Variants in DDX53 and other X-linked genes offer genetic insights into the higher prevalence of ASD in males.
A recent study published in The American Journal of Human Genetics has uncovered a previously unknown genetic link to autism spectrum disorder (ASD). Researchers identified that variants in the DDX53 gene, located on the X chromosome, contribute to ASD, shedding new light on the genetic factors underlying the condition.
ASD is a group of neurodevelopmental disorders characterized by challenges in communication, social interactions, and behavior. It is more prevalent in males than females. Although the DDX53 gene is known for its role in brain development and function, this study is the first to establish a definitive connection between DDX53 variants and autism.
The research, conducted by teams at The Hospital for Sick Children (SickKids) in Canada and the Istituto Giannina Gaslini in Italy, involved clinical testing of 10 individuals with ASD from 8 different families. The results revealed that variants in DDX53 were maternally inherited and present in these individuals, with the majority being male. This finding underscores the potential role of DDX53 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,” says senior author Dr. Stephen Scherer, Senior Scientist, Genetics & Genome Biology and Chief of Research at SickKids, and Director of the McLaughlin Centre at the University of Toronto.
“Identifying this new gene as a confirmed contributor to ASD underscores the complexity of autism and the need for comprehensive genetic analysis.”
Additional Genetic Insights
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 behavioral 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 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.
Implications for Autism Research
The team notes that the absence of a gene similar to 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.”
References: “Genetic variants in DDX53 contribute to autism spectrum disorder associated with the Xp22.11 locus” by Marcello Scala, Clarrisa A. Bradley, Jennifer L. Howe, Brett Trost, Nelson Bautista Salazar, Carole Shum, Marla Mendes, Miriam S. Reuter, Evdokia Anagnostou, Jeffrey R. MacDonald, Sangyoon Y. Ko, Paul W. Frankland, Jessica Charlebois, Mayada Elsabbagh, Leslie Granger, George Anadiotis, Verdiana Pullano, Alfredo Brusco, Roberto Keller, Sarah Parisotto, Helio F. Pedro, Laina Lusk, Pamela Pojomovsky McDonnell, Ingo Helbig, Sureni V. Mullegama, Emilie D. Douine, Rosario Ivetth Corona, Bianca E. Russell, Stanley F. Nelson, Claudio Graziano, Maria Schwab, Laurie Simone, Federico Zara and Stephen W. Scherer, 19 December 2024, The American Journal of Human Genetics.
DOI: 10.1016/j.ajhg.2024.11.003
“Chromosome X-wide common variant association study in autism spectrum disorder” by Marla Mendes, Desmond Zeya Chen, Worrawat Engchuan, Thiago Peixoto Leal, Bhooma Thiruvahindrapuram, Brett Trost, Jennifer L. Howe, Giovanna Pellecchia, Thomas Nalpathamkalam, Roumiana Alexandrova, Nelson Bautista Salazar, Ethan A. McKee, Natalia Rivera-Alfaro, Meng-Chuan Lai, Sara Bandres-Ciga, Delnaz Roshandel, Clarrisa A. Bradley, Evdokia Anagnostou, Lei Sun and Stephen W. Scherer, 19 December 2024, The American Journal of Human Genetics.
DOI: 10.1016/j.ajhg.2024.11.008
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.
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37 Comments
I would take everything asserted by this study with many many many grains of salt.
The diagnosis of autism in general is made subjectively(whatever supposed objective standards they barely use that never actually fits real world autism cases even adequately, let alone precisely or reliably)
I’m not saying there isn’t a good reason to do research or good that can come from doing research.
I can tell immediately however by the way the people writing this article and doing this research frame things they have ulterior motivations that theyre trying to see made actionable, and they have less than zero interest in the truth or helping anybody.
I don’t have the time to break down all the ways in which these truths are exposed in detail, but I assure you with absolute certainty the people doing this work are not good people, and they do not want to do good things.
For anybody(except arguably themselves, but even then…. Short term gains for outright failure on a long enough scale without serious correction)
Don’t ignore these kinds of research…. But like I said, take them with several grains of salt, and be ready to break down the dishonesty in their framings to extreme detail, lest they use lies to do atrocities to the most vulnerable of us, all while getting back pats from their next victims
I agree with you 100%. Also, what of millions of persons that one of maybe 134 Gene’s that show up in mostly males, do not have Autism/ADHD. They mostly end with their summary, more $$$$ research is required. What was the dollar value on the total research that may have left out conveniently age of parents at conception, on medication of any kind, or birth injury or harvesting of trapped placental/cord blood by imposing a policy of premature umbilical cord clamping. Policy, world wide, is called, ACTIVE MANAGEMENT.
Your vocabulary lacks subject specific terminology.
