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DNA Deletion Linked to Autism

A massive study takes a major step forward in explaining the genetics of autism.
January 10, 2008

A specific structural variation on chromosome 16 dramatically boosts the risk of autism, according to a study published today in the New England Journal of Medicine. The finding–one of the most significant to date–permits the development of new diagnostic tests to identify children at risk, and could ultimately point to specific biochemical pathways to target in drug development.

Probing autism: Shown here is a DNA microarray. Each dot represents a specific sequence of donor DNA bound to DNA probes on the microarray. Bright green indicates an area where a chunk of DNA has been deleted, red indicates a duplication of DNA, and yellow indicates an area with no duplications or deletions.

“This is one of the single largest [influences] and most frequent genetic causes for autism identified so far,” says Bai-Lin Wu,director of the Genetics Diagnostic Laboratory at Children’s Hospital Boston and one of the senior authors on the study.

Autism spectrum disorder–or autism, as it is commonly called–refers to a group of developmental disabilities with wide-ranging language, social, and behavioral symptoms. The disorder is known to have a strong genetic influence, with up to 90 percent of cases thought to have a genetic component. However, because the disorder is linked to a combination of genetic variations, each playing a minor role, identifying specific genetic triggers has been difficult. Now new microarray technologies, which allow scientists to screen a million or more genetic variations in thousands of patients, are enabling the much larger studies needed to pinpoint these triggers.

In the new paper, scientists say that they used microarrays to scour the DNA of more than 2,000 individuals with autism. They found that deletion or duplication of approximately 500 of the same DNA letters on chromosome 16 was strongly linked to autism, accounting for about one percent of cases. “While that doesn’t sound like a huge number, the fact that these people carry the identical spontaneous deletion or duplication would be incredibly unlikely to happen by chance,” says Mark Daly, a geneticist at Massachusetts General Hospital’s (MGH) Center for Human Genetic Research, in Boston, and at the Whitehead Institute, in Cambridge, and one of the study’s senior authors.

The results were independently identified by three different groups–at MGH; Children’s Hospital Boston; and deCODE Genetics, in Iceland–that are studying three different populations, giving added weight to the work.

The findings build on previous reports that autism is linked to genetic deletions or duplications that arise spontaneously, rather than being passed down through generations. In almost all cases, parents of the affected people did not carry the chromosome 16 variation.

One of the most immediate clinical benefits of the research will be the development of inexpensive diagnostic tests. “Because the variation occurs so frequently, you could directly test for the presence or absence of a duplication or deletion as part of standardized genetic testing for autism,” says James Gusella, a neurogeneticist at Harvard Medical School, in Boston, who participated in the research. For example, children who show developmental delays but are too young to undergo clinical autism testing could be screened for this variation, allowing parents and doctors to prescribe intervention for those who test positive. “We will be able to find at-risk children early on so that language and behavior problems can be treated much earlier,” says Yiping Shen, director of research and development at Children’s Hospital’s Genetics Diagnostic Laboratory, who was also involved in the work.

Such testing could also predict if parents with one autistic child are at greater risk of having another; if their child’s autism is linked to a spontaneous variation, they are at no greater risk than the general population. Researchers at Children’s Hospital, which provides genetic testing to families, are already developing a clinical diagnostic test.

Scientists are also trying to pinpoint the specific gene or genes within this section of DNA that underlie the increased risk. Daly and his collaborators plan to sequence this region of the genome in another group of people with autism, in search of single-letter mutations that might disrupt the function of specific genes. “Genetics provides us with the only opportunity to gain insight into the biological mechanisms that underlie autism,” says Daly. “We can look at individual gene discovery as a small first step in the overall path to develop treatments.”

Previous studies have identified autism risk genes. However, these studies have focused on people with genetic disorders that often co-occur with autism, such as Fragile-X syndrome, complicating the role those genes play in the disorder. “Up until now, we haven’t had the capacity to look at a single gene that is associated with pure autism,” says Gusella.

The findings could point to additional spots in the human genome to search for autism risk genes. The variation on chromosome 16 lies within a genetic “hot spot,” an area that is predisposed to undergoing structural duplications due to the architecture of the DNA, says Evan Eichler, a geneticist at the University of Washington in Seattle, who wrote an editorial accompanying the paper. “Every time we produce gametes, there’s a finite probability of this region to duplicate,” he says. In addition, the region has a high concentration of genes that are rapidly evolving in humans. While the significance of that finding is not yet clear, it may explain autism’s status as a relatively young disease.

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