A new study by a US research consortium has discovered that a small segment of chromosome 16 is either missing or duplicated in about 1 per cent of people with an autism spectrum disorder (ASD). What is surprising about this particular discovery is that the omission or duplication is not inherited from a parent but appears to occur spontaneously, perhaps around the time of conception.

The study is published in the January 9th early online issue of the New England Journal of Medicine (NEJM) and is the work of the Autism Consortium, which includes 14 leading universities and medical centres in and around Boston, Massachusetts.

Autism Spectrum Disorders (ASDs) are diagnosed in as many as 1 in 150 children under three years of age. Symptoms range from mild to severe, and have social, cognitive and behavioural components.

The 1 per cent frequency is comparable to a number of other genetic syndromes that have been tied to ASDs, said the researchers. Also, around 90 per cent of ASDs are thought to have a genetic component, but so far only 10 per cent of cases can be tied to known genetic and chromosome syndromes.

Dr Mark Daly, who works at the Massachusetts General Hospital (MGH) Center for Human Genetic Research, and was senior researcher of the gene discovery team on the study said:

“While epidemiologic studies indicate a very large genetic component to autism, little is known about how specific genes are involved.”

Daly is a member of the Autism Consortium and is an assistant professor of Medicine at Harvard Medical School and a member of the Broad Institute of Harvard and Massachusetts Institute of Technology.

“We’re still a long way from understanding how this chromosomal deletion or duplication increases the risk for autism, but this is a critical first step toward that knowledge,” added Daly.

Scientists were already aware of several chromosome deletions or duplications tied to ASD, including one particular type of deletion on chromosome 15 which is passed on from a parent. So in this study the researchers decided to carry out a complete scan of the genome.

They used samples from the Autism Genome Research Exchange, which holds DNA from families with at least one child with ASD.

The researchers scanned more than 1,400 samples of individuals with ASDs and a similar number of unaffected parents. They found one particular region of chromosome 16 was deleted in 5 of the individuals with an ASD, but not in any of their parents. This suggested the deletion had occurred spontaneously and was not inherited.

Daly and colleagues confirmed these results by examining clinical data from a separate group of nearly 1,000 patients who had attended Children’s Hospital Boston, about half of whom had been diagnosed with an ASD or a related disorder.

Among those with an ASD or related disorder, they found 5 children with the same chromosome 16 deletion, and another 4 children where the chromosome segment was not deleted but duplicated. These chromosome flaws were not present in the DNA of children who were not diagnosed with an ASD or related disorder.

The findings were confirmed again by another set of data obtained from deCODE Genetics, a biopharmaceutical company in Iceland that uses population studies to identify human genes linked with common diseases. They found the same deletion in 3 out of nearly 300 people with an ASD, and also in some samples from people who had psychiatric or language disorders. The deletion was found in only 2 out of 20,000 members of the deCODE database who had not been diagnosed with an associated disorder.

Further analysis of the deCODE data suggested that while this chromosome deletion was likely to be present in only 0.01 per cent of the general population, it was 100 times more likely to be found in people with an ASD.

Daly explained that:

“These large, non-inherited chromosomal deletions are extremely rare,so finding precisely the same deletion in such a significant proportion of patients suggests that it is a very strong risk factor for autism.”

“We’re now pursuing more detailed genetic studies to figure out which genes in this region are responsible for this effect in order to gain a better understanding of the underlying biology and potential clues to therapeutic approaches,” he added.

In an accompanying editorial, Drs Evan E. Eichler, from the Howard Hughes Medical Institute and the Department of Genome Sciences, University of Washington, Seattle, and Andrew W. Zimmerman, from the Kennedy Krieger Institute and Johns Hopkins University, Baltimore, wrote that the discovery of the spontaneous deletion or duplication of a segment of a chromosome heralds a new “paradigm” in genetic research of ASDs. The examples cited in this study could be the “tip of the iceberg”.

“Deeper sample collection and new cost-effective genomic techniques may be needed to peel away the remaining layers of the onion,” wrote Eichler and Zimmerman.

This type of chromosome deletion and duplication discovery also has immediate clinical implications, according to a statement released by the Autism Consortium earlier this week.

A new type of test called the chromosome microarray is now being used in clinical settings. This can detect chromosome deletion and duplications in diagnosed patients and their parents and helps clinicians assess risk of recurrence in subsequent pregnancies, which is a worry for many parents.

But the tests are expensive and not always covered by insurance. The Consortium researchers are working on ways to bring the costs down, for example by developing a simpler test to detect the specific chromosome 16 flaw.

“Association between Microdeletion and Microduplication at 16p11.2 and Autism.
Weiss, Lauren A., Shen, Yiping, Korn, Joshua M., Arking, Dan E., Miller, David T., Fossdal, Ragnheidur, Saemundsen, Evald, Stefansson, Hreinn, Ferreira, Manuel A.R., Green, Todd, Platt, Orah S., Ruderfer, Douglas M., Walsh, Christopher A., Altshuler, David, Chakravarti, Aravinda, Tanzi, Rudolph E., Stefansson, Kari, Santangelo, Susan L., Gusella, James F., Sklar, Pamela, Wu, Bai-Lin, Daly, Mark J., the Autism Consortium.
N Engl J Med, published online January 9, 2008, in print February 14, 2008.
DOI: 10.1056/NEJMoa075974.

Click here for Article.

“A Hot Spot of Genetic Instability in Autism.
Evan E. Eichler, and Andrew W. Zimmerman.
N Engl J Med, published online January 9, 2008, in print February 14, 2008.
DOI: 10.1056/NEJMe0708756.

Click here for Editorial.

Sources: NEJM press release, journal article and editorial, Autism Consortium press release.

Written by: Catharine Paddock