Unknown Origins

Estimates of the genetic contribution to autism vary widely. One study, published this year, indicates that as much as half of all cases of autism derive from harmful, spontaneous mutations in single genes. Other estimates suggest a more significant role for combinations of milder mutations present in the general population. No single autism-linked mutation seems to contribute to more than about 1% of autism cases, however.

For years, many researchers considered idiopathic autism -  meaning autism arising from unknown causes -  to be separate from the condition seen in genetic syndromes such as fragile X or Williams. That perception is changing.

“In the past, people used to segregate syndromic autism from idiopathic, or ‘pure,’ autism. It’s pretty clear that this distinction is getting blurred now,” said Mustafa Sahin, MD, PhD, associate professor of neurology at Children’s Hospital Boston. “At the neurological and circuit level, it seems that they are converging.”

One reason why disorders such as fragile X syndrome seem only peripherally related to autism is that not everyone with a mutation in the fragile X gene has autism. But as researchers identify more autism mutations, it is becoming clear that this variability in symptoms may be the rule rather than the exception.

For example, only about 25% of people with a deletion in the 16p11.2 chromosomal region have autism. But a closer look reveals that all of them have social deficits when compared with their parents, said Ledbetter.

Klein-Tasman works with children who have both autism and Williams syndrome, a disorder characterized by excessive sociability and intellectual disability. Some of these children display autism traits -  social communication challenges and repetitive behaviors -  well in excess of most children with Williams syndrome, said Klein-Tasman. This is often the case with other syndromes as well: The children who meet the bar for an autism diagnosis have more severe social deficits or repetitive behaviors than those who have only the related syndrome.

In these cases, Klein-Tasman said, more than one gene may be at play. “My hypothesis would be that these [more severely affected] kids have a double hit,” Klein-Tasman said. “They have Williams syndrome and probably some other vulnerability for an autism spectrum disorder.”

Clinicians often stop looking for mutations once a child has tested positive for a known genetic syndrome. But a few researchers are taking a second look at these cases. For example, Thomas Bourgeron, PhD, at the Institut Pasteur in Paris is sequencing the entire genomes of people known to have one strong autism mutation, with the goal of uncovering additional mutations.

Predictive Patterns

Adding to the complexity in studying autism’s shape is the fact that its symptoms may change as children grow up.

In a 2009 study, Klein-Tasman and her colleagues found that more than half of 30 children with Williams syndrome have autism diagnoses at ages 2 to 5. But an unpublished study from the same team shows that once children can speak in phrases, the proportion of autism diagnoses drops to around 25%. This may be because as children begin talking, their interest in socializing becomes more apparent.

To get a better picture of autism, researchers should focus on how it evolves over time, Klein-Tasman said. “We tend to get these snapshots of a single point in development. Maybe what we’re going to find is there’s a prototypical autism in the developmental trajectory.”