Scientists from The Hospital for Sick Children (SickKids) and University of Las Vegas Nevada (UNLV) have uncovered a genetic link between autism spectrum disorder (ASD) and a rare genetic condition called myotonic dystrophy type 1 (DM1). The study, published today in Nature Neuroscience, suggests that while ASD has previously been characterized by a loss of gene function, another mechanism may be leading to the social behaviours often observed in individuals with ASD. 

DM1 is an inherited condition which causes progressive muscle loss and weakness. While ASD is present in around one per cent of the general population, it is 14 times more likely to develop in people with DM1.  

The study revealed that the genetic variation that causes DM1 — tandem repeat expansions (TREs) in the DMPK gene — also impacts brain development. The research team found that the effects of TREs interfere with a critical process called gene splicing, which is essential for gene function. The disruption causes a protein imbalance that can result in mis-splicing of multiple genes involved in brain function, and may explain why some of the social and behavioural outcomes of ASD develop in people 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 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. 

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.