Genetic Hot Spot for Autism?

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Rare genetic hot spot is linked to autism

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. T. of

Children's Hospital Boston. " It's going to change how the recipe

turns out. "

One percent may sound small, 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, , 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 - iel and Austin,

who are developmentally delayed - both tested positive for mutations

in the key hot-spot area when 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, 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 , 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 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 goldberg@....