Pam Harrison

May 06, 2013

DONOSTIA / SAN SEBASTIÁN, Spain — Females carry almost twice as many mutations that confer risk for autism spectrum disorder (ASD) than males, yet they are less likely to develop the disorder, new research shows.

This finding suggests that females are relatively protected from developing ASD, because it takes more ASD risk factors for females to develop clinical manifestations of the disorder than it does males.

"The excess of males with autism has been a striking and consistent finding since 1943, when autism was first described," Stephan Sanders, MD, assistant specialist in psychiatry, University of California, San Francisco, told Medscape Medical News.

"Our study suggests that there is a different threshold of risk in males than in females, so you need more autism risk factors in females for them to develop the disorder. This suggests that our focus needs to change towards understanding how the male and female brains differ and what that means for autism risk instead of looking for specific male risk factors for ASD."

The study was presented here at the 12th Annual International Meeting for Autism Research (IMFAR).

First-Time Finding

For the study, samples from the Simons Simplex Collection were analyzed by genotyping array and whole-exome sequencing to identify de novo and rare variants predicted to alter protein composition.

In the first of 2 studies, researchers looked at large-scale mutations called copy number variations, or CNVs, which are large deletions or duplications of up to a million base pairs of DNA.

Results from this study showed that affected females had a 1.7-fold increase in de novo CNVs per sample than affected males, a difference that was statistically significant (P = .03).

In the second study, researchers used whole-exome sequencing to look at de novo point mutations or single nucleotide variations (SNVs) that disrupt a specific gene.

"Again, we see the same increase in SNVs in females compared to males, and strikingly, that difference is the same as it is for large-scale mutations, a difference of 1.7 fold (P = .008)," Dr. Sanders noted.

That 1.7-fold difference between the sexes for both CNVs and SPVs would explain roughly 20% to 50% of the difference in ASD prevalence between males and females — "and this is the first time that this difference has been directly observed, as previous attempts looking at this on a population scale have been somewhat inconclusive," Dr. Sanders said.

Dr. Sanders cautioned that researchers need to keep in mind the possibility that ASD might be a different disorder in males than in females. "From this small snapshot, it looks very similar," he said. For example, when they analyze genes that are disrupted in ASD females and those that are disrupted in ASD males, "we find that both point towards chromatin regulation," Dr. Sanders said.

Chromatin regulation is the process by which cells determine their identity and differentiate into neurons or other types of cells.

However, Dr. Sanders felt that it was important for investigators to consider the possibility that there may be a fundamental difference in autism between males and females, because if they do not consider such a possibility, "by the time we are working on treatments, it might be that those treatments only work in males with autism but not in females."

Real Evidence of Sex Differences

Asked by Medscape Medical News to comment on the findings, John Constantino, MD, professor of psychiatry and pediatrics, Washington University School of Medicine, St. Louis, Missouri, said they were a "major addition" to a line of research that now suggests females inherit and transmit autism susceptibility factors as often as males do, but appear much less likely to develop severe clinical symptoms.

"[These current] findings add the important observation that for females who do show clinical signs, the burden of genetic risk seems to be significantly higher than that of the average male affected by autism — in other words, that for the types of autism caused by these types of CNVs and SNVs, it requires a greater genetic load to bring about clinical disease," he said.

The relative "resilience" of females to autism susceptibility also appears to occur across numerous causes of familial autism — that which runs in families and affects multiple members of each family, he added.

"This therefore offers hope that scientific discovery of how this gender-based phenomenon occurs may provide major clues to new interventions for many (or even most) forms of autism," Dr. Constantino said.

Also commenting, Geraldine Dawson, PhD, chief science officer of Autism Speaks and professor of psychiatry, University of North Carolina, Chapel Hill, pointed out that it has long been speculated that there is something "protective" about the X chromosome against not only ASD but also other disabilities.

"What is really significant here is that it's the first time that we have real evidence – and in this case, genetic risk factors – where we see a higher proportion of these de novo CNVs and other rare mutations in the affected female population," Dr. Dawson said.

This is important, she added, inasmuch as females have been largely excluded from research in autism because the sample size was too small to be analyzed and was often discarded.

"We can't take what we have learned about autism in males and generalize it to females," Dr. Dawson said.

"We're just scratching the surface here now, but what's going to be important is to understand that females may have different causes of autism, they may have different brain development and different protective factors, and ultimately, they may require different treatment."

Dr. Sanders, Dr. Constantino, and Dr. Dawson report no relevant financial relationships.

12th Annual International Meeting for Autism Research (IMFAR). Abstract 155.003. Presented May 4, 2013.


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