Study uncovers a previously unknown genetic link to autism spectrum disorder

New research published in The American Journal of Human Genetics has identified a previously unknown genetic link to autism spectrum disorder (ASD). The study found that variants in the DDX53 gene contribute to ASD, providing new insights into the genetic underpinnings of the condition. 

ASD, which affects more males than females, encompasses a group of neurodevelopmental conditions that result in challenges related to communication, social understanding and behaviour. While DDX53, located on the X chromosome, is known to play a role in brain development and function, it was not previously definitively associated with autism. 

In the study published today, researchers from The Hospital for Sick Children (SickKids) in Canada and the Istituto Giannina Gaslini in Italy clinically tested 10 individuals with ASD from 8 different families and found that variants in the DDX53 gene were maternally inherited and present in these individuals. Notably, the majority were male, highlighting the gene’s potential role in the male predominance observed in ASD. 

By pinpointing DDX53 as a key player, particularly in males, we can better understand the biological mechanisms at play and improve diagnostic accuracy for individuals and their families. Identifying this new gene as a confirmed contributor to ASD underscores the complexity of autism and the need for comprehensive genetic analysis.” 

Dr. Stephen Scherer, Senior Author, Senior Scientist, Genetics & Genome Biology and Chief of Research at SickKids, and Director of the McLaughlin Centre at the University of Toronto

At the same location on the X chromosome, the researchers found evidence that another gene, PTCHD1-AS, might be involved in autism. The study highlights a case where a boy and his mother, both with autism with little support needs, had a specific gene deletion involving the DDX53 gene and parts of PTCHD1-AS. 

The study cohort was assembled through an international collaborative effort, involving several renowned clinical and research institutions from Canada, Italy and the U.S. Further analysis of large autism research databases, including Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, identified 26 more individuals with ASD who had similar rare DDX53 variants to the study participants. 

“This gene has long eluded us, not previously linked to any neuropsychiatric condition. Our findings support a direct link between DDX53 and autism, which is not only crucial for future clinical genetic testing, but its discovery suggests that the pathway it affects is related to the behavioural traits of autism, opening a whole new area of exploration,” says lead author Dr. Marcello Scala, researcher in Medical Genetics at the Istituto Giannina Gaslini, affiliated with the University of Genoa (Department of Neuroscience). 

In another paper published today in the same journal, Scherer and lead author Dr. Marla Mendes, a research fellow at SickKids, identified 59 genetic variants on the X chromosome significantly associated with ASD. The variants were found in genes linked to autism, including PTCHD1-AS (near to DDX53), DMD, HDAC8, PCDH11X, and PCDH19 beside novel ASD-linked candidates ASB11 and ASB9. Additionally, the FGF13 gene was highlighted as being related to ASD, with sex-specific differences, adding more evidence to the role of sex chromosomes in the condition. 

“These findings provide new insights into the biology of the X chromosome in ASD, providing additional evidence for the involvement of certain genes like DDX53 and FGF13, and suggesting they should be investigated further,” says Scherer. 

The team notes that the absence of a similar gene like DDX53 in commonly used mouse models may require future researchers to reconsider how they study ASD. Since it lacks a functional equivalent in these models, findings in DDX53 cannot be easily replicated. 

“Insights from this study could significantly influence the design and interpretation of autism research, particularly in developing new models. Identifying these variants is an important step towards developing more precise diagnostics and therapeutics for patients and families with ASD,” says Scherer. 

Scherer also added “both studies provide even more evidence that complex neurobehavioral conditions like autism can sometimes have simple biologic (genetic) underpinnings.” 

The study was funded by the University of Toronto McLaughlin Centre, Autism Speaks, Autism Speaks Canada, Ontario Brain Institute, the Italian Ministry for Education, University and Research and SickKids Foundation. Additional funding was provided by National Institutes of Health and the California Center for Rare Diseases at UCLA.