On the cause of autism.

A new Nature Medicine (subscription requried) "News & Views" article by Art Beaudet at Baylor College of Medicine summarizes some new discoveries about autism. As it turns out, somewhere between 10-30% of autism patients can be demonstrated to have de novo mutations (i.e. occurring in the sperm or egg) that cause their symptoms. This is cool work, as two different groups found copy number changes in 10-30% of autism patients that wasn't present in the parents. Why is this cool? Because it answers a longstanding question:

Autism is thought to be highly heritable, largely because of a very high concordance in monozygous (identical) twins—although the concordance in dizygous (fraternal) twins is low.

One would expect the frequency to be lower in fraternal twins, but for autistic patients, this was lower than normal. Well:

All of the genetic abnormalities discussed here would be expected to be associated with virtually 100% concordance in monozygotic twins and, for the de novo majority, very low concordance in dizygotic twins ... ... Thus, for a fraction of cases, this new understanding of the genetic etiology of autism fits perfectly with the previously puzzling data from twins.

So, if many of the changes are mutations occurring in the sperm or eggs, one would expect identical twins to have the same disease, as they would both carry the mutation. But the odds of both fraternal twins getting sperm or eggs that carry a brand new mutation are astronomical.

Beaudet hypothesizes two things:

Higher density arrays focused at the level of single exons are likely to be very productive in identifying smaller abnormalities that may be immediately traceable to specific genes.

That is, once we look more closely, it may turn out that an even higher percentage of autism patients are due to de novo mutations. And second:

Our view is that epigenetic abnormalities of chromatin that are not associated with nucleotide sequence changes might contribute to the etiology in this group; particularly given the male predominance, epigenetic abnormalities affecting the X or Y chromosome might be hypothesized. We have proposed a mixed epigenetic and genetic and mixed de novo and inherited model for autism, in which individual patients could have a genetic (mutation) or epigenetic (epimutation) etiology and these components could be inherited in some cases and de novo in others.

He suggests that epigenetic factors will prove to be important for other patients, that is that improper modification of chromosomes in the mother or father, will be the causative agent. Though to be fair, he says:

an epigenetic component, if one exists, remains elusive

Nonetheless, we are now discovering the cause of autism in some patients. Now, some important questions remain. Are the sites that are mutating de novo particularly susceptible to mutation? Or are other sites that mutate just less important? And importantly, what do these sites tell us about the pathology of autism? And can we design treatments and diagnostic tests to find and help autism patients? Can we find the cause of autism in other autistic patients?

This paper raises the possibility that we could know the causes of all autism in the near future. Very exciting, indeed!