New research shows that several gene mutations sharply increase the chances that a child will develop autism spectrum disorders. The researchers have found further evidence that the risk increases with the age of the parents, particularly in fathers over age 35.
Researchers add that the gene mutations are extremely rare and together account for a tiny fraction of autism cases. But the odds that two or more people in any small group will have such problems in the same genetic location are vanishingly small, strongly suggesting that the mutations are related to the diagnosis.
Till date there has been a debate on the relative influence of inherited risk and environmental factors in autism and few today doubt that there is a strong genetic component. However no underlying genetics has been clarified of these so-called autism spectrum disorders, including Asperger's Syndrome and related social difficulties that are being diagnosed at alarmingly high rates - on average, in one in 88 children, according to a government estimate released last week.
The latest report comes in three papers published online Wednesday in the journal Nature, provides a measure of both, giving scientists something they have not had: a clear strategy for building an understanding of the disease’s biological basis.
There are probably hundreds, perhaps more than a thousand, gene variations that could disrupt brain development enough to result in social delays. An intensified search for rare mutations could turn up enough of these to account for 15 percent to 20 percent of all autism cases, some experts say, and allow researchers a chance to see patterns and some possible mechanisms to explain what goes wrong.
“These studies aren’t so much a breakthrough, because we knew this was coming,” said Jonathan Sebat, a professor of psychiatry and cellular and molecular medicine 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 or two.”
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.”
All three 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 mutations 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 majority of them are harmless.
In one of the new studies, 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. They found that 14 percent of subjects with autism had genetic mutations at a rate of five times the normal rate. And, 39 percent of these mutations were found to affect a key pathway for communications in the brain.
The team found that two unrelated children with autism in the study had de novo mutations in the same gene - and nothing similar in those without a diagnosis. “That is like throwing a dart at a dart board with 21,000 spots and hitting the same once twice,” Dr. State said. “The chances that this gene is related to autism risk is something like 99.9999 percent.” The team found that a third child had a de novo mutation in another gene suspected of a possible link to autism risk - but one such mutation is not enough to make the case.
Another team led Dr. Evan E. Eichler, a professor of genome sciences at the University of Washington in Seattle, independently found the same thing in a study of 677 individuals from 209 families: one child with autism - and a problem in the very same gene. The researchers added still another gene, finding two unrelated children with autism in their own sample who had de novo mutations in the same location. No such coincidences occurred among people in the studies who did not have an autism diagnosis. The study found 126 de novo mutations - coming from neither parent - that were predicted to contribute to autism. The study also found that these mutations occurred four times more frequently in sperm than in egg cells. And the older the father, the more likely his sperm was to contain these mutations.
Finally - in the third paper - a team led by Mark J. Daly of Harvard ran its own analysis of these three genes, among others, and found yet more cases. Everyone typically has at least one de novo mutation, Dr. Daly said, but his study suggested that “kids with autism have a slightly higher rate, on average, and the effects are more severe.”
All three studies also found evidence that the risk of de novo mutations increases with parental age. In an analysis of 51 de novo mutations, Dr. Eichler’s group found that mutations were four times more likely to originate in DNA from the male than from the female. The risk is higher in fathers at age 35 than at age 25 and seems to creep upward with age. This offers one possible explanation for earlier research linking older fathers with autism’s rise: older male sperm is more subject to small, perhaps random glitches that in rare cases effect brain development.
“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.” Dr. State added, “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 significantly increased risk.
“We now have a path forward to capture a great part of the genetic variability in autism - even to the point of being able to predict how many mutations in coding regions of a gene would be needed to account for illness,” Dr. Thomas Lehner, chief of the NIMH Genomics Research Branch, which funded the Daly study and helped to create the Autism Sequencing Consortium, said in a news release. “These studies begin to tell a more comprehensive story about the molecular underpinnings of autism that integrates previously disparate pieces of evidence.”