Researchers at Baylor College of Medicine, the Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital and collaborating institutions have identified new genetic candidates that help explain why autism is diagnosed about four times more often in boys than in girls. The study, published in the American Journal of Human Genetics , reveals that small changes in the gene MECP2 on the X chromosome might help explain part of this difference.
“Autism is a common, heritable neurodevelopmental trait that affects how a person communicates, interacts with others and experiences the world, and is characterized by altered social interactions and restricted, repetitive behaviors or interests,” said corresponding author Dr. Huda Zoghbi , Distinguished Service Professor at Baylor, director of the Duncan NRI and a Howard Hughes Medical Institute investigator.
The fact that autism is diagnosed about four times more often in males than in females suggests sex-specific factors may increase male vulnerability. In the current study, the researchers drew from their long experience with gene MECP2 , which is on the X chromosome (X and Y are the sex chromosomes) and has been associated with neurodevelopmental conditions, including autism.
“We tested the idea that the predominance of autism in males could be explained in part by mild mutations in an X chromosome gene’s regulatory regions. Females might be protected from such a mild mutation because of their second X chromosome, but males, who have only one copy, would be more vulnerable,” said first author Dr. Rebecca Meyer-Schuman , a postdoctoral associate in the Zoghbi lab. “The regulatory regions are like dials that control whether a gene will be expressed and by how much. And what better place to start looking at these regulatory regions than the gene MECP2 , where brain health depends on how much of the gene is expressed, and where mutations can cause neurodevelopmental disorders that include autism.”
Previous studies in mice from the Zoghbi lab and others have taught researchers that MECP2 produces a Goldilocks protein, meaning that it must maintain a "just right" concentration or activity level for a healthy brain. Having too little – about 50% or less of the normal levels – leads to Rett syndrome, and having twice the normal levels causes a different neurodevelopmental condition called MECP2 duplication syndrome.
“Previous studies in mice also showed us that milder changes in MECP2 levels, for instance reducing the expression by 30% or increasing it by 50%, do not cause the more severe features of Rett syndrome or MECP2 duplication syndrome like seizures or motor problems, but lead to autism-like behaviors,” Meyer-Schuman said.
In the current study, the team screened the regulatory regions of the MECP2 gene with a laboratory tool called Massively Parallel Reporter Assay (MPRA). “This allowed us to identify and manipulate the regulatory regions and determine what kinds of changes would alter their function,” Meyer-Schuman said.
The researchers also screened MECP2 regulatory regions in autistic individuals and tested the genetic variants they identified using the MPRA assays.
“We identified two regulatory regions where male autistic individuals inherited a variant from their unaffected mother that altered regulatory activity,” Meyer-Schuman said. “One of these variants reduced MECP2 expression by approximately 30% in human neurons, a magnitude that produces social deficits, hyperactivity and anxiety-like characteristics in mice. As predicted by the mouse model, this individual was diagnosed with autism and ADHD but had none of the defining characteristics of Rett syndrome.”
“These findings, a result of integrating human and animal studies, suggest that MECP2 regulatory variants can contribute to male-biased autism and reveal just the tip of the iceberg, providing a framework for uncovering regulatory variants in other X chromosome neurodevelopmental genes that may contribute to autism’s missing heritability,” Zoghbi said.
Other contributors to this work include Fisher Cherry, Yang Sui, Athanasios Papastathopoulos-Katsaros, Yi Zhong, Yidan Li, Tianyun Wang, Kelsey Hennick, Druha Karunakaran, Hanna Berk-Rauch, Zhandong Liu, Aravinda Chakravarti, Tomasz Nowakowski and Evan E. Eichler.
For the complete list of author affiliations and financial support for this work, see the publication.
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American Journal of Human Genetics
Experimental study
Cells
A massively parallel reporter assay of MECP2 cis-regulatory elements reveals genetic candidates for male-biased autism
9-Oct-2026