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Hundreds of Tiny Mutations Linked to Autism

Many arise spontaneously in germ cells; may explain why autism risk higher among children of older fathers


Over the last 20 years, researchers have uncovered a number of genes that greatly increase the risk of autism. These high-impact genes account for a relatively small percentage of autism cases. Still, scientific evidence remains strong that genes play an important role in the development of autism.

This year, a group of papers helped shed light on what may be autism’s missing genetic “dark matter.” Together, they show that that hundreds of tiny mutations – not just handful of high-impact genes – may contribute significantly to the development of autism spectrum disorder (ASD).

Any one of these small gene changes is rare. But together with other mutations known to be associated with autism risk, they may be involved in the development of nearly a quarter of ASD cases. Importantly, many are de novo, or spontaneous, mutations. They show up in the genes of children but not their parents. Most likely, they arise in sperm, egg or very early embryo development.

Moreover, the studies found these tiny mutations to be more abundant in children born to older parents – especially older fathers.

In the four papers, published by different research teams in the highly respected journal Nature, scientists used DNA sequencing to examine the genomes of families with one child affected by autism. Specifically, they scanned for de novo changes in the active, or protein-coding, part of the genome. This “exome” makes up about 2 percent of our total genome.

All people have some de novo changes in their DNA. Most prove harmless – so long as they do not affect crucial areas of the exome. However, all four Nature studies indicated that such mutations were significantly more common in those with autism. This would increase the likelihood that one or more would affect a gene critical to early brain development.

“These findings spotlight a possible gene-environment interaction associated with increased risk of autism,” commented Andy Shih, Ph.D., Autism Speaks senior vice president for scientific affairs. “If the children of older fathers have significantly more tiny mutations in their DNA – as these studies suggest – it may be that increased age brings cumulative exposure to influences that produce gene changes in the father’s germ cells.” These genetic glitches could then end up in a child’s DNA.

Such studies also illustrate how scientists are using new tools and approaches to expand the search for autism’s genetic risk factors and the environmental factors that may interact with them, Dr. Shih added. “They also shed light on why the children of older parents – particularly older fathers – are at higher risk for developing ASD.”

The small genetic glitches the studies found include single nucleotide polymorphisms (SNPs) and copy number variations (CNVs). SNPs involve a switch in a single DNA nucleotide pair. (See image at right.) CNVs include duplications or deletions of longer DNA sequences – including entire genes.

In the first of three papers in the April 4 issue of Nature, a team of researchers from across the United States identified hundreds of spontaneous mutations in the DNA of children with autism. They also found that the mutations were increasingly frequent in children born to older fathers.  

In the issue’s second paper, researchers from the University of Washington, Seattle, described their discovery that spontaneous mutations associated with ASD come primarily from the father and increase in frequency with a father’s age at time of conception.

In the third paper, another multi-center team of U.S. researchers described sequencing all the protein-coding genes of 175 persons with autism and their parents. They found CNVs in more than a hundred genes previously associated with increased risk of autism.

In Nature’s August 23 issue, Icelandic scientists likewise reported that children of older men had a greater number of de novo mutations than children fathered by younger men. The researchers analyzed the whole genome of 78 trios (mother, father and child). In each trio, the child had been diagnosed with autism or schizophrenia, but neither parent had signs of either disorder. They found that the number of de novo mutations in a child’s genome increased with the father’s age – by around two per year. The study also found a slight association between a mother’s age and these mutations.

”Taken together, these findings are starting to give us a better picture of the biology of autism, of the possible underlying disease mechanisms,” said Dr. Shih. “They are one piece of a larger puzzle that is helping us understand the causes of autism.”

Kong A, Frigge ML, Masson G, et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature. 2012; 488(7412): 471-5.

Sanders SJ, Murtha MT, Gupta AR, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012; 485(7397): 237-41.

O’Roak BJ, Vives L, Girirajan S, et al. Sporadic autism exomes reveal a highly inter-connected protein network of de novo mutations. Nature. 2012; 485(7397): 246-50.

Neale BM, Kou Y, Liu L, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012; 485(7397): 242-5.

Next: Insights into Immune Changes & Autism

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