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Autism and the Female Protective Effect

Large study provides further evidence that more-severe genetic mutations required for a girl to develop autism than for a boy
February 27, 2014

A large new study adds evidence to the idea that something protects the developing female brain from neurodevelopmental disorders including autism. This "female protective model" proposes that more extreme genetic mutations are required for a girl to develop autism than for a boy.

It’s long been known that autism affects around five times more boys and men than girls and women. A similar pattern is seen with other neurodevelopmental disorders such as attention deficit disorder and intellectual disability.

“Why” has been less clear. Does the lack of a second X-chromosome put a boy at greater risk? Are girls less likely to be diagnosed because their symptoms are less obvious?

In 2012, Harvard researchers published findings suggesting that, on average, more genetic and environmental risk factors are required for girls to develop autism, compared to boys. The new study – published today in the American Journal of Human Genetics – supports this idea.

The researchers analyzed DNA samples of nearly 800 families affected by autism and nearly 16,000 individuals with a variety of neurodevelopmental disorders. They looked for various types of gene mutations. Overall, they found that females diagnosed with autism or another neurodevelopmental disorder had a greater number of harmful mutations throughout the genome than did males with the same disorders.

These findings support the idea that the female brain requires more extreme genetic changes than does the male brain to produce neurodevelopmental disorders. The results also broaden scientists' focus beyond the X chromosome in their search for the source of this gender difference. Indeed, the findings suggest that the protective effect in girls may span the entire genome.

"We have known for years that when it comes to risk for autism, girls have a clear advantage over boys." says Robert Ring, chief science officer at Autism Speaks. "This study offers exciting new insights into the science behind these differences. It also emphasizes the importance of genome as a place where gender, environment and even chance converge biologically to shape risk for autism."

More research is needed to understand the nature of the broad protective effect seen in girls and women, Dr. Ring adds. Such understanding may provide insights for preventing or treating disorders of brain development.