Autism has a significant and persistent gender stigma, with approximately four boys diagnosed for every girl. Experts have long believed that this disparity stems primarily from diagnostic inequality, as much of the autism research and the screening tools that result from it have historically focused on boys, effectively setting a male standard for what autism “looks like.” As a result, girls and women are more likely to be overlooked, misdiagnosed, or diagnosed much later in life.
This disparity has also shaped the science around autism. With fewer women with the disorder, fewer women will participate in research, creating a feedback loop in which scientific understanding of autism in women remains limited. This underrepresentation of women has made it difficult for scientists to tease out how much of the gender bias in autism reflects social inequality or underlying biological differences between men and women.
Although the search for biological explanations has largely lagged, one leading theory, known as the “female protective effect,” proposes that women, unlike men, may be biologically attenuated from developing autism.
This idea can be traced back to studies that showed that women diagnosed with autism tend to carry more genetic mutations, or “hits,” than autistic men, and that autism requires more of the same genetic mutations to manifest. But until now, little was known about the exact biological mechanisms behind this apparent resilience.
Now, Whitehead Institute member David Page’s perspective from the lab was published on March 30th. natural genetics, proposed a genetic explanation for the protective effect of women and suggested that biological differences between men and women contribute to the strong sex bias of autism.
This study is one of many projects in the Page lab that uncover the biological basis of gender bias in everything from heart health and autoimmune diseases to certain cancers.
The fact that we see gender bias in systemic illnesses lends credence to the idea that gender bias in autism does not simply result from diagnostic inequalities or gendered expectations about what symptoms should look like. ”
David Page, Professor of Biology, Massachusetts Institute of Technology, Howard Hughes Medical Institute (HHMI) Investigator
The researchers propose that this protective effect extends beyond autism and may help explain why 17 other congenital and developmental disorders primarily affect men. Scientists believe that by characterizing the biological factors that make one gender more or less likely to develop certain health conditions, there is an opportunity to improve how these conditions are diagnosed and how people receive care.
Page and Harvard-MIT MD student Maya Talukdar trace protective effects in women to the X chromosome. Talukdar is a graduate student in Page’s lab and lead author of this Perspective.
Most women have two X chromosomes (XX), while most men have one X chromosome and one Y chromosome (XY). Sex chromosomes increase or decrease the expression of thousands of genes on the other 22 pairs of chromosomes in the cell, influencing cellular functions throughout the body.
Historically, scientists believed that a woman’s second X chromosome was largely inactive. But in recent years, research in the Page lab has revealed that so-called “inactive X,” also known as Xi, plays an important role in regulating gene expression on the active X chromosome and the rest of the chromosomes.
In this light, researchers have pointed to a subset of genes expressed from both active and inactive X chromosomes, well known as genes that “evade” X chromosome inactivation. Many of these genes are dose-dependent regulators of important cellular processes. These processes affect thousands of other genes throughout the genome, including genes associated with autism.
Because women have extra copies of these regulatory genes expressed from the Xi, Page and Talukdar propose that women may be better able to mitigate the effects of mutations associated with autism than men.
Protective effects for women beyond autism
Researchers say this mechanism extends beyond autism to a variety of congenital and developmental disorders that skew male.
“Many of the other congenital or developmental conditions we point to are not subject to the same diagnostic inequalities as autism,” Talukdar says. “This strengthens the idea that the protective effect of women stems from genetic differences between men and women.”
One example is pyloric stenosis, which, like autism, affects four boys for every girl. Infants with this disease experience severe vomiting because the pyloric sphincter, the passageway between the stomach and small intestine, thickens. Similar to autism, girls with pyloric stenosis appear to require more genetic “hits” to develop the condition.
The researchers’ new framework for looking at Xi to understand gender differences in disease could have implications for the treatment and care of diseases that primarily affect men, as well as diseases that are more prevalent in women, such as autoimmune diseases.
“Our biology is not one-size-fits-all, and it’s clear that sex differences play a major role in health, so understanding them is critical,” Talukdar said.
sauce:
Whitehead Biomedical Research Institute
Reference magazines:
Talukdar, M., Page, DC (2026) The inactive X chromosome as a female protector in autism and beyond. natural genetics. DOI: 10.1038/s41588-026-02534-w. https://www.nature.com/articles/s41588-026-02534-w
