NEW YORK – A pair of new studies by investigators at Toronto's Hospital for Sick Children (SickKids) has uncovered autism spectrum disorder (ASD)-associated variants on the X chromosome, including in a helicase-coding gene called DDX53.
In one paper, published in the American Journal of Human Genetics on Thursday, Stephen Scherer, chief of research at SickKids and director of the University of Toronto's McLaughlin Centre, and colleagues presented findings from an X chromosome-wide association study performed with the help of whole-genome sequencing data for 6,873 individuals with ASD and 8,981 unaffected controls.
The ASD patients included 5,639 male and 1,234 female participants, while 5,070 women were included in the control group, along with 3,911 men.
The team noted that three to four male individuals are diagnosed with ASD for every case diagnosed in females, prompting the notion of a "female protective effect" in ASD that they explored by focusing on the X chromosome.
Based on data spanning nearly 418,652 variants on the X chromosome, the team focused in on variants at 20 loci, including at least one long noncoding RNA, with significant ties to ASD.
"After performing the four different XWAS tests, which included sex-stratified tests (male-XWAS and female-XWAS), sex combined mega-analysis (both-XWAS), and meta-analysis (meta-XWAS), we identified 59 variants as significant in at least one of the four approaches," the authors reported.
All told, the team tracked down variants in 91 genes, while highlighting variants in linkage disequilibrium with lead SNPs in nearly two dozen genes. Of those, 17 genes showed their own associations with ASD, including the X-linked gene FGF13 and a helicase-coding gene called DDX53 at the Xp22.11 locus, which members of the same team profiled in more detail in another paper appearing in the same journal.
"These findings provide new insights into the biology of the X chromosome in ASD," Scherer said in a statement, offering "additional evidence for the involvement of certain genes, like DDX53 and FGF13, and suggesting they should be investigated further."
Through further clinical testing, the team tracked down eight men and two women with ASD from eight unrelated families who had rare variants in DDX53 that were predicted to be damaging or result in a loss of function.
In a series of follow-up analyses, the investigators identified an ASD-affected son and a high-functioning mother who both carried a DDX53 deletion in combination with a nearby lncRNA-coding isoform PTCHD1-AS, along with 26 ASD-affected individuals with rare DDX53 mutations, which tended to be maternally inherited.
"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," Scherer said.
Despite the apparent importance of the gene to understanding ASD risk, and shared phenotypic features found in individuals with variants in it, the investigators cautioned that they were unable to track down an orthologous gene in mice, which will need to be taken into account when studying mouse models of ASD in the future.
"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," first author Marcello Scala, a researcher affiliated with the University of Genoa and the Giannina Gaslini Institute in Italy, said in a statement.