A recent study conducted by scientists at The Hospital for Sick Children (SickKids) and the University of Las Vegas, Nevada (UNLV) has uncovered a significant genetic connection between autism spectrum disorder (ASD) and myotonic dystrophy type 1 (DM1), a rare inherited condition characterized by progressive muscle weakness.
The study results were published in Nature Neuroscience, the research challenges previous assumptions that ASD primarily results from loss-of-function mutations. Instead, it introduces an alternative mechanism that may contribute to the development of ASD-related social behaviors, particularly in individuals with DM1.
DM1 is caused by tandem repeat expansions (TREs) in the DMPK gene. These expansions, segments of DNA that are abnormally repeated, interfere with normal gene function when they become excessively long. While ASD affects approximately 1% of the general population, individuals with DM1 are 14 times more likely to develop ASD, suggesting a strong link between the two conditions.
The study demonstrated that TREs in the DMPK gene negatively affect brain development by disrupting gene splicing, a fundamental biological process required for proper gene function. This interference leads to an imbalance of proteins, resulting in incorrect splicing of various genes associated with brain function. These mis-splicing events could underlie the social and behavioral features commonly seen in individuals with ASD, especially those who also have DM1.
The researchers discovered that the RNA produced from the expanded repeats in the DMPK gene behaves abnormally by binding to and depleting proteins responsible for gene splicing regulation. This toxic RNA acts like a sponge, capturing essential proteins and preventing them from performing their normal roles elsewhere in the genome. The resulting protein imbalance disrupts the correct splicing of several genes crucial for brain development.
The study findings present a paradigm shift in understanding the genetic underpinnings of ASD. Rather than focusing solely on gene loss, the findings emphasize the importance of splicing defects caused by toxic repeat expansions.
Yuen et al in a previous study highlighted the connection between TREs and neurological dysfunction, identified over 2,500 locations in the genome where TREs were more common in individuals with ASD. This new research builds upon that foundation by pinpointing the overlap between DM1 and ASD at a molecular level. The combined efforts have opened new avenues for understanding how genetic disruptions can lead to complex neurodevelopmental disorders.
Future research is already underway to explore whether similar mis-splicing mechanisms are at play in other genes linked to ASD. These discoveries not only shed light on the new genetic mechanism behind autism but also lay the groundwork for potential precision therapies that could improve outcomes for individuals with both DM1 and ASD.
References
- Sznajder ŁJ, Khan M, Ciesiołka A, Tadross M, Nutter CA, Taylor K, et al. Autism-related traits in myotonic dystrophy type 1 model mice are due to MBNL sequestration and RNA mis-splicing of autism-risk genes. Nat Neurosci. 2025 Apr 21;1–14.
- (PDF) Whole-genome sequencing of quartet families with autism spectrum disorder. ResearchGate [Internet]. 2024 Oct 22 [cited 2025 Apr 22]; Available from: https://www.researchgate.net/publication/271534853_Whole-genome_sequencing_of_quartet_families_with_autism_spectrum_disorder