NEW YORK – Expanded tandem DNA repeats appear to contribute to the genetics of autism, a new analysis has found.
Autism spectrum disorder affects 1 in 54 children in the US, and while the condition has a heritability of between 50 percent and 90 percent, genetic variants currently associated with autism account for less risk than expected, suggesting there are other variants to be linked to the condition.
Previous studies have uncovered an increase in rare copy number and other complex structural variants in individuals with autism spectrum disorder. Now researchers from the Hospital for Sick Children have analyzed the frequency of tandem repeats in affected and unaffected individuals. As they reported on Monday in Nature, they found that rare tandem repeat expansions were present at a higher rate among children with autism than their unaffected siblings. These expansions were commonly located near exons and splice junctions as well as near genes tied to nervous system development and the cardiovascular system, hinting at how they may influence disease.
"Our results revealed a strong contribution of tandem DNA repeat expansions to the genetic etiology and phenotypic complexity of autism," Sick Kids' Ryan Yuen and his colleagues wrote in their paper.
Using the algorithm ExpansionHunter Denovo, the researchers searched for evidence of tandem repeat expansions within more than 20,000 genomic samples from Autism Speaks' MSSNG project, the Simons Simplex Collection, and the 1000 Genomes Project. This algorithm detects tandem repeats whose motifs are between two and 20 base pairs in length and that are longer than the sequencing read length.
Within their cohort, the researchers identified 37,865 tandem repeat motifs in 31,793 distinct regions of the human genome. As expected, most motifs were AC- or AG-rich and were commonly located in known tandem repeat regions. Still, about 42 percent of the tandem repeat-containing regions had not been reported previously.
Through a burden analysis, the researchers noted that children with ASD were more likely to harbor rare, genic tandem repeat expansions than their unaffected siblings. They detected repeat expansions in 23.3 percent of ASD-affected children and in 20.7 percent of unaffected children, indicating that as much as 2.6 percent of ASD risk could be conferred by these expansions.
These expansions appear to be further growth of tandem repeats that were already large within the affected children's parents, the researchers reported.
The ASD-linked expansions were more likely to be found in exonic regions and splicing regions, and to be located near transcription start sites and splice junctions, as well as to affect genes that are generally under more constraints than other genes. The affected genes were also more likely to be involved in nervous system development, the cardiovascular system, and muscle tissue.
One expansion, a CTG repeat, occurs in the DMPK gene, which has previously been associated with myotonic dystrophy type 1. That condition is marked by muscle weakness, but about 5 percent of individuals with DM1 also have ASD. The researchers identified seven individuals with ASD from unrelated families and one unaffected sibling with this expansion, which they confirmed experimentally. This, they noted, confirmed a previous suspicion that there was a tie between ASD and DMPK tandem repeat expansions.
Repeats in nine other genes, the researchers added, appeared to be top ASD-relevant candidates, but as the repeats were so rare, they were unable to evaluate their individual contribution to ASD. Larger cohorts and new algorithms may be needed to fuel such analyses, they added.
"Our findings represent a significant advancement in ASD genetics, as we discovered many genes involved in the tandem repeat expansions that had not been previously identified using conventional genomic analyses," the researchers wrote in their paper.