Summary: Researchers identified variants in the DDX53 gene, located on the X chromosome, as contributors to autism spectrum disorder (ASD). These genetic variants, found predominantly in males, provide critical insights into the biological mechanisms behind autism’s male predominance.
The study also uncovered another potential gene, PTCHD1-AS, near DDX53, linked to autism, emphasizing the complexity of ASD’s genetic architecture. This research highlights the importance of the X chromosome in ASD and opens avenues for more precise diagnostics and therapeutics.
The findings challenge current models, urging a re-evaluation of how autism is studied. These discoveries mark a significant step in understanding the genetic underpinnings of autism.
Key Facts:
- Gene Discovery: Variants in the DDX53 gene on the X chromosome are associated with ASD, particularly in males.
- Additional Insight: PTCHD1-AS, another gene near DDX53, may also contribute to autism’s genetic basis.
- Research Impact: Findings suggest sex chromosomes play a pivotal role in autism and call for new models to study these genetic pathways.
Source: Hospital for Sick Children
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,” 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.”
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.”
Funding: 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.
About this autism and genetics research news
Author: Jelena Djurkic
Source: Hospital for Sick Children
Contact: Jelena Djurkic – Hospital For Sick Children
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Genetic variants in DDX53 contribute to Autism Spectrum Disorder associated with the Xp22.11 locus” by Stephen Scherer et al. American Journal of Human Genetics
Open access.
“Chromosome X-wide common variant association study in autism spectrum disorder” by Stephen Scherer et al. American Journal of Human Genetics
Abstract
Genetic variants in DDX53 contribute to Autism Spectrum Disorder associated with the Xp22.11 locus
Autism spectrum disorder (ASD) exhibits an ∼4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors.
Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ∼1 Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS.
While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been comprehensively examined, in part because there is no apparent functional murine ortholog.
Through clinical testing, here, we identified 8 males and 2 females with ASD from 8 unrelated families carrying rare, predicted damaging or loss-of-function variants in DDX53.
Additionally, we identified a family consisting of a male proband and his affected mother with high-functioning autism, both harboring a gene deletion involving DDX53 and exons of the noncoding RNA PTCHD1-AS.
Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 26 additional individuals with ASD harboring 19 mostly maternally inherited, rare, damaging DDX53 variations, including two variants detected in families from the original clinical analysis.
Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing.
These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mice, may also influence the design and interpretation of murine modeling of ASD.
Abstract
Chromosome X-wide common variant association study in autism spectrum disorder
Autism spectrum disorder (ASD) displays a notable male bias in prevalence. Research into rare (<0.1) genetic variants on the X chromosome has implicated over 20 genes in ASD pathogenesis, such as MECP2, DDX3X, and DMD.
The “female protective effect” in ASD suggests that females may require a higher genetic burden to manifest symptoms similar to those in males, yet the mechanisms remain unclear.
Despite technological advances in genomics, the complexity of the biological nature of sex chromosomes leaves them underrepresented in genome-wide studies.
Here, we conducted an X-chromosome-wide association study (XWAS) using whole-genome sequencing data from 6,873 individuals with ASD (82% males) across Autism Speaks MSSNG, Simons Simplex Collection (SSC), and Simons Powering Autism Research (SPARK), alongside 8,981 population controls (43% males).
We analyzed 418,652 X chromosome variants, identifying 59 associated with ASD (p values 7.9 × 10−6 to 1.51 × 10−5), surpassing Bonferroni-corrected thresholds.
Key findings include significant regions on Xp22.2 (lead SNP rs12687599, p = 3.57 × 10−7) harboring ASB9/ASB11 and another encompassing DDX53 and the PTCHD1-AS long non-coding RNA (lead SNP rs5926125, p = 9.47 × 10−6).
When mapping genes within 10 kb of the 59 most significantly associated SNPs, 91 genes were found, 17 of which yielded association with ASD (GRPR, AP1S2, DDX53, HDAC8, PCDH19, PTCHD1, PCDH11X, PTCHD1-AS, DMD, SYAP1, CNKSR2, GLRA2, OFD1, CDKL5, GPRASP2, NXF5, and SH3KBP1).
FGF13 emerged as an X-linked ASD candidate gene, highlighted by sex-specific differences in minor allele frequencies.
These results reveal significant insights into X chromosome biology in ASD, confirming and nominating genes and pathways for further investigation.
