To decipher the code of autism, researchers are also looking outside of the ASD patient community to other developmental and social disorders.
One of the few rare mutations that cropped up in some autistic children in the studies were extra copies of 7q11.23 (shorthand for denoting the positions, or loci, of the genes on the chromosome—in this case on the long arm, or "q," of chromosome 7). As several of the research teams pointed out, deletion of this region has been implicated in Williams-Beuren syndrome (WBS), a disease that tends to make people especially gregarious, empathetic and social.
"There's clearly something in that small region—of 25 or so genes—that's having a significant impact of social interactions," State says. "Within that relatively very small region in the genome there are going to be keys to studying neurology and social development."
Mutations at other regions of the genome did crop up more than once in the study group. And a copy error at 7q11.23 or other loci did not necessarily translate into similar levels of IQ or developmental disability in different patients. Hence, factors other than errors at these loci must also be playing a role in the manifestation of ASD.
Rather than wait for additional genome scans to turn up more potential mutations, however, many research teams are already creating models of how these mutations might impact neurological development.
Although such model building might seem premature given the ever-changing genetic terrain of the disease, "having a way to begin to interrelate them might actually help to study them," says Huda Zoghbi, of the Department of Molecular and Human Genetics of Baylor College of Medicine, who co-authored an analysis of the three Neuron studies published online today. So rather than get mired in finding each possible gene, she says, it makes sense to "go back and forth between the genetics and the functional studies."
Finding the function—and dysfunction
Vitkup and his team conducted just such a functional, model-based approach. Their paper, published online in the same issue of Neuron, looked closely at the location and likely effects of the mutations among families that have only one ASD child. By figuring out which genes communicate with each other, he says, you can "see if mutations try to disrupt genes that are next to each other," and thus what common pathway different mutations might be messing up. He likens it to a hunt for a criminal that might be committing robberies in different states but with the same modus operandi, perhaps choosing similar targets each time.
With a little computer-assisted detective work he and his team found one cluster of pathways that many of the errant genes seemed to be interrupting. And it turned out to be a crucial cluster, involved in synaptic development and the movement of neurons in the young, developing brain. As neurons branch out to form connections, if some pathways are disrupted, the connections can become abnormal. In a sample of about a dozen cases, Vitkup says, most of the patients had disruptions that would encourage an overabundance of particular neuronal connections. Such a pattern provides evidence for the excess of connections in autistic children producing the opposite behavior pattern from WBS, whose patients have fewer than normal connections. But, he says, the jump from genetic mutations to social skills is difficult.
Nevertheless, that mutations implicated in ASD would be linked to this sort of neuronal network "is logical by the phenotype," Vitkup says. And for future studies and diagnoses, he says, it "can help because we can now look to see if there is a new mutation somewhere in the genome and we can see how close—or how related—the new mutation is to our cluster."
He and his team currently have several dozen genes mapped into their network, but he expects the list to grow to as many as 500 in the next few years as more individuals with ASD are included in these studies and as sequencing technology improves. And there might well turn out to be other key clusters of pathways that are discovered, which will have an entirely different list of implicated genetic mutations, Vitkup says.
Zoghbi and her team, whose work published online June 8 in Science Translational Medicine, have gone through much of the same data to find patterns in the types of proteins that these rare mutations might be affecting. A new genetic mutation can change the way proteins are made—they might be made incorrectly, too often or not at all. "This can have a domino effect on many other proteins that could affect how a neuron talks to another neuron," Zoghbi explains. She likens it to a self-contained neighborhood in which each person has a particular skill set. If everyone is present and working well together, the garbage will get collected and the streetlights will stay on. But if one or two people are missing or unable to do their work properly, major systems will start to falter, "because the other ones don't have those skills," she says. Likewise, "a group of proteins is needed for a cell to function well."
With just a couple dozen proteins flagged a few years ago, Zoghbi and her team now have hundreds that they have added to the growing list of autism instigators.
"The more we understand the function of the proteins involved in autism—and by what pathways they might impart that change—we might begin to ask, 'Where can we intervene, and would one intervention help just one patient or a group?'"