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Scientists Link Gene Mutation to Autism Risk
Kevin P. Casey for The New York Times
Teams of scientists working independently have for the first time identified
several gene mutations that they agree sharply increase the chances that a
child will develop autism. They have found further evidence that the risk
increases with the age of the parents, particularly in fathers over age 35.
The gene mutations are extremely rare and together account for a tiny
fraction of autism cases — in these studies, only a handful of children.
Experts said the new research gave scientists something they had not had: a
clear strategy for building some understanding of the disease’s biological
basis.
Scientists have been debating the relative influence of inherited risk and
environmental factors in autism for decades, and few today doubt that there
is a strong genetic component.
But biologists have groped in vain for a reliable way to clarify the
underlying genetics of these so-called autism spectrum disorders, including
Asperger 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.
Previous studies have produced a scattering of gene findings but little
consensus or confidence in how to proceed.
The new research — reported in three papers posted online on Wednesday in
the journal Nature — provides some measure of both, some experts said.
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 awry.
“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.”
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 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. 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 one 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.
But a 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 209 families: one child with autism — and a glitch 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.
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 glitches were four times more likely to
originate in DNA from the male than from the female. The risk is higher in
fathers at 35 than at 25 and seems to creep up 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 affect brain development.
The emerging picture suggests that the search for therapies will probably be
a very long one, and that what is known generally as autism may represent a
broad category of related but biologically distinct conditions. But both Dr
. Eichler’s and Dr. Daly’s groups found some evidence that high-risk genes
interact in shared biological processes.
“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.
Scientists Link Gene Mutation to Autism Risk
Kevin P. Casey for The New York Times
Teams of scientists working independently have for the first time identified
several gene mutations that they agree sharply increase the chances that a
child will develop autism. They have found further evidence that the risk
increases with the age of the parents, particularly in fathers over age 35.
The gene mutations are extremely rare and together account for a tiny
fraction of autism cases — in these studies, only a handful of children.
Experts said the new research gave scientists something they had not had: a
clear strategy for building some understanding of the disease’s biological
basis.
Scientists have been debating the relative influence of inherited risk and
environmental factors in autism for decades, and few today doubt that there
is a strong genetic component.
But biologists have groped in vain for a reliable way to clarify the
underlying genetics of these so-called autism spectrum disorders, including
Asperger 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.
Previous studies have produced a scattering of gene findings but little
consensus or confidence in how to proceed.
The new research — reported in three papers posted online on Wednesday in
the journal Nature — provides some measure of both, some experts said.
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 awry.
“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.”
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 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. 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 one 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.
But a 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 209 families: one child with autism — and a glitch 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.
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 glitches were four times more likely to
originate in DNA from the male than from the female. The risk is higher in
fathers at 35 than at 25 and seems to creep up 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 affect brain development.
The emerging picture suggests that the search for therapies will probably be
a very long one, and that what is known generally as autism may represent a
broad category of related but biologically distinct conditions. But both Dr
. Eichler’s and Dr. Daly’s groups found some evidence that high-risk genes
interact in shared biological processes.
“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.