Researchers have discovered a new genetic cause of autism—a finding that provides additional knowledge about a complex condition but also highlights how far the scientific community is from fully explaining the disorder. The chromosome 16 abnormality identified by Weiss and colleagues and reported in the New England Journal of Medicine appears to account for about 1% of autism cases.
“This is going to help a small percentage of parents, and it’s going to frustrate the other 99%,” says Chantelle Wolpert, MBA, PA-C, CGC, Research Assistant, Department of Human Development and Family Studies, University of North Carolina (UNC) at Greensboro. “We’re in this area where none of these findings is going to be simple. We’re just not at the point where it’s one gene, one disease anymore.”
The “16p Form” of Autism
This particular finding eventually will enable clinicians to test children diagnosed as having autism spectrum disorder to determine whether their condition is caused by the chromosomal change. As with all genetic testing, the results will not provide definitive answers for every parent of a child with autism: The patient might not have the abnormality tested for, but that does not preclude the possibility that the child’s autism is caused by another, as-yet-unidentified, genetic change—or by something else entirely.
For parents whose children do receive a positive test result for “the 16p form of autism,” as it will likely be called in the literature, the greatest benefit may be an ounce of certainty about what is otherwise an uncertain and not-fully-understood disorder. Because autism spectrum disorder actually encompasses many different, behaviorally defined conditions, diagnosis is based on clinical judgment. The standardized method of evaluation enables clinicians to make the diagnosis, but until recently, Wolpert notes, “there wasn’t something black and white that a parent could grasp. Now there will be—at least for this 1% of people.”
Approximately 10% to 15% of children with autism have a condition that is identifiable; for example, clinicians can test for fragile X syndrome or the previously reported chromosome 15 anomaly associated with autism. Offering answers to another 1% of patients and parents “sounds small,” Wolpert observes. “Big deal, you can [provide results] in all specialties. But you can’t in autism, and that’s why” these findings are significant.
What Weiss and colleagues actually identified is a section at the top of chromosome 16 that is either duplicated or deleted in some autistic patients. The strength of the research lies in the fact that this chromosomal anomaly was found in patients from three distinct populations. There are many genes within that section of chromosome 16, so geneticists will have to map them to determine what those particular genes do or don’t do and how their multiplication or deletion can impact human development. Someday, these genes might provide a therapeutic target for patients with this type of autism—but such a day remains far in the future.
A Genetic Risk Factor
Meanwhile, an article and two reports recently published in the American Journal of Human Genetics describe a different type of genetic association with autism. In the study led by Alarcón, a variant on chromosome 7 was identified as a risk factor for autism. Chromosome 7 and the specific gene (contactin associated protein-like 2, or CNTNAP2) have been associated with language development. Now, based on these new findings, CNTNAP2 may be considered an autism susceptibility gene.
“This is a risk for autism,” Wolpert stresses. “It’s not enough to have this genetic variant. If you have a copy of this particular gene, it doesn’t mean you’re going to develop autism.”
Reports by Arking et al and Bakkaloglu et al provide an additional line of evidence for CNTNAP2 as an autism susceptibility candidate. Furthermore, one of the reports also identified a genetic heritability component: Autistic children were significantly more likely to inherit the gene variation from their mothers than from their fathers.
“Again, we’re one step closer,” Wolpert says. But “there is no genetic testing for this right now”—whereas, for the 16p form of autism, “there will be genetic testing for that sooner rather than later.”
Still, clinicians should not expect a flurry of test ordering. Parents who have heard about these findings, and who have long wished for answers about their children’s condition, may approach the topic at an office visit (or even demand that their child be tested). Clinicians will have to explain to parents the likelihood of finding a definitive explanation.
“If they know that ahead of time, they’re usually fine,” says Wolpert, who spent 12 years at Duke University’s Center for Human Genetics before entering the PhD program at UNC–Greensboro. “It’s when you send off a genetic test and you don’t explain what it means” that parents can feel a deeper sense of frustration at receiving a negative test result. “They may leave the office thinking, ‘OK, it wasn’t this thing that the researchers discovered, so it’s not genetic!’” Or they might have their own personal theories about what caused their children’s autism, including blaming themselves in some way.
Recommendations will have to be developed so clinicians have a guideline of who should be tested for genetic causes of autism. With the average test costing $2,000 to $5,000, insurers may question the validity of testing for a chromosomal anomaly that occurs in a mere 1% of autistic persons.
Looking Beyond Thimerosal
One of the most persistent theories about autism is that it is caused, at least in some cases, by exposure to thimerosal, which was used as a preservative in many vaccines until about 10 years ago, when manufacturers started removing it from their products. Numerous studies have failed to identify such a link, but many parents remain unconvinced.
A study by Schechter and Grether in the Archives of General Psychiatry is among the most recent to dispel the autism-thimerosal link. The researchers discovered that rates of autism continued to rise in California even after thimerosal had been removed from vaccines. “[T]ime trends are inconsistent with the hypothesis that thimerosal exposure is a primary cause of autism in California,” the authors write. However, “we support the continued quest for the timely discovery of modifiable risk factors for autism and related conditions.”
Eric Fombonne, MD, from the Department of Psychiatry at Montreal Children’s Hospital, expressed frustration in his accompanying editorial: “How many more negative study results are required for the belief to go away, and how much more spending of public funds on this issue could even be justified?”
While remaining neutral about thimerosal, Wolpert acknowledges the “need [for] more research funding—for all aspects, not just genetics.”
Since pharmacologic therapy for autism, let alone a cure, is little more than a dream at this stage, it might be beneficial to explore ways to address the issues experienced by patients and parents living with autism. “How are we going to help the parents and patients who already have this [diagnosis]?” Wolpert asks. “What factors in a family or educational system help a child to achieve his or her highest level of ability?”
Identification of additional genetic factors will also open the doorway to exploring the role of environmental factors in autism. “If you can control for one variable in a study, then you can examine the others,” Wolpert points out.
Progress may be slow, but clinicians, parents, and patients have reason to hope. “The bad news is 85% to 90% of autism is still unexplained,” Wolpert says. “Then again, what great progress! Ten years ago, we knew autism had a genetic basis, but that’s all we knew. Now, we have causative genes and genes that increase risk. We’re making headway.”