WEDNESDAY, April 4 (HealthDay News) -- Genetic mutations that
arise spontaneously, as opposed to being passed through
generations, could play an important role in the development of
autism, new research suggests.
Three research teams sequenced the genes of children with
sporadic autism, meaning it did not run in their families, and
compared the sequences with those of their parents and siblings.
Their results were published in three separate articles on April 4
in the journal
"We found that 15 to 20 percent of sporadic patients could be explained by 'de novo' [or spontaneous] mutations," said Evan Eichler, professor of genome sciences at the University of Washington in Seattle, who led one of the studies.
Overall, the researchers identified hundreds of spontaneous
mutations in gene sequences that they predicted would upset the
function of the genes in the children with autism. Most of them
were only found in single patients.
The good news, according to Eichler, is that the multitude of
affected genes seems to belong to just a handful of pathways --
involved in, for example, development or cognition. That suggests
that mutations in a diverse set of genes could have a similar
"This kind of investigation is of tremendous value for understanding the genetic architecture of risk for autism," said Andy Shih, vice president of scientific affairs at Autism Speaks, a national advocacy group.
"We can probably explain genetic risk factors that might lead to autism in less than 30 percent of the population" from previous research, Shih added.
Autism spectrum disorders, which include both mild and serious
forms of autism, affect one in 88 children in the United States,
according to just-updated statistics from the U.S. Centers for
Disease Control and Prevention.
The study led by Eichler involved 677 individuals representing
209 different families, each with one child who had sporadic
autism. The researchers found a total of 126 spontaneous mutations
that they predicted would have a severe effect on the genes in
which they occurred.
Eichler's team relied on samples from the Simons Simplex
Collection, a nationwide project that gathers blood and DNA from
children with sporadic autism and their unaffected family
A second study, led by researchers at Yale University in New
Haven, Conn., looked at 238 families from the Simons project, some
of which overlapped with Eichler's study. They identified 125 de
novo mutations that would change the readout of genes among the
children with autism and 87 among their unaffected siblings.
The third study in the trio found that just under half of
children, both with and without autism, had readout-altering
spontaneous mutations, but that the mutation rate was comparable
between children with autism and their unaffected siblings. This
study was led by researchers at Harvard Medical School,
Massachusetts General Hospital in Boston and the Broad Institute in
Cambridge, Mass., and involved 175 sets of children with autism and
Altogether, this body of research suggests that the frequency of
de novo mutations is not significantly higher in children with
autism, but that the types of mutations, which occur by chance, are
more detrimental in children with autism than those in their
unaffected siblings, Eichler said.
Eichler's team also found that de novo mutations were four times
as likely to lie on DNA strands inherited from the father, and that
the number of mutations increases with paternal age.
The possible paternal influence suggests that many of the de
novo mutations originate in the father's sex cells, which give rise
to sperm. Presumably, mutations would be more likely in paternal
sex cells rather than maternal ones because paternal cells continue
to divide throughout a man's lifetime, giving them more chances to
pick up mutations.
Although the link with paternal age agrees with some
epidemiological studies that have found higher rates of autism
among children of older parents, it probably only plays a part in a
modest 10 percent or so of patients, Eichler said.
From the three studies, mutations in two genes, called CHD8 and
KATNAL2, emerged as likely autism risk factors because they were
found in more than one patient. "Almost never did we see lightning
strike the same place twice," Eichler said.
Unlike the myriad mutations identified in genes involved in
neuronal development, these mutations could have more universal
effects on regulating gene expression, cell growth and
These two genes were also among the 49 genes that fell into the
same biological pathway, Eichler's team found. "This one is a
monster pathway," Eichler said, because it involves the largest
number of identified de novo mutations.
The gene mutations identified in this research "underscores that
autism is a complex interplay between genes and the environment,"
Shih said. For example, CHD8 can control the expression of other
genes in response to environmental stimuli.
This research is also a reminder that autism is a group of
related disorders involving many genes in different pathways, he
added. "Each of the genes [in these studies] seem to confer only a
small risk, and are only readily found in a small percentage of
individuals with autism," he noted.
However, Shih said, these studies show that with more genetic
analyses involving more patients, "there could be some unifying
principles revealed that could allow identification of individuals
at risk of autism and guide therapeutics."
To learn more about autism, visit the
Society of America.
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