How disappointing to see once again a study was done focusing on males. How on earth can these people think their research will be relevant to autism when it is only being studied on males? Especially male children? There’s already a plethora of Information about autism in male children. Why not females? Why not adults? And how do these people STILL not understand that autism is completely different for each individual? Ok so they found a gene in one specific type of subject (male child) and now they think they can “influence the interpretation of autism research” just yikes
For Sam: The study did Not “focus on males”. The study focused on Autism Spectrum Disorders and Autism. The subjects just happen be be predominantly male. The implicated gene was found on the X chromosome (from the mother) of Autistic subjects/patients. Boys are XY, girls are XX. Some genetic disorders, like Muscular Dystrophy, are predominantly male; because, the other X chromosome of girls “cancels-out” the “bad” gene. Sometimes, the girls can get a “double-whammy” of a “bad” gene on chromosome X from mom & a “bad” X from dad. Serious disorders can be fatal to these girls before birth. The study was not biased.
REPLYING To Tandava’s comment: How can you “assure (anybody) with absolute certainty, the people doing this study are not good people”? Do you know every single one of them personally? How do you know if one or two or more do not have a child with Autism? The subjects in the study were not harmed. The parents would only need to provide INFORMED CONSENT for a small sample of blood. The researchers may have required confirmation testing of the original diagnosis of Autism. That mostly requires observation of behaviors and questioning parents about their child’s milestones, behaviors, disabilities/abilities, and medical history. I hope your experiences have not tarnished your view of scientific knowledge; parents are eager for, on behalf of their children or themselves.
I believe you mean a tiny grain of salt. Many grains would imply that it’s a large finding.
Is it the fene or sownrhing rhay turns off protection front rjr gene like chemicals in iir food and all the medications oeole take?
These things have increased over the last 50 years. I do not recall anyone in school in the 1970’s with thr symptoms of autism and back then, I never heard of autism.
There were autistic people in my small town when I was a child in the 60s. I am no expert here, but my Mom was friends with a lady who had an autistic daughter. Autistic people used to be hidden back then. They were either in a psych home or hidden away in the parents home. All the autistic/ASD people that I know have some kind of superpower and for the most part very interesting people. IMHO
For Sam: The study did Not “focus on males”. The study focused on Autism Spectrum Disorders and Autism. The subjects just happen be be predominantly male. The implicated gene was found on the X chromosome (from the mother) of Autistic subjects/patients. Boys are XY, girls are XX. Some genetic disorders, like Muscular Dystrophy, are predominantly male; because, the other X chromosome of girls “cancels-out” the “bad” gene. Sometimes, the girls can get a “double-whammy” of a “bad” gene on chromosome X from mom & a “bad” X from dad. Serious disorders can be fatal to these girls before birth. The study was not biased.
People have always had autism spectrum disorders. Knowing what it is, and collecting the behaviours under a name is new. Which is why you never heard of it in the 70s. You probably just called those people something different back then like weird or annoying. Besides it’s a spectrum, I wouldn’t be surprised if we were all on it somewhere and the ones with only a little are just considered “poorly socialised”.
There’s no big pharma conspiracy here, we’re just trying to label something that’s tricky to pin down and have a little more empathy than we offered people in the past.
Thank you! So tired of the intellectually lazy conspiracy-lovers perpetuating their tired smoking-gun theories.
Exactly! I was just about to respond to this as well. In fact, there are videos that were recorded during studies done further back than that. Due to those children being perceived to have little to no emotions (they claimed) or inappropriate emotional responses, it wasn’t uncommon for children with ASD that presented as more severe to simply be thought of as Psychopathic. So so sad. And as a mother of 3 on the spectrum, gut wrenching.
Exactly!
Did you really just come here to say the very thing that pisses off actually autistic people more than just about anything? “We’re ALL a little autistic.” You can’t be taken seriously as someone who cares about how research methods affect autistic people if you’re going to spout out ridiculously harmful statements like that. Autistic people want life to be a little easier, not statements that are nothing more than a ‘pat on the head’.
In my experience, I know way more autistic females and AFAB than males. But they’re all late diagnosed or without an official diagnosis (due to cost) because it was never picked up in their childhood. Autism is not a male condition, and we need to stop thinking that it is.
If the authors even thought to look into hypermobility and it’s link to autism, you may have found even more related genes! I have EDS, and of the thousands of other patients I know with this genetic disease, all over Australia, 90% are female, and 70% have autism.
There are so many genes that are associated with autism – I’m taking this study with a grain of salt to be honest… It autism really was x-linked there wouldn’t be so many females with autism.
I wouldn’t be surprised to learn that ASD has a lower negative affect on sexual selection in females than males. Which is maybe why it could be perceived as worse in males. It’s odd to jump right to “ASD is male only” in my opinion. 🤷
100% … It presents differently in men and women mirror far more so it is not “seen”.
No research scientist will be taken seriously, or gain respect from the community at large, if they start off with the idea of pushing that narrative.
Exactly!
Research shows it is under-diagnosed in those that are cis women or gender diverse folks in general, with an emphasis on those that started out with stereotypical female upbringing.
