Genes known to be essential to life — those we need to survive and thrive in the womb — may play a significant role in the development of autism spectrum disorder (ASD), according to a new study by geneticists at Pennsylvania Medicine.
Based on a genetic analysis of more than 1,700 families, researchers found that a greater level of mutations in these “essential genes” was significantly linked to an increased risk for ASD and decreased social skills. Specifically, siblings with ASD had much higher levels of damaging mutations in essential genes compared to their non-affected siblings. Essential genes also constituted a significant fraction of known ASD risk genes.
Brain function may be especially sensitive to an accumulation of mutated genes, say the researchers. Therefore, identifying specific sets of genes in which mutations might trigger a behavioral effect will help shed light on how such an accumulation can result in diseases, such as ASD.
“This makes our jobs harder, with respect to treatment, but these findings are absolutely critical for our understanding of the disease,” said senior author Maja Bucan, Ph.D., a professor of Genetics in the Perelman School of Medicine at the University of Pennsylvania. “We know it’s not one gene that’s causing autism spectrum disorders; it’s a background of mutations, which we know is important. Here, we show what this background is.”
The findings suggest that ASD stems from a combined effect of many damaged essential genes that “work” together during the early stages of development in the womb — as early as eight weeks after conception. ASD is what’s known as a polygenic disease, the authors said, where many small gene effects contribute to a disorder.
For the study, researchers analyzed almost 4,000 essential genes and 5,000 non-essential genes in 2,013 males with ASD and 317 females with ASD, as well as their siblings who did not have ASD, for known exonic de novo (began in the child) and inherited mutations.
The researchers used data from the Simons Simplex Collection, a repository of genetic samples from 2,500 families with ASD under the Simons Foundation Autism Research Initiative.
They found that those with ASD had statistically significant elevated levels of mutations in essential genes compared to their siblings. The essential gene mutations were associated with a higher risk of ASD and disruption in normal social behavior.
On average, those with ASD had 44 percent more early-in-childhood mutations and 1.3 percent more inherited mutations in essential genes than their non-affected siblings.
The researchers put together a list of 29 “high-priority” essential genes that are co-expressed in the developing human brain with previously identified ASD-associated genes. Such genes could serve as targets for future functional and behavioral studies that could not only add to the growing body of knowledge on the disease but also potentially impactful treatments.
“We provided another way to prioritize autism genes,” said first author Xiao Ji, a doctoral student in Bucan’s lab. “We now see that essential genes are much more likely to be associated with autism than non-essential genes. Focusing in on this group of genes will help shed more light on the complex genetic architecture of this disorder.”
The study is published online in the journal Proceedings of the National Academy of Science.