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Researchers closing in on the genetic structure of autism and related disorders

By Jim Dryden

A research team at Washington University School of Medicine in St. Louis has identified regions of DNA that may be related to risk for autism.   The researchers are learning how autism is inherited, and to identify genetic factors, they're studying families and looking for traits that normally aren't considered autistic but have connections to autism risk. 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.

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.  

It's 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. Autism also is not an "all-or-nothing" disorder, according to John N. Constantino, M.D., associate professor of psychiatry and of pediatrics at Washington University School of Medicine. There is a wide range of possibilities between the extremes.   "Although we once believed you either had this condition or you didn't, we now know there's a continuous distribution of autism symptoms from very mild to very severe," Constantino says.   That means it's possible for healthy people to have very subtle impairments that may indicate genetic tendencies that contribute to autism when they occur in certain combinations.

Constantino, a staff physician at St. Louis Children's Hospital, measures such subtle indicators with a diagnostic interview tool called the Social Responsiveness Scale (SRS) that he developed with colleague Richard D. Todd, Ph.D., M.D., the Blanche F. Ittleson Professor of Psychiatry, professor of genetics and director of the William Greenleaf Eliot Division of Child Psychiatry at Washington University.   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 says. "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 on average, 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 at which 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 them very focused on details might be at an advantage under many circumstances and in a variety of occupations," Constantino says. "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 those 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 that when both parents had elevated levels of such traits as 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 says. "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 colleagues at the David Geffen School of Medicine at UCLA, 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 also are observing behavior, studying very 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 says.

The Washington University 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," he says. "As soon as infants are born into these families, we hope 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."

For more information about autism studies at Washington University, call Teddi Gray at (314) 286-0068.