Study Reveals Shared Genetic Basis for Autism Spectrum Disorder and DM1

Researchers from the University of Las Vegas Nevada (UNLV) and The Hospital for Sick Children (SickKids) have uncovered a genetic connection between autism spectrum disorder (ASD) and myotonic dystrophy type 1 (DM1), a rare inherited disease known for progressive muscle weakening. The findings, published in Nature Neuroscience, challenge long-held assumptions about autism’s genetic roots and open new possibilities for targeted treatments.

Rethinking the Genetics of Autism

Traditionally, ASD has been associated with gene loss-of-function mutations. However, this new study highlights an alternative mechanism: the disruption of gene splicing caused by tandem repeat expansions (TREs), a type of genetic variant responsible for DM1. TREs in the DMPK gene appear to interfere with normal brain development, potentially triggering the social and behavioral traits seen in individuals with ASD.

DM1 affects roughly 1 in 8,000 people, but individuals with the disorder are up to 14 times more likely to be diagnosed with autism, suggesting a deeper genetic link.

“Our findings represent a new way to characterize the genetic development of autism,” said 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 and Why Do They Matter?

Tandem repeat expansions occur when short DNA sequences are repeated multiple times in a row. These repetitive stretches can disrupt gene function especially when they appear in critical regulatory regions. In 2020, Dr. Yuen and his team identified over 2,500 TRE sites in the genome that appeared more frequently in individuals with autism.

The TRE in DM1 affects RNA function in a unique way. The expanded RNA sequence acts like a sponge, binding to and depleting a key splicing protein required for proper gene expression during brain development. Without this protein, other genes are mis-spliced, resulting in abnormal protein production across the genome.

“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,” Yuen explained.

This disruption in gene splicing appears to underlie the shared features of DM1 and ASD.

Connecting the Dots: From Muscle Disorder to Autism

Dr. Łukasz Sznajder, research lead and assistant professor at UNLV, recalls the moment of realization:

“A variation really stood out to me that we see in rare neuromuscular disease. 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.”

The study, which also involved collaborators from the University of Florida and Adam Mickiewicz University in Poland, pinpoints how a single mutation in DMPK can cascade into widespread effects on brain function. This insight could transform how both disorders are understood and treated.

Toward Targeted Therapies

The research teams are already exploring the potential for precision therapies that reverse this protein imbalance. Some early efforts are promising: in 2020, Dr. Christopher Pearson at SickKids identified a chemical capable of contracting TREs in models of Huntington’s disease. While more studies are needed, similar strategies could one day benefit individuals with DM1 and ASD.

The Sznajder and Yuen labs are now investigating whether this mis-splicing process occurs in other autism-related genes and how to counteract it with targeted drugs.

Final Thoughts

This discovery marks a significant step forward in understanding the complex genetics behind autism and related conditions. By identifying a shared molecular mechanism between ASD and DM1, the research lays the groundwork for more accurate diagnoses and new avenues for treatment moving us closer to personalized care for individuals affected by these disorders.