springerlink.com/content/d53g890m56w6825h/fulltext.pdf

Name: Autism Dad
2 September 2012 - 11:05AM

Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number.
Hogart A, Leung KN, Wang NJ, Wu DJ, Driscoll J, Vallero RO, Schanen NC, LaSalle JM.
Source

Medical Microbiology and Immunology, School of Medicine, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2634820/?tool=pubmed

"Molecular investigation of gene expression in brain samples with extra copies of 15q11-13 provides insight into the potential complexities of other copy number variations in autism [33, 34]. Extra copies of genes are predicted to lead to increased expression, however our study revealed that gene expression can be altered in unexpected ways through epigenetic changes. Epigenetic differences between individuals with the same genetic copy number variation could be stochastic, environmentally determined, or influenced by genetic background. Although more samples are needed before broader conclusions can be made, we speculate that compensatory epigenetic alterations led to gene expression changes and distinct clinical features in Case 6856. These findings bring to light the possibility that gene expression changes beyond the expected maternally expressed imprinted genes contribute to the variability in phenotypes in 15q11-13 duplication syndrome."

Name: Steve White
4 September 2012 - 2:36PM

I hope this comment will not be taken the wrong way. I understand this is necessary and very important work, but 1 in 500 cases is not a lot in terms of the parents looking for answers, in fact, it's extremely disheartening to think of the second most common problem effecting that few people.
I know this might be speculative but I am wondering if someone can give a breakdown of how many genes will likely be involved in developmental delay and what percentage will be attributed to any one gene.
In other words, is it going to be like this, hundreds of genes, no single one causing even 1% of cases?
I appreciate all the work everyone has done, it's just seeming like worse and worse news from the patient's standpoint.
I

Name: Emily Singer
4 September 2012 - 4:27PM

Thanks for your comment. I asked David Ledbetter for an answer to your question. He says:
"This is a great question and the answer for intellectual disability and for autism appear the same: likely hundreds, perhaps even 1000 genes or more involved in each, with each one representing less than 1% of total. So, given this, dup 15q is one of the most common and therefore very important regions."

Name: David Ledbetter
18 January 2013 - 11:51AM

I would like to offer a positive twist to Steve White's comment above. Although it can seem overwhelming that we are findings hundreds of rare genetic causes of intellectual disability and autism, this is the same path that scientists and doctors have traveled with cancer. The good news is that for a growing number of cancers, especially those in children, knowledge of the rare genetic causes has led to "targeted therapies" that can result in complete cure of the cancer. So, we have a huge job ahead of us to find and understand all of the genes that can go wrong and cause intellectual disability or autism, but there is hope that this knowledge can lead to improved quality of life and some day to prevention or cure for at least some families.

Name: Crystal A.
16 January 2013 - 10:11PM

Either our family geneticist was a liar or there are a lot of missing pieces to my son's puzzle here. Everything i read says its carried maternally or just randomly happens that this chromosome disorder if it is passed on paternally does not cause symptoms, well guess what people his father is the carrier as the blood work said and my son has every hell on earth symptom in the book from behavior, to organ problems to autism. I would really love if some legit info was out there for once. I am sick and tired of feeling like i am in another world and the only one out there this confused.

Name: David Ledbetter
18 January 2013 - 11:54AM

Nothing in Genetics is 100% (true in most of medicine), and we are learning all the time. While it is true that MOST duplications of 15q are maternally derived, research into this common cause of autism is ongoing. Recently, individuals with paternally derived duplications have been identified with some indicating multigenerational inheritance. Dr. Larry Reiter at the University of Tennessee is studying these exceptional families. You can learn more about this and other research studies at the Dup15q Alliance at www.dup15q.org

Name: Crystal A
19 January 2013 - 8:25PM

I belong to that site and quite a few others. Yes the multigenerational inheritance you speak of is what I am curious about because his dad has cognitive issues himself that were pretty much swept under the rug. Our geneticist left us literally in the dark. His father isn't even totally sure of what he is carrying, the chances of another child etc.

Name: James Brasic
14 August 2013 - 5:25PM

Since I conduct research on autism, I would like to include examinations for chromosome 15q11–13 duplications on participants. Please recommend resources to check for chromosome 15q11–13 duplications. What is the cost of this test?

Name: Greg Boustead
15 August 2013 - 7:58PM

James,

There's not a specific kit, test or screen for this. 15q11–13 duplications are detected by whole genome chromosomal microarray offered by many laboratories. To learn more, contact David Ledbetter (dhledbetter at geisinger.edu), from the who can fill you on more details.

Greg
SFARI.org, community manager

Name: Cary Dorsey
20 October 2013 - 3:52PM

How do we participate in this study? Or any study? My son is autistic (not diagnosed yet) and I want to help.

Name: Greg Boustead
21 October 2013 - 3:10PM

Hi Cary,

For research related to individuals with 15q11–13 duplications, see the Dup15q Alliance membership information:

http://www.dup15q.org

For information on a broad range of autism studies, check out the research participation directory at the Autism Science Foundation:

http://www.autismsciencefoundation.org/participate-research

or at Autism Speaks: http://bit.ly/GXXUeE


Greg Boustead
Community Manager, SFARI.org

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