Summary: Researchers identified variants in the DDX53 gene, located on the X chromosome, as contributors to autism spectrum disorder ( ASD ). These genetic variations, found mostly in males, provide important insights into the natural mechanisms behind autism’s male presence.
The investigation also uncovered another possible protein, PTCHD1-AS, near DDX53, linked to autism, emphasizing the difficulty of ASD’s biological structures. This study opens up new strategies for more detailed diagnostics and therapeutics and emphasizes the significance of the X chromosome in ASD.
The results challenge current types, urging a re-evaluation of how dementia is studied. These revelations represent a major step in the development of a better understanding of autism.
Important Facts:
- Gene Discovery: Variants in the DDX53 protein on the X genome are associated with ASD, mainly in males.
- More Insight: PTCHD1-AS, another protein near DDX53, may likewise help to autism’s genetic base.
- Research Implications: New models must be developed to analyze these hereditary pathways because research has suggested that sex chromosomes play a crucial role in autism.
Origin: Hospital for Sick Kids
A previously undiscovered genetic link to autism spectrum disorder ( ASD ) has been discovered in a new study published in the American Journal of Human Genetics ( AJHG).
The research found that variations in the , DDX53 , protein help to ASD, providing new perspectives into the biological underpinnings of the condition.  ,
ASD, which affects more men than women, encompasses a group of developmental conditions that result in challenges related to conversation, cultural understanding and behavior.
While , DDX53, located on the X chromosome, is known to play a role in mental development and function, it was not originally firmly 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.
Importantly, the majority were female, highlighting the bacteria’s potential part in the female predominance observed in ASD.  ,
” By pinpointing , DDX53 , as a major player, especially in men, we can better comprehend the natural methods at play and improve clinical accuracy for people and their people”, 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.  ,  ,
The existence of this new gene as a confirmed contributor to autism highlights the need for thorough 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 and was unrelated 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 points out that future researchers may have to reevaluate how they study ASD if there isn’t a similar gene like DDX53 in common mouse models. Since it lacks a functional equivalent in these models, findings in , DDX53 , cannot be easily replicated.  ,
” Insights from this study could significantly affect the design and interpretation of autism research, particularly when developing new models. According to Scherer, identifying these variants is a crucial step in the development of more precise diagnostics and therapeutics for patients and families with ASD.  ,  ,
Scherer added that “both studies provide even more proof that complex neurobehavioral conditions like autism can occasionally 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. National Institutes of Health and the California Center for Rare Diseases at UCLA provided additional funding.
About this news from research into autism and genetics
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.
The study of the genome X-wide common variant association in autism spectrum disorder was co-authored by Stephen Scherer and colleagues. 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, in addition to the finding that mice do not have a functional orthologous gene, may affect how well the murine model of autism is designed and interpreted.
Abstract
A study of the chromosome X-wide common variant association 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” of ASD suggests that females may have to deal with more of a male-like genetic burden, but the mechanisms are still undetermined.
Despite recent advances in genomics, sex chromosomes are underrepresented in genome-wide studies due to their complexity and complexity.
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
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 findings confirm and nominate genes and pathways for further investigation in addition to providing important insights into the ASD X chromosome biology.
