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Autism Spectrum Disorder Study Finds Contribution From De Novo Tandem Repeat Mutations

NEW YORK – Individuals with autism spectrum disorder have higher numbers of de novo tandem repeat mutations than unaffected persons, suggesting a role for these repeats in the condition, a new study has found.

Tandem repeats are known to be involved in other diseases, including, for instance, the autism-related fragile X syndrome. Researchers from the University of California, San Diego, examined the prevalence of small — between one and 20 base pairs in size — de novo tandem repeat mutations among individuals with autism.

Using a bioinformatics tool they developed, the researchers analyzed whole-genome sequencing data for families with unaffected parents, a neurotypical child, and a child with autism spectrum disorder. As they reported today in Nature, they found that evolutionarily predicted deleterious de novo tandem repeat mutations were more common among individuals with autism spectrum disorder and were often found in regions involved in fetal brain development.

"I think an important general takeaway from our study is, it will be important to consider tandem repeats in future studies of de novo mutation," senior author Melissa Gymrek, an assistant professor of medicine and computer science and engineering at UCSD, said in an email. "We believe that tandem repeat expansions and contractions are likely to play a role in many other human traits. By excluding these regions, studies have been missing a significant portion of mutations in each individual."

For this study, Gymrek and her colleagues analyzed whole-genome sequencing data collected from 1,637 quad simplex families from the Simons Simplex Collection. Simplex cases, she noted, are more likely to be due to a de novo mutation in the affected person.

After using the GangSTR algorithm to genotype the samples, the researchers fed the results into a new analysis tool they developed, dubbed MonSTR, to identify de novo tandem repeat mutations in parent-offspring trios. After filtering, they uncovered nearly 95,000 loci in 1,593 families.

On average, each child, whether they had autism spectrum disorder or were neurotypical, had about 50 de novo tandem repeat mutations. But children with autism spectrum disorder tended to have slightly more de novo tandem repeat mutations — a mean 54.65, as compared to a mean 53.05. They also found an enrichment of de novo tandem repeat mutations within annotated fetal brain promoters among individuals with autism spectrum disorder.

Still, the researchers noted that the excess of de novo tandem repeat mutations in individuals with autism spectrum disorder was modest.

But with a population genetics framework they developed — dubbed selection inference at short tandem repeats (SISTR) and developed by second author Bonnie Huang, an undergraduate student at UCSD — the researchers measured the negative selection exerted on individual tandem repeat alleles. Through this analysis, they found that individuals with autism spectrum disorder had an enrichment of evolutionary deleterious de novo tandem repeat mutations, as compared to their neurotypical siblings. Following this analysis, the relative risk increased to 2.5-fold.

In a related commentary in Nature, the University of Melbourne's Anthony Hannan noted that the findings, in combination with similar, recent work from researchers at the Hospital for Sick Children finding expanded tandem repeats in individuals with autism spectrum disorder, "provide compelling evidence that tandem repeats contribute significantly to the genetic burden associated with" autism spectrum disorder.

Gymrek noted that a number of genetic and other factors are involved in autism spectrum disorder risk. Short tandem repeats (STRs) "add another piece to the complex puzzle geneticists are beginning to chip away at, but probably only explain a small fraction of all cases," she said. "We estimate around 1.6 percent of the cases included in our study can be explained by STR mutations."

Her lab is next expanding its analysis to additional samples and is examining the repeats the researchers suspect might have the strongest biological effects in cells. They are additionally pursuing other studies into tandem repeat mutation mechanisms in general.

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