Gene Studies of Autism Point to Mutations and Parents’ Age

By BENEDICT CAREY
Published: April 4, 2012

Three teams of scientists working independently to understand the biology of autism have for the first time homed in on several gene mutations that they agree sharply increase the chances that a child will develop the disorder, and have found further evidence that the risk increases with the age of the parents, particularly the father.

The gene mutations are extremely rare and together account for a tiny fraction of autism cases, suggesting that the search for therapies will be a long one, and that what is loosely known as autism may represent a broad category of related but biologically distinct conditions. There are likely hundreds, perhaps thousands, of rare mutations that could disrupt brain development enough to result in social and developmental delays.

But experts said that the overlapping results — reported in three papers posted online Wednesday in the journal Nature — give scientists working on the genetics of autism something they have not had: a clear strategy for building a real understanding of the disease’s biological basis. Researchers hope to find more similar, rare mutations in the next year or so that they estimate could account for 10 percent to 20 percent of all cases.

Biologists have been groping in vain for a reliable, verifiable foothold from which to investigate the underlying genetics of so-called autism spectrum disorders, including Asperger syndrome and related social difficulties that are being diagnosed at alarmingly high rates — on average, in one of 88 children, according to a government estimate released last week.

Previous studies have produced a scattering of gene findings but little consensus or confidence in how to proceed. The new work provides a measure of both, as well as strong backing for earlier studies linking autism to the age of new fathers.

“These studies aren’t so much a breakthrough, because we knew this was coming,” said Jonathan Sebat, a geneticist at the University of California, San Diego, who was not a part of the research teams. “But I’d say it’s a turning point. We now have a reliable way forward, and I think it’s fair to expect that we will find 20, 30, maybe more such mutations in the next year.”

Other researchers were more cautious, saying that the genetics of rare mutations was not yet well enough understood to make conclusive statements about their effect on the behavior of specific genes.

“This is a great beginning, and I’m impressed with the work, but we don’t know the cause of these rare mutations, or even their levels in the general population,” said Dr. Aravinda Chakravarti, of the Institute of Genetic Medicine at the Johns Hopkins University Medical School, who was not involved in the studies. “I’m not saying it’s not worth it to follow up these findings, but I am saying it’s going to be a hard slog.”

The three research teams took a similar approach, analyzing genetic material taken from blood samples of families in which parents who have no signs of autism give birth to a child who develops the disorder. This approach gives scientists the opportunity to spot the initial mutations that accompany the condition, rather than trying to work though possible genetic contributions from maternal and paternal lines. In all three studies, the researchers focused on rare genetic glitches called de novo mutations.

De novo mutations are not inherited but occur spontaneously near or during conception. Most people have at least one and the overwhelming majority of them are harmless.

In one of the new studies, a team led by Mark J. Daly of Harvard found that the rate of such mutations was slightly higher among 175 people with a diagnosis of autism than in the general population. The group named glitches in two genes that were strongly associated with increased risk of autism.

Everyone typically has at least one mutation, but the study found that “kids with autism have a slightly higher rate, and the effects are more severe on average,” Dr. Daly said.

In another of the experiments, Dr. Matthew W. State, a professor of genetics and child psychiatry at Yale led a team that looked for de novo mutations in 200 people who had been given an autism diagnosis, as well as in parents and siblings who showed no signs of the disorder. The team found one autism case in which two de novo mutations disrupted a single gene — and nothing similar in those without a diagnosis. Further analysis, drawing on data from a larger sample, turned up two more genes disrupted by multiple de novo glitches, also named by Dr. Daly’s group.

“From my standpoint this is a big deal, because I’ve been at this a long time and for years and years you couldn’t get anyone to believe you’d even found one gene” that sharply increased autism risk, Dr. State said.

In the third study, Dr. Evan E. Eichler, a professor of genome sciences at the University of Washington in Seattle, led a team that investigated de novo mutations in 209 families, each with one child who had received an autism diagnosis. It found that such glitches were four times more likely to originate in the male DNA than in the female, and more likely to occur in children of middle-age fathers than in those of young fathers; the risk began to increase for fathers at about age 35.

The Washington team also found several high-risk genes, naming some of the same ones identified in the other two studies.

“This is really the tip of the tip of the iceberg,” Dr. Eichler said, “but I think the important thing is all of us agree on where to start” in pursing the contribution of rare mutations.

http://www.nytimes.com/2012/04/05/he...of-autism.html