Variants in DDX53, and other genes on the X chromosome, provide new clues as to why autism spectrum disorder (ASD) is prevalent in males, according to two recently published studies.
One study, from the Hospital for Sick Children (SickKids) in Canada and the Istituto Giannina Gaslini in Italy, clinically tested 10 individuals with ASD from eight 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.
In another paper, also including researchers from SickKids, the team identified 59 genetic variants on the X chromosome significantly associated with ASD.
Both studies were published in the American Journal of Human Genetics. The lead author of the first study is Marcello Scala, MD, PhD, from the University of Genoa. The lead author of the second paper is Marla Mendes, PhD, a research fellow at SickKids.
“Identifying this new gene as a confirmed contributor to ASD underscores the complexity of autism and the need for comprehensive genetic analysis,” said senior author Stephen Scherer, PhD, senior scientist, genetics & genome biology and chief of research at SickKids, and director of the McLaughlin Centre at the University of Toronto.
ASD describes a group of neurodevelopmental conditions that feature challenges related to communication, social understanding, and behavior. The prevalence in males to females is ∼4:1. Why that is, is one of the most urgent questions in the field.
DDX53, located on the X chromosome, is known to play a role in brain development, but its function has not previously been definitively associated with autism.
“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,” said Scherer.
At the same location on the X chromosome, the researchers found evidence that another gene, PTCHD1-AS, might be involved in autism. The first study also 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.
That team’s study cohort was assembled through an international collaborative effort, involving several renowned clinical and research institutions from Canada, Italy, and the United States. 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, [it was] 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 behavioral traits of autism, opening a whole new area of exploration,” said lead author Scala, who is a researcher in medical genetics at the Istituto Giannina Gaslini, affiliated with the University of Genoa (Department of Neuroscience).
In the second paper, Scherer and his team 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 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,” said Scherer.
The team noted that commonly used mouse models don’t have a gene similar to DDX53, which may require 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,” said Scherer.
Scherer added: “Both studies provide even more evidence that complex neurobehavioral conditions like autism can sometimes have simple biologic (genetic) underpinnings.”
