Autism’s Genetic Structure Offers Insights

By Jim Dryden

A School of Medicine research team has identified regions of DNA that may be related to risk for autism.

Several studies have demonstrated that autism has a strong genetic component. If one child in a family is autistic, there’s about a 10 percent chance that a sibling also will have autism.

Constantino, John John Constantino The researchers are learning how
autism is inherited. To identify genetic factors, they’re studying families
and looking for impairments that aren’t normally considered autistic but
would be diagnosed as autism in their most severe forms.

The disorder also is four times more prevalent in boys than in girls,
but autism does not seem to affect any racial, ethnic or social group more
than others.

The Centers for Disease Control and Prevention estimates that one baby
in every 250 is born with autism. As many as 1.5 million Americans are
believed to have some form of autism – and that number is on the rise.
Epidemiologists estimate the number of autistic Americans could reach
4 million in the next decade.

Autism also is not an “all-or-nothing” disorder, according to John N.
Constantino, M.D., associate professor of psychiatry and of pediatrics.
There is a wide range of possibilities between the extremes.

“Although we once believed patients either had this condition or they
didn’t, we now know that there’s a continuous distribution of autism
symptoms from very mild to very severe,” Constantino said.

That means it’s possible for healthy people to have very subtle
impairments that would be considered autistic in their most severe forms.
Those behaviors may indicate genetic tendencies that contribute to autism
when they occur in the proper combinations. Constantino measures such
subtle indicators with a diagnostic interview tool called the Social
Responsiveness Scale (SRS) that he developed with his colleague Richard D.
Todd, M.D., Ph.D., the Blanche F. Ittleson Professor of Psychiatry,
professor of genetics and director of the William Greenleaf Eliot Division
of Child Psychiatry.

They study families in which at least one child is autistic, and they’ve been able to measure the presence of sub-threshold traits – social impairment, language problems and stereotypic, repeated behaviors – that appear to have the same genetic causes as the more severe forms that occur in autism.
Their effort is concentrated on families with twins.

“When you look at identical twins, if one twin has autism, the other
has an autistic syndrome about 85 percent of the time,” Constantino said.

“But concordance in non-identical twins, is only about 10 percent to 15
percent.”

Identical twins share 100 percent of their DNA and non-identical twins
about 50 percent, so the researchers would expect that if autism was caused
by a single gene, it would be half as common in non-identical twins as in
identical. The big difference in the rates non-identical twins are affected
means several genes probably are involved.

And in spite of the devastating disability associated with autism,
it’s possible that individually, some of those genes that contribute to
autism might actually be beneficial.

“A person who has a genetic susceptibility factor that makes him or
her very focused on details might be at an advantage under many
circumstances and in a variety of occupations,” Constantino said. “But in
autism, more extreme symptoms can lead to severe levels of impairment.”
The SRS can measure such traits not only in individuals with autism
but also in their parents and siblings who are not affected with the
disorder. When combined with DNA samples from family members, those traits can help the researchers hunt for genes that can contribute to autism.
Reporting recently in the journal Biological Psychiatry, Constantino
and Todd found when both parents had elevated levels of traits measured by
the SRS, their children were 10 times more likely to have levels of social
impairment in the clinical range for an autistic syndrome.

“Neither parent would be diagnosed as autistic or even considered
abnormal,” Constantino said. “But they have subtle manifestations of traits
that appear to be genetically related to autism itself, and that gives us
some clues about how the disorder might be transmitted.”

Constantino and Todd have been working to correlate the subtle
impairments measured by the SRS with DNA samples to learn how unaffected
parents might pass on those subtle impairments that can coalesce into
autism.

With their colleagues at the David Geffen School of Medicine at the
University of California, Los Angeles, Constantino and Todd reported this
month at the annual International Meeting for Autism Research that tracking
those subtle traits and studying DNA from apparently unaffected parents and
siblings has led them to identify regions on chromosome 11 and chromosome 20 that may be related to autism.

They plan to look more closely at those regions of DNA for genes that
might influence autism.

Knowing which genes are involved could make it possible to identify
autism earlier and intervene to try to keep symptoms from progressing.
As gene sequencers analyze the DNA, the researchers are observing and
studying the behavior of young children. It’s now possible to detect signs
of autism during infancy, so the researchers are working to detect and
diagnose autism as early as possible.

Because it is so much more common in boys than in girls, Constantino’s
group has begun studying the infant brothers of children with autism.
“We observe these young boys right from the time of birth and follow
them closely at monthly intervals to get a better handle on how the
symptomatology of autism manifests itself very early in development,” he
said.

The WUSTL group is pooling its findings with other autism researchers
around the country to learn the general symptoms that characterize autism
and related disorders, including Asperger’s disorder, at their earliest
stages.

“We are actively requesting that families with an autistic child and
an infant sibling consider participating in this research,” Constantino
said.

“As soon as infants are born, we are hoping to include them in our
ongoing studies so that we can get a better handle on which children will
develop autism, how the disorder unfolds early in development and how it can be prevented or treated early in life.”