The Multiple Mutations of Autism

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Autism Spectrum Disorder (ASD)

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by fundamental deficits in social reciprocity and the presence of restricted interests and/or repetitive behaviors. ASD is among the most prevalent developmental disorders, with an estimated prevalence of about 1 in 100, with males affected at a rate four times that of females. A substantial portion of the risk for ASD traces to genetic variation, either inherited or arising de novo. Studies of simplex families - those with only one member with autism, rather than multiple members - provide details of the disorder’s genetic basis. There are likely dozens of different mutations responsible for autism.

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Researchers from the University of Washington School of Medicine report most cases of autism appear to be associated with the appearance of new mutations that are not inherited from the child's parents. These new mutations occur in regions of the genome that contain genes, which code for proteins, and in "non-coding" regions, which do not contain genes but regulate gene activity, the researchers found.

The first author of the study, which was published online in the journal Cell, was Tychele Turner, a postdoctoral fellow in the Eichler Lab.

"We are excited by these early findings because they suggest that multiple new mutations in a child, both coding and non-coding, are important to understanding the genetics of the disease," said Evan Eichler, UW professor of genome sciences, who led the team that conducted the study.

Although some forms of autism appear to run in families, most cases occur in families with no history of the disorder. This form of autism, called simplex autism, is thought to occur from new mutations that first appear when the parent's sperm or eggs form.

These newly formed, or de novo, mutations are found in the affected child's genome but not in either parent's genome. They are unlikely to occur in the affected child's siblings.

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In the new study, researchers used a huge genomic database created by the Simons Foundation Autism Research Initiative. The scientists compared the genomes of 516 individuals with simplex autism with their parents' genomes and one sibling unaffected by the disorder.

By comparing these family members, researchers hoped to identify new mutations that were more likely to appear in the affected child and more likely to be associated with an increased risk of developing autism.

Most previous studies had limited such comparisons to the small portion of the genome, including the instructions for synthesizing proteins. This coding region contains genes. The new study compared almost the entire genomes of the study participants, including the regions that do not include genes.

Although these "non-coding" regions do not include instructions for making proteins, they play an important role in regulating protein production by turning genes on and off and dialing their activity up or down.

The researchers observed that mutations that tended to appear in non-coding regions of the genomes occurred in areas known to influence gene activity in neurons located deep in the brain in a striatum structure. This part of the brain is thought to play a role in some autism behaviors. Typically, the striatum coordinates planning, reward perception, motivation, and other cognitive functions.

Mutations were also located in areas of the genome influencing genes for embryonic stem cell development and fetal brain development.

The findings suggest that relatively few new mutations in genes linked to autism risk were needed to increase the odds of having the disorder. The risk rose with as few as two of these newly appearing mutations.

Eichler said that to nail down the autism risk role played by mutations in the regulatory, non-coding regions of the genome, it will be necessary to repeat the study with many more sets of parents and their children.

The study's collaborators included researchers from the New York Genome Center, Lawrence Berkeley National Laboratory, University of California, Davis, Rockefeller University, and the U.S. Department of Energy Joint Genome Institute. Eichler is a Howard Hughes Medical Institute investigator.

Attribution/Source(s):

This peer reviewed article relating to our Autism Information section was selected for publishing by the editors of Disabled World due to its likely interest to our disability community readers. Though the content may have been edited for style, clarity, or length, the article "The Multiple Mutations of Autism" was originally written by University of Washington Health Sciences/UW Medicine, and published by Disabled-World.com on 2017/10/13 (Updated: 2022/09/21). Should you require further information or clarification, University of Washington Health Sciences/UW Medicine can be contacted at uw.edu. Disabled World makes no warranties or representations in connection therewith.

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