When it comes to developmental disorders of the brain, men and women are not created equal. Decades of research have shown that males are at far greater risk for neurodevelopmental disorders such as autism spectrum disorder (ASD) than females. Boys, on average, are five times more likely to have autism than girls . What causes this disparity has largely remained unknown. Now scientists have uncovered compelling genetic evidence to explain why the biological scales aren’t balanced. According to a team of geneticists in the U.S. and Switzerland, it all boils down to what’s called the “female protective model.” This suggests that girls have a higher tolerance for harmful genetic mutations and therefore require a larger number of them than boys to reach the diagnostic threshold of a developmental disorder. With identical genetic mutations, then, a boy could show symptoms of ASD while a girl could show none. But because the female mutation threshold is higher, when girls are diagnosed with ASD, they tend to fall on the more severe end of the spectrum. Researchers believe the same dynamic could explain why more boys are diagnosed with ADHD, intellectual disabilities and schizophrenia. The findings were published Thursday in the American Journal of Human Genetics.

All in the Genes

Geneticists analyzed DNA samples from 16,000 boys and girls with neurodevelopmental disorders. They found that, on average, females diagnosed with ASD had 1.3 to 3 times more harmful genetic alterations than males diagnosed with the disorder. The findings suggest that as the male brain develops, smaller and more subtle genetic changes can trigger autism spectrum disorders. Female brains require a greater number or severity of mutations before showing symptoms, so their symptoms tend to be worse. “There’s no application in terms of treatment,” said study author Sébastien Jacquemont of University Hospital of Lausanne in Switzerland, but “it does help understand the inheritance dynamics in families.” Jacquemont also studied some 800 families in which a family member was affected by ASD. He found that children were more likely to inherit gene mutations linked to autism from their mothers. Jacquemont says this may be because a male with a severe form of autism may have more trouble forming relationships and be less likely to have children. In contrast, the same genetic glitches in a female could go unnoticed, Jacquemont says, so that woman may be more likely to start a family and unknowingly pass the genes to her offspring.

Unclear Cause

The study doesn’t answer the most profound question surrounding the genetics of neurodevelopmental disorders: “What causes these disorders?” It’s still unclear which particular genetic glitches are responsible for different manifestations of developmental disorders. Or if genetic alterations are even passed down from parents, rather than simply appearing in children as they develop. Jacquemont is hoping to form larger cohorts to study which mutations put children at risk for ASD and other neurodevelopmental disorders. Still, some researchers aren’t convinced that genetics are even the way to answer questions about neurodevelopmental disease. Irva Hertz-Picciotto, an epidemiologist at the University of California-Davis, told USA Today,

"Boys are swimming in measurably more testosterone than girls are. Some evidence suggests that social behaviors are in part determined by such early life exposures to sex steroids."

Still, advances in the genetics of neruodevelopmental disorders could help families gain insight into whether their children are likely to inherit genetic markers associated with disorders like autism. Image credit: Zurijeta/Shutterstock