Dr. Stephen Scherer (left), Chief of Research at SickKids Hospital, and Dr. Marla Mendes, a research fellow, inside a lab at SickKids Hospital in Toronto, on Dec. 20. They identified 59 genetic variants on the X chromosome significantly associated with autism.EDUARDO LIMA/The Globe and Mail
In the tangled forest that is the genetics of autism, scientists have a new guidepost.
For the first time, a gene called DDX53 has been associated with the complex developmental disorder. Its identification is an important piece of new information for those seeking answers about the causes of autism – still a mystery. And its location, on the human X-chromosome, is particularly noteworthy, because it helps shed light on why boys are about four times more likely to present with autism than girls.
“If you’re male and you don’t have a copy of this gene, you’re going to be on the spectrum,” said Stephen Scherer, chief of research at Toronto’s Hospital for Sick Children (SickKids), which played a key role in the discovery.
The find makes up one of a pair of studies published Thursday in the American Journal of Human Genetics. A second study led by researchers at SickKids involves an examination of the entire X-chromosome, including the region where the DDX53 gene is located, and further unpacks its role in neurodevelopment.
Autism, or more broadly autism spectrum disorder (ASD), is a condition whose symptoms relate to how individuals socialize, communicate and learn. It arises in about 1 per cent of females and 4 per cent of males and consists of multiple subtypes, many of which are likely to involve rare genetic variants that can affect brain development at an early age.
Dr. Scherer, a molecular geneticist, has spent the past two decades leveraging the growing power of DNA sequencing technologies to look for commonalities between people who develop ASD. In 2022, his group at SickKids published a mammoth study that involved sequencing the entire genomes of more than 7,000 individuals on the autism spectrum in addition to some 13,000 family members. The results yielded 134 genes that, if altered or absent, were predictive of autism. But those genes are only implicated in about 15 per cent of all cases, which suggests that many additional genetic pathways to the disorder have yet to be uncovered.
The new find came about when Dr. Scherer was contacted by a colleague in Italy who had noticed that the DDX53 gene was affected in a handful of his patients with ASD. The gene was not previously associated with autism and is not well studied, in part because it does not have an analogue in the mouse genome.
Dr. Scherer and colleagues at SickKids conducted clinical testing and saw a similar pattern.
“To be honest, we had overlooked it,” Dr. Scherer said of the gene. But on closer inspection the connection was unmistakable.
In total, the study found 10 individuals with ASD, eight males and two females, in whom the gene was shown to be affected. Researchers also combed through a large database and found another 26 cases with rare variants of the gene. In particular, every male with a damaged or deleted DDX53 gene showed all the classic features of autism.
Males are especially susceptible to genetic problems that arise on the X-chromosome because they possess only one copy of it. For females, if a gene is not working properly on one X-chromosome, their second X can confer a protective effect. And while many of the genes linked to ASD are located on chromosomes that are inherited from both parents, any that occur on the X-chromosome are likely to contribute to a higher rate of the disorder among boys.
The find is likely to stimulate further research because the DDX53 gene sits within a larger region of DNA that contains the code for a gene known as PTCHD1-AS, which has previously been linked to both autism and other disabilities related to cognitive skills.
At the functional level, DDX53 provides the genetic sequence needed to construct a form of protein known as an RNA helicase. Such proteins are found in the nucleus of the cell where their role is to act on RNA molecules that turn other genes on and off at different stages of development. It’s the upstream position of DDX53 in the process that helps explain how it can have such a defining and cascading affect on neurodevelopment.
“We think this is kind of a higher-order monitoring system that needs to be intact for other genes that we have not yet defined,” Dr. Scherer said.
In many cases, Dr. Scherer noted, a single gene variant may not be a direct cause of autism but rather present an increased risk factor in combination with other influences.
In the second study, which was independent of the first, the SickKids team looked for variations across the entire X-chromosome of thousands of individuals with ASD. This led them to 17 different genes in the X-chromosome that might be affected and could be a cause of autism. Once again, both DDX53 and PTCHD1-AS showed up along with 15 others.
Myriam Srour, a pediatric neurologist at the Montreal Children’s Hospital who was not involved in the studies, said that such results can be extremely helpful for families who are looking for answers about why a child may have ASD or which version of it is relevant to them. In some cases, a genetic diagnosis can help identify which interventions are likely to be successful.
“I find that for my patients, having a specific diagnosis helps them find their own community, so they become experts of their own gene,” Dr. Srour said.
The new research comes at a time of increased public discussion about autism, much of it driven by U.S. president-elect Donald Trump’s selection of Robert F. Kennedy Jr. as his nominee for health secretary. Mr. Kennedy is known for promoting false and repeatedly debunked claims about vaccines and autism.
