Rare genetic hot spot is linked to autism

Email|Print| Text size + By Carey Goldberg
Globe Staff / January 10, 2008

Boston-based autism researchers have pinpointed a genetic hot spot where DNA errors appear to increase a child's chances of developing autism one-hundred-fold.

The discovery, reported online in the New England Journal of Medicine yesterday, stems from the most extensive genome scanning for autism done so far. The scans found that in just over 1 percent of people with autism, a chunk of about 25 genes had been either duplicated or deleted, mainly in spontaneous mutations not carried by their parents.

Some researchers believe that such errors help explain how autism can often crop up in families seemingly out of nowhere. Diagnoses of autism have skyrocketed in recent years, and the disorder now affects an estimated 1 in 150 American children.

"It's like having a recipe where you take some of the ingredients and use half as much or twice as much," said Dr. David T. Miller of Children's Hospital Boston. "It's going to change how the recipe turns out."

One percent may sound small, Miller said. But "it is significant in terms of getting another piece of the puzzle solved," he said, a puzzle that has largely stymied researchers even as parents have pleaded for answers and cures.

The findings also hold the promise that other hot spots will be found, explaining a much larger portion of autism cases. There is also hope that studying the genes involved will cast light on what goes wrong in autism, possibly leading to new treatments.

The hot-spot paper is the first major publication by a broad new Boston group, the Autism Consortium, that brings together families, doctors, and researchers to try to crack the complex questions of autism. Autism, a spectrum of social and communication disorders that usually begin in early childhood, is seen as largely genetic, but researchers have not yet found genetic smoking guns.

The collaboration helped speed the hot-spot research and bring it quickly into use for genetic diagnoses, said Mark J. Daly of Massachusetts General Hospital, the paper's senior author.

"In genetics, it's almost unprecedented to have an initial scientific finding so immediately validated in active clinical samples and to see relevant diagnostic information fed back to clinicians and families," he said.

Using new, high-resolution gene tests, Miller, working with a team at Children's, noticed the hot spot in a few patients a year ago, he said, but he could only tell their parents, "Well, we found something," but "we don't quite know what it means."

Meanwhile, Daly and his colleagues at Mass. General were using the new generation of gene scans on DNA samples from families with autistic children nationwide, seeking new genetic culprits. Among hundreds of children from that nationwide sample and hundreds more who had been tested at Children's, they found mutations in an area of Chromosome 16 in about 1 percent of those with autism.

They were able to confirm their findings in the extensive DNA samples gathered in recent years in Iceland. Analysis of Icelandic samples showed mutations in the hot spot in 1 percent of people with autism; one-tenth of 1 percent in people with different language or psychiatric problems; and just one one-hundredth of 1 percent in the general population.

For Morrie and Robin Lewin of Grafton, the hot-spot findings have personal relevance. Their 10-year-old twins - Nathaniel and Austin, who are developmentally delayed - both tested positive for mutations in the key hot-spot area when Miller had their genes tested. At first, he could not tell them what that meant; now he can identify a likely factor in their problems.

"For us, it basically means that we now have a diagnosis," Robin Lewin said, "and sometimes that makes it easier when you're trying to get services for your child."

The boys have none of the classic social symptoms of autism, she said, but it could help that she can say they have "this new chromosomal disorder."

The findings could also help other parents as they make family-planning decisions, Miller said. When parents have one autistic child, their chances of having another one are about 5 percent. But if testing shows that a parent has the mutation and could thus pass it down, the chance of having another autistic child could be as high as 50 percent, he said.

More generally, he said, "one of the things parents struggle with is, 'Why does my child have autism? Was it something I did? Was it something I didn't do?' "

New genetic findings, he said, can help parents know "there really was another explanation they had nothing to do with."

Scientists have no explanation for why such spontaneous mutations happen, said Miller, other than that they seem to occur randomly during the complex reshuffling of parental genes in earliest development and that certain spots are especially susceptible to it. Certain toxins are known to increase the likelihood of spontaneous genetic mutations.

The hot-spot paper is extremely well done, said Michael Wigler of Cold Spring Harbor Laboratory in New York, who was not involved with it but works on genetic hot spots himself.

Last year, Wigler and his team published a paper boldly predicting that, as the resolution of gene scans improves and as more new mutations can be detected, they will turn out to explain some 75 percent of autism cases. "I predict we will find many more new mutations causing severe cognitive disorders," he said.

Carey Goldberg can be reached at

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