Scientists found a genetic link between autism and DM1, where repeat DNA sequences disrupt brain gene splicing. This sheds light on ASD’s development and opens new paths for targeted treatments.
Researchers from The Hospital for Sick Children (SickKids) and the University of Nevada, Las Vegas (UNLV) have identified a genetic connection between autism spectrum disorder (ASD) and a rare inherited condition known as myotonic dystrophy type 1 (DM1). Published in Nature Neuroscience, the study challenges the long-held belief that ASD is primarily caused by gene loss-of-function, pointing instead to an alternative mechanism that may underlie social behaviors commonly seen in autism.
DM1 is a genetic disorder characterized by progressive muscle weakness and wasting. While ASD affects approximately 1% of the general population, individuals with DM1 are 14 times more likely to be diagnosed with autism.
The researchers discovered that the genetic mutation responsible for DM1, tandem repeat expansions (TREs) in the DMPK gene, also disrupts normal brain development. These TREs interfere with a crucial biological process known as gene splicing, which is necessary for proper gene expression. This disruption leads to an imbalance in protein production and widespread mis-splicing of several genes involved in brain function. These molecular changes may contribute to the development of ASD-related social and behavioral traits in individuals with DM1.
“Our findings represent a new way to characterize the genetic development of autism,” explains Dr. Ryan Yuen, Senior Scientist in the Genetics & Genome Biology program at SickKids. “By identifying the molecular pathway behind this connection, we can begin to investigate new approaches to ASD diagnosis and the development of precision therapies that release these proteins back into the genome.”
What are TREs?
TREs occur when sections of a DNA strand are repeated two or more times, and the likelihood of those repeats causing errors in gene function increases each time.
In 2020, Yuen discovered that TREs are genetic contributors to autism, identifying more than 2,588 different places in the genome where TREs were much more prevalent in people with ASD. Similarly, people with DM1 have a TRE in the DMPK gene.
“A variation really stood out to me that we see in rare neuromuscular disease,” says Dr. Łukasz Sznajder, a research lead and Assistant Professor at UNLV. “This is how we started connecting the dots. We found a molecular link, or overlap, which we believe is the core of causing autistic symptoms in children with myotonic dystrophy.”
Gene splicing is a key contributor to the development of ASD
As the tandem repeat expands in the DMPK gene, the research team, including collaborators at the University of Florida and Adam Mickiewicz University (Poland), found its altered RNA binds to a protein that is involved in gene splicing regulation during brain development. This so-called “toxic RNA” depletes the protein and prevents it from binding to other RNA molecules in important areas of the genome, causing a protein imbalance which results in mis-splicing other genes.
“TREs are like a sponge that absorbs all these important proteins from the genome. Without this protein, other areas of the genome don’t function properly,” explains Yuen.
The Yuen Lab and Sznajder Lab are already exploring whether this mis-splicing is happening in other genes associated with ASD, as well as how their findings could inform precision therapies that release these proteins back into the genome.
Some of this work is already underway. In 2020, Dr. Christopher Pearson, Senior Scientist in the Genetics & Genome Biology program at SickKids, identified a molecule that can contract TREs in Huntington’s disease. While more research is needed to identify how this could be applied to other conditions, the team remains optimistic their findings could inform future research and care for DM1, ASD, and other conditions.
Reference: “Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes” by Łukasz J. Sznajder, Mahreen Khan, Adam Ciesiołka, Mariam Tadross, Curtis A. Nutter, Katarzyna Taylor, Christopher E. Pearson, Mark H. Lewis, Rochelle M. Hines, Maurice S. Swanson, Krzysztof Sobczak and Ryan K. C. Yuen, 21 April 2025, Nature Neuroscience.
DOI: 10.1038/s41593-025-01943-0
This study was funded by the Azrieli Foundation, the National Institutes of Health (NIH), Myotonic Dystrophy Foundation, Muscular Dystrophy Association, the UNVL startup fund, the University of Florida Centre for Autism and Neurodevelopment, the National Science Centre, Poland, SickKids Research Institute, Brain Canada, the Government of Ontario, the University of Toronto McLaughlin Centre, the Canadian Institutes of Health Research (CIHR), The Petroff Family Foundation, Tribute Communities, The Marigold Foundation and SickKids Foundation.
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