Most research is being done on cis males.
There is a HUGE overlap between Autism, AuDHD, and gender diversity. This article is flawed and we are really underrepresenting the majority of the autistic folks by continuing to focus on cis boys.
The X chromosome is passed down from the mother to her children. It is also passed down from a father to his daughter (he only passes the Y chromosome to his son) So daughters get XX chromosomes (one from mom, one from dad) and sons get XY (X from mom, Y from dad) Now, if I understand correctly, the article states they’ve found variants in the DDX53 gene on the X chromosome to be linked with ASD predominantly in males. The only way this could happen is if the mothers passed the DDX53 genes on to their sons and their daughters inherited their mothers other X chromosome without the gene along with their fathers X chromosome.
I am curious if there’s a strong connection between DDX53, ASD and Turner syndrome. My 6 year old granddaughter has Turner syndrome, an X0 variant which means she has 1 X chromosome and no other chromosome. People with Turner’s Syndrome may have various combinations of sex chromosome variations. Turner Syndrome is viewed as intersex because of the variations of chromosome pairings. If ASD is predominantly X linked then some people with only one X or people with X Mosaic or with more than one X, such as XXY or XXXY, might be found to have higher incidences of ASD. I’d love to find any studies on this. My granddaughter is profoundly Autistic. She is 6 years old and is nonverbal. She’s a beautiful child who loves to interact but she’s also in her own little world. 🥰
Awww, she’s got something good going for her. A Gramma who cares, (and is obviously intelligent) enough to be on here going right to the science! Even though some research isn’t up to par, there’s plenty that IS, and it’s up to us to learn about the scientific method. Good luck with your Granddaughter, I’m sure she’s going to thrive.
I believe the cause of aurism is toxoplasma gondii. It is the cause of so-called autoimmune, many cancers dementia and more (probably including autism spectrum) and is never dormant but is activated by modern meds.
Autism, sorry for typo!
I believe the cause of autism is toxoplasma gondii. It is the cause of so-called autoimmune, many cancers dementia and more (probably including autism spectrum) and is never dormant but is activated by modern meds.
Do you have a source for this? The genetic link to autism has already been proven.
I’m disappointed the article doesn’t give a disclaimer that Autism Speaks is widely considered a hate group by autistic people.
“It is more prevalent in males than females.” Bull 💩 it is, that’s all anyone believes because nobody bothers to do research that includes women, and ignores the traits that girls show in childhood. It’s not more prevalent in males, y’all just ignore women.
You’re not wrong on this one!
EXACTLY
Yup, that and that the study methodology is atrocious. Almost like cherry-picking your subjects to support your hypothesis leads to biased research and conclusions 😑. As I was reading the description of the methodology, I started to have a suspicion that this study was created/funded by people with a very particular set of beliefs about autism, who have not updated their understanding of our experience as actual autistic folks and autistic researchers provide new insights and perspectives about our neurotype. So it was not surprising to see that Autism Speaks was involved. This article, however, is surprisingly uncritical of the study and conclusions, in addition to the glaring omission about the nature of Autism Speaks. I would hope for better from science writers.
I would like to see less articles with the unnecessary bias’s insinuating that autistic people are “disordered”. Enough has been learned for a more widespread understanding that we are not “disordered”. There is nothing “wrong” with us. What makes us “disabled” is the complete lack of understanding of our neurotypes and the fact that we are different from non autistic people in the same way that a brunette and blonde are different. Yes, this neurotypes is genetic; in the same way that it’s counterpart is genetic. When alone, we function quite well. The problems arise when dealing with the public in learning environments, jobs, typical life situations. For a very long time, non autistic people have tried to make us behave the way they do without the understanding that it’s harmful to us and we don’t want to. Would you demand a blind person describe a rainbow to you? We don’t need or want to be cured or treated. We want to be accepted as we are and left alone. We want non autistic people to focus more on their own behavior and neurotypes and let us just exist because that is our birthright.
I get your point about autism not being a disorder. Where we disagree is that autistic folks just want to be left alone and just do their own thing the way they are most comfortable and healthy to do it. There are autistic folks that aren’t as high functioning as folks you are describing
They aren’t able to successfully live independently and work to support themselves. I see no problem with them taking therapy or learning skills to make life easier on them. You also say “when left alone we function quite well.”
I would posit that most people believe when alone they function quite well because there is no one to tell us any different. No one to correct us or make us self conscious. It doesn’t necessarily mean we are actually doing well. It is when we are in situations and spaces where our behavior is observed and judged that we get a true picture of how well we were doing while alone. Just my opinion on the matter.
All but one of my Cousins from my Paternal Grandfather’s side (Dad’s Father) has either Bipolar or Autism.
This gene seems unlikely in at least some neurodivergent families.
But near discovery no less. 🙂
Beat discovery I mean. 😉
Oh come on Auto correct, I said “neat discovery”. Lol