Two groundbreaking studies are revealing exactly how genetic mutations cause autism spectrum disorder, opening doors to earlier diagnosis and personalized treatments that target the root cause rather than just symptoms. Scientists at UT Southwestern Medical Center have identified how specific genes disrupt the brain's ability to form connections and develop normally, findings that could transform how we understand and treat autism in children.

What Are Researchers Learning About Autism's Genetic Causes?

Autism spectrum disorder affects how children communicate, interact socially, and develop behaviors. For decades, doctors knew autism ran in families, but the genetic mechanisms remained mysterious. Now, researchers are piecing together the puzzle. The Chahrour Lab at UT Southwestern led two studies published in March 2026 that focused on two genes: KDM5A and UBE3B. Each gene appears to cause autism through different biological pathways, suggesting that autism isn't one disease but rather a collection of individually rare genetic disorders.

The research team discovered that KDM5A variants cause severe speech impairment and intellectual disability alongside autism. Using a genetic database called GeneMatcher, researchers identified 24 additional individuals from 21 families with pathogenic KDM5A variants, bringing the total known variants to 31. What's striking is that each unrelated person had a different variant in the same gene, yet all experienced similar developmental challenges.

The second gene, UBE3B, tells an equally compelling story. When researchers studied mice lacking this gene in their central nervous systems, the animals showed severe deficits in vocalization, social behavior, learning, memory, and motor skills. Under the microscope, their neurons revealed the problem: reduced connections between brain cells and immature structures that receive signals from other neurons.

How Do These Genetic Changes Affect Brain Development?

Understanding the mechanism is crucial for developing treatments. KDM5A controls how DNA is packaged inside cells, which determines which genes cells can read to make proteins. When this gene is mutated, the packaging goes wrong, and cells express thousands of genes abnormally. In one case, a single variant caused more than 4,000 genes to be expressed differently compared to normal cells.

UBE3B works through a different mechanism called ubiquitination, a cellular process where proteins are tagged with a small protein called ubiquitin. This tagging marks proteins for destruction or regulates their function. When UBE3B is missing or defective, cells accumulate 116 extra proteins that should have been degraded. Many of these proteins are involved in building connections between neurons, and several are already known to be disrupted in autism.

Steps Researchers Are Taking to Translate Findings Into Clinical Tools

• Genetic Testing Development: Researchers are working to create diagnostic tests that identify pathogenic variants in KDM5A and UBE3B, allowing doctors to diagnose autism earlier and more accurately based on genetic cause rather than behavioral observation alone.
• Protein-Targeting Therapies: By understanding which proteins accumulate or are missing in autism caused by UBE3B mutations, scientists can design drugs that restore normal protein levels and rebuild neural connections.
• Pathway Mapping: Researchers are identifying the specific biological pathways disrupted by each genetic variant, revealing that different mutations may cause autism through overlapping mechanisms, which could lead to treatments that work across multiple genetic forms.

"Our ultimate goal is to understand what these genes are doing in the brain and identify actionable pathways that we can translate into genetic tests and targeted therapies," said Maria Chahrour, Ph.D., Associate Professor in the Eugene McDermott Center for Human Growth and Development at UT Southwestern.

Maria Chahrour, Ph.D., Associate Professor, UT Southwestern Medical Center

Why Does This Matter for Families Right Now?

The prevalence of autism has increased dramatically. In 2000, approximately 1 in 150 children received an autism diagnosis, but by 2022, that number had risen to 1 in 31 children. Better screening and a broader understanding of autism's presentation account for some of this increase, but the reality is that more children than ever need support. Current treatments focus on behavioral therapy and educational interventions, which are valuable but don't address the underlying genetic cause.

These new discoveries suggest a future where doctors could identify autism's genetic cause early, potentially before behavioral symptoms fully emerge. This could enable interventions at critical windows of brain development when the brain is most plastic and responsive to treatment. For families, this means the possibility of more targeted, effective therapies tailored to their child's specific genetic variant rather than one-size-fits-all approaches.

The research also reveals that different genetic mutations may disrupt the same underlying biological pathways. This is significant because it means a single therapeutic approach might help children with autism caused by different genes, expanding the potential impact of future treatments.

"It's all about genes and proteins and molecules in the brain and how developing and mature brains function and change in different contexts," explained Christopher Cowan, Ph.D., Professor and Chairman of the Department of Neuroscience at the Medical University of South Carolina, whose lab is also investigating genetic causes of severe autism.

Christopher Cowan, Ph.D., Professor and Chairman, Department of Neuroscience, Medical University of South Carolina

The work at UT Southwestern and other research institutions represents a fundamental shift in how scientists approach autism. Rather than viewing it as a single disorder with a single cause, researchers now recognize that autism encompasses many different genetic conditions that produce similar behavioral outcomes. This distinction is crucial because it means treatments developed for one genetic form of autism may not work for another, but it also means that as researchers identify more genes and their mechanisms, they can develop increasingly precise interventions.

The studies were funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health, the Simons Foundation Autism Research Initiative, and other foundations committed to understanding neurodevelopmental disorders. As this research continues, families affected by autism can look forward to a future where genetic testing and targeted therapies offer hope for earlier intervention and better outcomes.