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Interviewer: New insights into the complexities of autism, up next on The Scope.

Announcer: Examining the latest research and telling you about the latest breakthroughs the Science and Research Show is on The Scope.

Interviewer: A recent report published in the journal Nature shows how incredibly complex autism is. Here to talk with me about the findings and what they mean is Dr. Hilary Coon, an author on the paper and research professor at the Ï㽶ÊÓƵ of Utah. Dr. Coon, what did you find in this study?

Dr. Coon: Well, this study involved a lot more data and human subjects than pretty much any other study that we've done so far. In this study, we greatly increased our knowledge of genes with definitive evidence for association with autism risk. Now we're up to about 30 of those. Probably about 70 more are very likely to be associated with risk. But the other thing that we did was just look at the number of occurrences of mutations in these genes, we can make an estimate that there are probably over a thousand genes that are actually associated with risk. So, many, many genes out there that we have not yet identified.

Interviewer: I mean, this just shows how complicated autism is. Was that surprising to you?

Dr. Coon: No, not at all. So when we started out doing this kind of work decades ago, people were hoping that this would be a disorder that was maybe a few genes and as studies progressed it became okay maybe a dozen, maybe 20. The more we study this, the more complicated it becomes which isn't probably all that surprising considering this is something that has to do with the brain which is a very complicated organ.

Interviewer: What implications do these findings have for genetic testing?

Dr. Coon: Well, certainly genetic testing is hopefully something that we'll identify, make early identification so that parents can get their kids into treatment earlier. Of course, the problem that a study like this brings about is that we know that there are many, many genes that wouldn't be on a genetic test because we simply don't know what they are yet. And, in addition, the genes that are on there have variable degrees of association with risk. So, for example, you might see a mutation in a person, assume that that's a risk mutation and define that that person may get autism where as they may need 5, 6, 10 other factors in order to actually get the diagnosis. So, our knowledge of the inner play between different risk factors is also so far very limited.

Interviewer: So at this stage, genetic testing couldn't definitively point out every person who may get autism or who may not get autism. This is actually kind of similar to other complicated conditions out there.

Dr. Coon: I kind of think about this as the way we conceptualize risk for something like heart disease or obesity where we all kind of know that yeah, there are genetic factors out there, but if you have any particular risk factor it doesn't necessarily mean that you'll get a diagnosis. So while the risk factors are important, and maybe knowing about them are important, then that would lead to some preventative measures. The way that we have of defining risk is far from complete.

Interviewer: In the report in the journal Nature you also looked at what types of genes are risk factors for autism. What did you find there?

Dr. Coon: Yeah, so one of the things that the big studies are trying to do because this looks so complicated is to take the risk mutations, look at those genes, and try to group those genes into biological pathways just to try to make the problem a little more simple. And one of the biological pathways that appears to be very important is genes that control synapses. So these are the communications that occur between nerve cells and that certainly makes some intuitive sense.
Another one, another pathway where there are several genes involved is in genes that work to control genetic expression during development. So, it's possible that for example if the child might have a mutation in one or more of these genes that then they're more vulnerable, for example, to particular environmental hits that may happen during development. So, that's a really interesting gene pathway to sort of becoming to the fore, it brings up possibilities for studying all kinds of genetic and environmental interactions.

Interviewer: I think one thing that strikes me about those different classes of genes that are hit is that they all are sort of at top of a cascade of effects. I mean, if you impact how a synapse is made or if you impact how genes are turned on or turned off, that's going to have a lot of consequences down stream of that.

Dr. Coon: Right, so the other thing to keep in mind though, again is, okay, say you have a mutation that's in a synaptic pathway, the brain is amazingly complex in that there are a lot of compensatory mechanisms. So you might have some sort of defect but as humans we have many ways of sort of getting around those particular defects. So, you're right, this cascade effect is probably hugely important.
But again, any one mutation may not put you over the edge as far as risk. It may take that mutation plus a number of other more subtle mutations that mean that maybe your compensatory mechanisms don't work as well or maybe that one environmental hit that occurred at a particular time in development was way more important than it would be for the next individual. But if you weren't exposed to that you'd be fine.

Interviewer: Do these findings also suggest something about autism itself, what autism is?

Dr. Coon: You know, this is maybe the way we used to think about mental retardation as being all one entity and now we know that even X-linked mental retardation there's dozen of different very specific syndromes. So, it's likely that autism is hundreds of different disorders and we lump them all together simply because we don't understand enough to be able to split them out.
There are some particular syndromes that have been very specifically identified, like rett syndrome, that result in autistic behaviors and a diagnosis of autism that they are very well characterized. And we know their genetic mutation. So that kind of thing is sort of like picking away at the iceberg, getting at one particular rare syndrome after another.

Interviewer: So how do you plan to untangle all of this? What is the future of this type of research?

Dr. Coon: Well, okay, there's a huge place for the large consortium studies. Really, with that kind of collaborative research you start to be able to have enough individuals that are participating, enough samples, enough people working on the problem together just to begin to make sense of it, begin to see patterns in the results. So that is an absolutely crucial part of this.
We're kind of lucky in Utah in that I think we have another part to play that's important and that maybe can't be done in many other places in the world and that is simply with our really big amazing families here. The families that participate are just incredibly unique in that they'll come in over and over and over, they will agree to be tested in multiple different ways so that we can start trying to figure out sort of the specificities of their traits that they're carrying in their family.

And because we have families with 3, 4, 5, sometimes 10 individuals in just one nuclear family, we can really see how these particular genetic mutations occur together with very specific traits and characteristics. We can look at their certain historical information and try to figure out if there were any other environmental exposures, we can look at all of their medical history and try to figure out exactly what some of these mutations might mean.

Interviewer: So something you just mentioned is the autism sequencing consortium and that you're part of that and that's who published the paper. I actually find it really interesting that you're referred to as autism sequencing consortium instead of your individual names and institutions.

Dr. Coon: You bring up a really good point. This is a collaboration of over I think, 37 different institutions and hundreds of scientists working on this. And everybody on this consortium is so concerned with making progress, scientific progress, much more concerned than their own careers or their own making their name in the world, right?
So, the authors actually agreed to simply list as the "author" of this paper being the consortium and then give a link to a website that lists all the consortium members. It's a really nice thing to be able to see the evolution of scientific work going towards this very collaborative collegial type of consortium where everybody's really working together to try to solve a very important problem.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.