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“With those families, we’re going to do a very high density genome screen,” Haines says. “That will be the definitive genome scan for autism, because it will include virtually all of the multiplex families in the world.”
At the same time, autism genetics researchers are trying to define some of the complexity of the disorder by sub-grouping patients according to their symptoms and by characterizing autistic traits in their parents and other family members. Folstein traces this idea back to her twin studies in England, when she noticed that co-twins and other family members had subtle symptoms of autism—compulsions, language problems, or social awkwardness.
“We realized that maybe we shouldn’t be looking for genes for autism, but maybe we should be looking for genes for the kinds of compulsions, for example, that you see in patients with autism and also in their parents,” Folstein says.
She and Dr. Joseph Piven, professor of Psychiatry at the University of North Carolina, divided their group of multiplex families into those in which the autistic children had very poor language and those who did not, and then they considered parents “affected” if they had a history of language problems. They thought it might be possible to improve the linkage signal—the finding that affected individuals share a particular chromosomal region—and that’s what happened, Folstein says. Other investigators soon followed suit.
For example, James S. Sutcliffe, Ph.D., assistant professor of Molecular Physiology & Biophysics at Vanderbilt, and his colleagues recently demonstrated that linkage to a region of chromosome 15 improved, or got stronger, in a subset of autistic patients with savant skills—extraordinary abilities in areas such as rote memorization, calculation, and mechanical achievement. Duke University investigators led by Margaret A. Pericak-Vance, Ph.D. found stronger linkage to the same chromosomal region in a subgroup of autistic patients who exhibit repetitive compulsions and extreme difficulty with changes to their daily routine.
“It seems like every time we use one aspect of the autism phenotype, one or another of the chromosomal regions that we suspect tend to make themselves better known, give better signals,” Folstein says. “This strategy is allowing us to disentangle the condition into its component parts, which we hope have a connection with the component genes.”
Combining this approach with the pooled resources of the Autism Genome Project may offer the best hope yet for making sense of the genetics of autism.
“The number of families we’ll be looking at collectively is so large that we will finally have the statistical power to ask these kinds of questions that essentially come down to statistics,” Sutcliffe says. “It will ultimately be much easier to find the genes, and I would be surprised if within the next two years, someone hasn’t identified the first autism gene.”