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Many Tiny Mutations May Contribute to Autism

April 05, 2012

Three new studies have identified hundreds of tiny genetic changes that may increase the risk of autism. Together, they also support earlier research suggesting that having an older father is a notable risk factor for autism spectrum disorder (ASD).

These small gene changes are called “copy number variants” (CNVs). Any one of them is rare. But together with previously identified CNVs, they may be involved in the development of up to 30 percent of autism cases.

Importantly, these tiny DNA glitches are spontaneous mutations that appear in the genes of children but not their parents. They are thought to arise in a sperm or egg prior to conception or during early embryo development.

All people have some spontaneous CNVs in their genes, and most of these prove harmless. However if these mutations are more common in those with autism – as these studies suggest – this could make it more likely that one or more CNVs alter a gene pathway critical to early brain development.

The findings also spotlight a possible gene-environment interaction associated with increased risk of autism. The spontaneous mutations were more common in the children of older fathers. In fact, their average number increased with paternal age at the time of conception. This might be because increased age brings increased exposure to environmental influences that cause gene mutations in a man’s sperm. These mutations can then end up in a child’s DNA.

This would help explain earlier research indicating that a child’s risk of autism increases with parental age at time of conception. The increased risk appears to be particularly marked with older fathers. One study, for example, found that fathers of girls with autism were 17 times more likely to be in their 40s than their 20s. Fathers of boys with autism were four times more likely to be in their 40s than in their 20s.

“While these studies are examining only about 2 percent of our genome and clearly suggest more research is needed, they show that we now have the tools to discover more genetic risk factors, as well as explore the possible environmental factors that interact with them,” comments Andy Shih, Ph.D., Autism Speaks vice president for scientific affairs.

In the first of the three papers, researchers at Yale University identified hundreds of spontaneous mutations in the DNA of children with autism and found that these mutations were increasingly frequent in children born to older fathers.  

In the second paper, researchers from the University of Washington discovered that spontaneous mutations associated with ASD came primarily from the father and increased in frequency with a father’s age at time of conception.

In the third paper, researchers described sequencing all the protein-coding genes of 175 persons with autism and their parents. They found alterations in hundreds of genes previously associated with increased risk of autism.

Autism Speaks continues to fund a wealth of important research into the genetics of autism, including gene-environment interactions. You can explore these and other studies using our Grant Search.