Autism and gender: Are boys 'predisposed,' girls 'protected'?

“We know there is gender bias in neurodevelopmental disorders, ranging from autism to intellectual disability,” begins Bradley P. Coe, PhD, senior fellow, Eichler Lab, Department of Genome Sciences at the University of Washington School of Medicine, Seattle, and coauthor of a new study that may help explain the gender chasm.¹

Studies of individuals with intellectual disability show up to 50% excess of males over females, and with autism spectrum disorder (ASD), the male-to-female ratio is 4:1.

Coe says that a number of researchers have tried to find a molecular basis for this gender divide by looking at 2 different kinds of genetic mutations: copy-number variants (CNVs)-large disruptions in the DNA that often affect several genes; and single-nucleotide variants (SNVs)-alterations of a single base in the genome that can result in the loss of functional proteins. He says that a few studies have found large differences between males and females with neurodevelopmental disorders in the number of deleterious autosomal CNVs and SNVs, but most of the studies have been relatively small.

So Coe and his colleagues from Switzerland looked at 2 large populations. They first considered a cohort consisting of more than 9000 males and more than 6000 females with neurodevelopmental disorders.

“When we compared the females to the males with neurodevelopmental disorders, the females on average had more large deleterious CNVs than males,” indicating, Coe says, that “females require a far greater deleterious genetic hit than males to push them from normal neurodevelopment to a development disorder category, whether that be an intellectual deficit or a social/behavioral deficit, like you see with autism.”

Coe and colleagues then looked at an independent ASD cohort of 762 families. “We saw a similar trend, where the females had larger, more deleterious CNVs than the males.” In fact, the affected females were 2 to 3 times more likely to have a deleterious CNV than the affected males.

The researchers then looked at whether they could see the same trend in point mutations disrupting only a single gene. Again they found that affected females had an excess number of severe mutation events compared with males. “It’s not just a difference in the number and deleteriousness of CNVs; it’s also a difference in SNVs, or truncating mutations-mutations that produce a shorter or more broken protein than what we’d expect,” Coe says, meaning that affected females have a larger mutational burden both from CNVs and from sequence mutations.

Coe says their findings complement the “extreme male brain hypothesis” posited by Simon Baron-Cohen, PhD, of the University of Cambridge, United Kingdom, and others. The hypothesis essentially states that males tend to exhibit more traits that could be considered mildly autistic to begin with, so they don’t require as severe a genetic defect to move them into the diagnostic realm of autism.

“Essentially, females need a much larger mutational burden to reach the autism diagnostic threshold,” says Coe. “That can either be interpreted as males being more predisposed to autism or females being more protected.”

Robert Naseef, PhD, a clinical psychologist at Alternative Choices in Philadelphia, Pennsylvania, and author of Autism in the Family: Caring and Coping Together,² says that while the study may provide part of the explanation for the gender difference, “girls present differently than boys do. On the whole, girls are more social than boys,” and, in general, they exhibit fewer of the behavior differences and challenges than boys do.

Naseef, who specializes in helping families cope with autism, says the study raises some important questions. He proposes that just because girls are able to carry a greater mutational burden without being diagnosed with ASD, it doesn’t necessarily mean that they do not have some degree of social learning issues.

He says that one of the implications of the study for him is that “we have to get a little better at diagnosing girls. Their presentation tends to be more subtle. We need experienced people doing the evaluations and more subtle instrumentation for the screening process.”

“We have to remember that girls tend to develop internal problems like anxiety and depression, while boys tend to develop external problems like hyperactivity and aggressive behavior. If a girl is quiet and cooperative, she may be struggling, but not be identified as needing help as quickly as a boy who keeps getting out of his seat and getting into scuffles,” Naseef comments.

He advises that we suspend our stereotypical image of the child with ASD and be especially sensitive to caregivers who bring girls to our offices with social problems. “These can be an early red flag.”

Coe concludes, “We have shown that a correlation exists between genetic burden and gender-associated risk. We hypothesize that future studies on even larger populations will begin to identify specific genes contributing to this gender-specific risk and provide insight into the mechanisms at play.”

REFERENCES

1. Jacquemont S, Coe BP, Hersch M, et al. A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders. Am J Hum Genetics. 2014;94(3):415-425. Available at: www.cell.com/AJHG/retrieve/pii/S0002929714000597. Accessed March 28, 2014.

2. Naseef R. Autism in the Family: Caring and Coping Together. Baltimore, MD: Brookes Publishing; 2013. Available at: http://alternativechoices.com/publications/. Accessed March 28, 2014.

Ms Hack is a medical writer and editor in New Jersey. She has 25 years’ experience in the field and is a long-time contributor to both Contemporary Pediatrics and sister publication Contemporary OB/GYN. She has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.