A Third of Suspect Mutations in ASD Just “Noise”

Leveraging natural selection narrows the field of potential non-inherited genetic causes

March 23, 2017 • Science Update

NIMH-funded researchers have narrowed suspected genetic causes of autism and related developmental disabilities by ruling out what they call the “noise of benign variation.”

A third of the same spontaneous, non-inherited gene glitches found in people with autism spectrum disorder (ASD), intellectual disability, or developmental delay also turned up in unaffected people and didn’t confer risk for the disorders. Such recurrent de novo variants were detected at triple the rate previously believed. Eliminating them as possible causes boosted risk attributable to variants found only in people with the disorders. The rarer glitches were much more prevalent in people with the disorders than in their unaffected siblings, further implicating them as risk factors.

Mark Daly, Ph.D., of Harvard Medical School and Massachusetts General Hospital, and colleagues in the NIMH-funded Autism Sequencing Consortium, reported on their findings February 13, 2017 in the journal Nature Genetics. 

While evidence suggests that ASD is at least 50 percent heritable, few specific inherited genetic causes have been identified. By contrast, recent years have seen rapid progress in understanding the potentially causal roles played by non-inherited, or de novo, genetic variation in a subset of people with ASD.

People with ASD have abnormally high rates of such de novo mutations, some of which can impair the functioning of proteins. Since people with the disorders are often so impaired that they rarely have children, such disease-causing de novo variants tend to quickly vanish from the gene pool through natural selection. So variants found in people with ASD that also occur in unaffected people are more likely benign.

This offered the researchers a strategy for narrowing the field of suspect risk genes found in affected families by eliminating those also present in the general population. They compared genomic data from 9,246 families with or the related developmental disabilities with data from more than 60,000 unaffected people (drawn from the Exome Aggregation Consortium ). They determined that the approximately one third  of spontaneous variants found in both groups didn’t confer risk for the disorders. Moreover, individuals with ASD had much higher rates of the most suspect disruptive variants than their healthy siblings.

“These results reinforce that not all de novo variants contribute to risk,” explained Geetha Senthil, Ph.D. of the NIMH Office of Genomics Research Coordination. “The findings also underscore that with a large enough sample size one can begin to distinguish even the rare de novo variants that confer risk from those that do not – demonstrating the utility of existing large scale data resources for discovery.”

About one third of spontaneous, non-inherited genetic mutations (red) found in people with ASD were also found in the general population. This helped researchers narrow the field of suspected risk-conferring mutations. Since few people with ASD have children, disease-causing mutations tend to disappear from the gene pool – so any spontaneous mutations shared with the general population are likely benign. Source: Autism Sequencing Consortium.

More information

Reference database helps narrow list of mutations suspected in ASD 

Reference

Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples.  Kosmicki JA, Samocha KE, Howrigan DP, Sanders SJ, Slowikowski K, Lek M, Karczewski KJ, Cutler DJ, Devlin B, Roeder K, Buxbaum JD, Neale BM, MacArthur DG, Wall DP, Robinson EB, Daly MJ. Nat Genet. 2017 Feb 13. doi: 10.1038/ng.3789. [Epub ahead of print] PMID: 28191890

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