Three Separate Studies Point to Abnormal Gene as Cause of Autism
By AUDREY GRAYSON
ABC News Medical Unit
When Ann Hotez's third child Rachel was diagnosed with autism at the age of 2, the mother's first reaction was to believe something she had done while pregnant had brought about the condition.
"I was blaming myself terribly, like it was something I did wrong during my pregnancy," Hotez said.
She began racking her brain for a possible explanation for possible causes of the condition. This was 1994 and comparatively little information was available about autism. Many doctors still believed the disorder was caused by environmental factors.
Hotez, desperate to find a reason for her daughter's disorder, landed upon the fish industry.
"For a while I was furious at all the fish companies for letting me eat tuna fish while I was pregnant with Rachel," she explained.
But as more research became available on the genetics of autism, Hotez reconciled her pain with the understanding that the disorder doesn't have one simple external cause. Indeed, for years now, scientists have suspected that autism is a complex genetic disorder, the development of which depends on a constellation of genes working together rather than the work of one single gene.
Now, three different laboratories across the country have identified the same gene abnormality as a possible cause of autism — adding to the growing body of evidence that the disorder is primarily genetic.
The gene — known to scientists as contactin-associated proteinlike 2 (CNTNAP2) — has been a prime autism suspect among scientists. The gene is a blueprint of sorts for an important protein involved in the ability of brain cells to communicate with each other properly.
Today, a group of studies published in the American Journal of Human Genetics not only confirmed the link between this gene and autism, but they begin to identify the specific role this gene plays in the development of the disorder.
Three Studies, Similar Findings
While each of the studies found that this genetic variant increases the risk of developing autism, one of them also revealed that the gene variation is especially risky when inherited from mothers rather than fathers.
In the first part of the study, researchers analyzed data from 145 children with autism whose families had two or more children with the condition. They found by chance that the subjects had a higher rate of the abnormal gene.
To validate these findings, researchers studied a separate group of participants, which included 1,295 autistic children and their healthy parents. They found again that the subjects had higher rates of the variant gene than would have occurred by chance.
When researchers combined the data from the two studies, they found that children with autism were about 20 percent more likely to have inherited this genetic variant from their mothers than from their fathers.
According to Aravinda Chakravarti, primary investigator and a professor at Johns Hopkins School of Medicine, this research may take us one step closer to a better understanding of the genetic causes of autism and how large a role environmental factors truly play in the development in the disorder.
"Environmental factors might be important, but we don't know which or how much they affect the development of this disorder," Chakravarti said. "But I'm very confident that this is a first step in a series of steps we need to take to study autism with some measure of comprehensiveness before we can estimate the totality of meaning for the role of environmental factors."
In another lab across the country, researchers at UCLA landed upon the same gene — CNTNAP2 — as a possible candidate for autism. But the UCLA researchers identified the specific role this gene might play in affecting language, thought and behavior for people with autism.
Taking a different approach, these investigators used data from the Autism Genetic Resource Exchange and studied the DNA of 291 families nationwide who had at least one autistic child. They also found that an unusually high number of the autistic subjects had this gene variant.
To verify their findings, researchers studied the DNA of a new group of 304 families and found that the CNTNAP2 gene variant showed up consistently in the autistic subjects.
Moreover, researchers took a closer look at the gene to see how it might bring about autism. Daniel Geschwind, principal study investigator and director of the UCLA Center for Autism Research, said they discovered that in young children, the gene was most active in language and thought.
"We found that the longer the language delay an autistic child had, the more likely they were to have the CNTNAP2 variant," Geschwind explained. "So having this variant at least partially explains amount of language delay in autism."
A third study released in the same journal identified specific mutations on the same gene, which were individually rare for each autistic patient. Researchers at Yale University sequenced the entire gene and found that autistic patients often had unique mutations on the gene, which were not found in any members of the healthy control group.
This finding exemplifies the complexity of the findings on this gene as well as the disorder itself, said Dr. Matthew State, principal investigator of the study and director of the Program on Neurogenetics at Yale University. He noted that even though his team took a different approach to unlocking the possible genetic causes of autism than the other two teams, "we still landed on the same gene which is quite interesting, but more work needs to be done to sort out what's going on here."
Could Genes Trump Environmental Factors?
Many experts support Chakravarti's belief that this research adds to the evidence that genetic factors play more of a role in the development of autism than environmental factors.
"Environmental factors in autism is a separate issue," said Carla Mazefsky, assistant professor of pediatrics and psychiatry at the University of Pittsburgh School of Medicine. "Given autism's strong genetic basis, identification of genes that play a role is of critical importance. This study further emphasizes the complexity of the genetics underlying autism."
"Autism is a disorder of fetal or early postnatal brain development with a genetic origin," agreed Vittorio Gallo, director of the Center for Neuroscience Research at the Children's National Medical Center in Washington, D.C.
Margit Burmeister, associate director of the Molecular and Behavioral Neuroscience Institute at the University of Michigan, said that "this study adds to the evidence that genetic factors play a role and adds strong results to the idea that cell adhesion in the brain plays a role in autism." However, she said she believes that environmental factors still play a role in the development of the disorder.
"This is similar to risk for diabetes, which is very strongly affected by exercise, weight and sugar consumption, but some people can be coach potatoes and eat what they want and don't get sick. Those with a more resilient genetic predisposition for autism may get the same environmental factors without ill effect," Burmeister explained.
But the findings that suggest genetics may play a stronger role than environmental factors may be a small measure of comfort for parents like Hotez, who may have blamed themselves for their child's condition.
"In my heart now I know it's a genetic disorder," she said. "I don't think it's caused by any of the environmental [factors] they talk about in the news."