Autism spectrum disorder (ASD) affects one in 54 children in the US and is associated with a heritability between 50-90%. However, genetics account for less risk than expected, indicating other variants may be linked to the condition.
A recent study published in Nature has found that expanded tandem repeats appear to contribute to the genetics of autism. Expanded tandem occurs in DNA when a pattern of one or more nucleotides are repeated next to each other.
While previous studies have found an increase in rare copy number in autistic patients, researchers from the Hospital for Sick Children have now analysed the frequency of tandem repeats in affected and unaffected individuals. The researchers found that rare tandem repeat expansions were present at a higher rate in individuals with autism spectrum disorder when compared with their unaffected siblings. The expansions were commonly found near exons, splice junctions and near genes tied to nervous system development and the cardiovascular system, giving new insights at how they may influence disease.
Ryan Yuen, one of the authors of the paper wrote: “Our results revealed a strong contribution of tandem DNA repeat expansions to the genetic aetiology and phenotypic complexity of autism”.
To study the expansions, the team used an algorithm called ExpansionHunter Denovo, where they searched for evidence of tandem repeat expansions within more than 20,000 genomic samples from the Autism Speaks’ MSSNG Project, the Simons Simplex Collection, and the 1000 Genomes Project. The algorithm detects repeats whose motifs are between 2-29 base pairs long and that are longer than the sequencing read length.
In this study, the researchers found 37,865 tandem repeat motifs in 31,793 distinct regions of the genome. Most of the motifs were AC- or AG- rich and were found in known tandem repeat regions, but around 42% of the tandem repeat-containing regions had not been previously reported.
The team detected repeat expansions in 23.3% of ASD-affected children and 20.7% of unaffected children, using burden analysis. This indicates that as much of 2.6% of ASD risk could be conferred by these expansions. The researchers also reported that the expansions appeared to be a further growth of large tandem repeats in the affected children’s parents.
Interestingly, one of the expansion repeats found was a CTG repeat that occurs in the DMPK gene. The DMPK gene has previously been associated with myotonic dystrophy type 1, a condition that is marked by muscle weakness, but around 5% of individuals with DM1 also have ASD.
Repeats in nine other genes appeared to be top ASD-relevant candidates, but as the repeats were so rare, they were unable to evaluate their individual contributions to ASD. The researchers wrote that their “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”.