Girls may require more mutations than boys to develop autism

Compared with males diagnosed with autism or other neurodevelopmental disorders, females with the disorders have more mutations in their DNA, scientists report in the March 6 American Journal of Human Genetics.  

In some still mysterious way, females may be better able to protect themselves against these mutations, some scientists think. That idea may help explain a striking difference: Four boys receive an autism diagnosis for every girl who does.

Small studies have hinted that girls can endure more harmful mutations than boys (SN: 8/13/11, p. 20), but the new results are especially convincing because they come from a large group of people with neurodevelopmental disorders including autism, says human geneticist Ivan Iossifov of Cold Spring Harbor Laboratory in New York.

Human geneticist Evan Eichler of the University of Washington School of Medicine in Seattle and colleagues wondered whether differences in DNA mutations were involved in the differing autism rates between girls and boys. The team tapped into two large genetic datasets: one from more than 15,000 people with intellectual disabilities and one from 762 families that include a child with autism, a repository of samples known as the Simons Simplex Collection.  

On average, females in both groups had more harmful mutations than males, the team found. This was true for large chunks of missing or duplicated DNA as well as for small, single letter mutations. “No matter what class of mutation we looked at, females had more than males,” Eichler says.

In the Simons group, females who had autism had double the number of large deletions or duplications that males had, for instance. When the analysis was restricted to genes that are probably involved in brain development, these females had three times as many of these mutations as males in the group.

In a different analysis, the researchers found that large duplications or deletions were more likely to come from a child’s mother than from the father. Overall, these mutations came from the mother 57 percent of the time.

These results show that moms are more likely to pass on this kind of mutation. But, Eichler says, “we also know that dads play a huge role.” Other studies have suggested that different mutations may also be involved in autism, such as those that arise spontaneously in sperm cells from the father (but aren’t in the rest of his cells).

Regardless of the mutations’ origins, the new result suggests that males are more susceptible to them, Eichler says. “No matter where the insults are coming from, a female is going to require more of these hits to push her to a disease state.”

Because the study examined only the association between mutations and an intellectual disability, it doesn’t show whether any mutations actually contribute to autism.

Scientists still have no idea why females may be more resilient to these mutations, or why males seem particularly vulnerable to them, Iossifov says. Differences in brain growth and development might be involved. Eichler’s best guess involves the X chromosome. Since females have two X chromosomes, they have backup DNA when there’s a problem on one. In contrast, males possess just a single X chromosome, rendering them more susceptible to mutations that may interfere with normal brain development.