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New Genetic Risk Factor for Autism Spectrum Disorder Identified

NEW YORK (GenomeWeb) – An international team led by Oregon Health and Science University researchers has identified new genetic risk factors for developing autism spectrum disorder (ASD). They noted that a small percentage of gene mutations in parents can lead to an extremely high frequency of genetic mutations that cause ASD in children.

Postzygotic mosaic mutations have been implicated in several neurodevelopmental disorders including epilepsy, cortical malformations, and syndromic and nonsyndromic ASD.PMMs typically occur after the embryo's fertilization. During development, an individual will have a mosaic of of mutated and nonmutated cells with the level of mosaicism dependent on the time and location of the mutation's occurrence.

The study, published yesterday in The American Journal of Human Genetics, focused on identifying and characterizing low-lying genetic mutations that researchers might have missed in previous research.  

Past work focusing on discovering germline de novo mutations (GDMs) in simplex ASD families validated 4 percent of de novo mutations as likely mosaic in origin, suggesting that mosaic mutations might be a common and unrecognized contributor to ASD risk. Whole-genome sequencing from simplex intellectual disability trios have also observed the behavior in de novo mutations. However, the mutation calling approaches used in the past have only been tuned to detect GDMs.

By leveraging whole-exome sequencing (WES) datasets of about 2,300 ASD-affected families culled from the Simons Simplex Collection, O'Roak and team evaluated the potential role of PMMs in autism risk. They discovered at least 11 percent of PMMs affecting a single DNA base occur during the embryonic development process.

"This initial finding told us that, generally, these mosaic mutations are much more common than previously believed," OHSU School of Medicine assistant professor Brian O'Roak said in a statement.

The team found missense PMMs in some of the highest-confidence ASD risk genes. New mutations of multiple types and origins at these sites contribute to AD risk. Taken together, the researchers believe that "proband PMMs and GDMs target many common risk genes."

Reasoning that re-analyzing the WES data with approaches tuned to detect PMMs would reveal novel mutations, the researchers developed a sensitive single-nucleotide variant (SNV) PMM calling approach integrating complementary callers, logistic regression modeling, and additional heuristics. Using this custom approach, they found that 22 percent of de novo SNVs were in fact PMMs present in children.

The supposedly "new" mutations present in children could actually be traced back to their parents' DNA. The team analyzed parents' genomes and saw that transmitted parental mosaic mutations account for about 7 percent of presumed de novo mutations in children with ASD. The mutations were present in 20 to 75 percent of the parents' blood cells, providing indirect evidence that many of PMMs occurring in children happened very early in development and possibly contributed to mosaicism across the body.  

"These mutations can go from being in a few percent of the cells of a parent to 100 percent of a child," O'Roak warned. "If present, at even low levels in the parents, the risk of additional children receiving this mutation is dramatically increased."

The study also noted preliminary evidence that mosaic mutations that alter the protein code of genes essential for embryonic development are also enriched in individuals with autism. The team estimates that exonic postzygotic mosaicism contributes to the overall genetic architecture of ASD, in potentially 3 to 4 percent of simplex ASD case subjects.

"Our data argues that physicians should be requiring more sensitive testing of both children and parents, when a new disorder-related genetic mutation is identified" O'Roak added.