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Unraveling autism one de novo mutation at a time
Sarah A. Webb, Ph.D.
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Remaining questions

Whole exome sequencing data should be available for the entire SSC within two years, according to Ronemus. But those mutations only represent a fraction of genetic changes that could boost autism risk. Researchers suspect that hundreds of genes might be contributing to autism spectrum disorders and uncovering and confirming all those genes could require sequencing the genomes of tens of thousands of families.

The importance of biological samples

In addition to sequencing technology, these types of studies require access to samples from individuals with autism and their unaffected family members. Three of these studies used samples from family groups in the Simon Simplex Collection (SSC), a permanent repository of 2700 families affected by autism. To simplify analysis, this collection was limited to families where the parents do not have autism and only one child has an autism spectrum disorder. They could not have other neurodevelopmental disorders, and, where possible, they include genetic material from an unaffected sibling.

This particular collection, operated by the Simons Foundation Autism Research Initiative (SFARI) and collected at 12 academic medical research centers, is unique because of its size, its focus on simplex families, and its inclusion of unaffected siblings, explains John Spiro, deputy research director at SFARI.

“The thing that cannot be underestimated is putting together a really good set of families. That's tough, and it requires a ton of money,” says Michael Ronemus of Cold Spring Harbor Laboratory. The sequencing and the molecular analysis are not the most expensive part of this research. “The expense is in finding and diagnosing people, and collecting biological samples from them in the first place.” -S.W.

In addition, simply finding the gene isn't enough—researchers need to understand the function of the gene, the protein it encodes for, and what other proteins it might interact with in biological pathways. Even with just 20 to 30 new genes, that's a tremendous amount of functional, molecular, and animal model research. The major question for Geschwind is whether or not there are convergent pathways. And then there are the clinical questions: As with cancer, will researchers be able to define molecular subtypes of autism that are treated with similar drugs or behavioral methods? Or will there be hundreds of subtypes? Answering those questions will be critical for identifying potential targets that pharmaceutical companies could use to develop drug treatments.

At the moment, the genes that have been discovered and linked to autism may be difficult to target with therapies. “They're tough genes, at least the ones that we're finding because they're so highly interconnected at the protein level and early in development,” says Eichler.

Mutations found in the exome will be easier to interpret than those found in other parts of the whole genome. “But there are plenty of people who are now throwing these samples onto whole genome sequencing platforms, and hoping that they'll find mutations in conserved extra-genomic regions,” says Spiro. After that, researchers might start to look for epigenetic changes in the same samples, he adds. But moving into whole genome sequencing may present a data interpretation bottleneck, Ronemus says. Even with the exome, it's not that simple. “I'm sure it will be done eventually, and I think it should be done, but I think the interpretive capacity, the computational capacity, if you analyze whole genome data it's really not anywhere near as advanced,” says Ronemus.

Eventually, as researchers learn more about the connections between the identified genes and the biology of autism, they may be able to use sequencing as a part of diagnosis, as a way to predict prognosis, and make treatment choices. Someday, families might be able to use sequencing data to determine whether inherited genes or de novo mutations contributed to their child's autism, which could help them understand the risk of autism for other children within their family, says Geschwind. If subtypes are identified, a genetic profile might eventually steer families toward effective therapies and away from ineffective ones, says Ronemus.

“The landscape is sort of coming into focus,” says Spiro, noting that the genetic work will be critical for the understanding of autism. But at this point, he adds, researchers are far from saying: “‘Aha, you know, now we understand it, and we're ready to just hand it off to a pharmaceutical company.’ I think everyone wishes that were the case, but we've got plenty more time to go.”

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