Boston researchers find genetic trigger for 1 percent of autism

January 9, 2008 05:01 PM
By Carey Goldberg, Globe Staff

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 on-line in the New England Journal of Medicine
this afternoon, 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 such copy-number 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 every 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" -- a puzzle that
has largely stymied researchers even as parents have pleaded for
answers and cures.

The findings also hold the promise that more such hot spots will
explain a much larger portion of autism cases, and that studying the
genes involved will cast new light on what goes wrong. Autism is seen
as a spectrum of social and communication disorders that usually begin
in early childhood.

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.

The collaboration it fosters helped speed both the research and its
applicability in the clinic, 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, had noticed the "hot spot" in a few patients a year ago,
he said, but he'd had to tell the 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
cutting-edge 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.

Further confirmation came from the extensive DNA testing done 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 twin sons, 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.

"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. Normally, 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 new mutation and
could thus pass it down, the chance of having another autistic child
could be 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 new mutations happen,
Miller said, other than that they seem to occur randomly during the
complex reshuffling of parental genes in earliest development, and
certain spots are especially susceptible to it.
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 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@globe.com.

http://www.boston.com/news/health/blog/2008/01/boston_research.html