Variants in Essential Genes Linked to Autism Spectrum Disorder

GenomeWeb – Genes that are essential for survival and development harbor an increased burden of variants in people with autism spectrum disorder, according to researchers from the University of Pennsylvania.

Autism affects some 1 in 68 children between the ages of three and 17 and is more common among boys. Hundreds of genes have been linked to the condition, including ones active at key developmental stages.

Researchers led by UPenn's Maja Bućan compared the complement of variants in essential genes in patients with autism and their unaffected siblings. As they reported today in the Proceedings of the National Academy of Sciences, the investigators found that patients with autism had an elevated amount of damaging variants in essential genes and they linked these variants to decreased social skills.

"This makes our jobs harder, with respect to treatment, but these findings are absolutely critical for our understanding of the disease," Bućan said in a statement. "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."

Using exome sequencing data on a cohort from the Simons Simplex Collection of 1,781 people with autism spectrum disorder and their matched, unaffected siblings, Bućan and her colleagues found that affected siblings had higher mutational burdens in essential genes. This essential genes set was compiled from human essential gene orthologs in mice and essential genes uncovered through cell-based assays. Bućan and her colleagues noted that a number of these essential genes have been associated with autism.

In particular, the investigators reported that siblings with autism had, on average, 0.06 de novo loss-of-function, 0.21 de novo nonsynonymous damaging, and 10.74 inherited rare damaging mutations in essential genes.

At the same time, the researchers noted no difference in mutational burden between the sibling groups for a set of some 5,000 non-essential genes.

Bućan and her colleagues then tied this increased mutational burden in essential genes to a lower measure of sociability. They gauged the siblings' sociability using their raw scores on the Social Responsiveness Scale and their cognitive abilities using three different IQ scores.

In the male siblings with autism, the researchers found that mutational burden in essential genes was positively correlated with their raw SRS scores. At the same time, they found that mutation burden overall — in both essential and non-essential genes — was associated with lower verbal and nonverbal IQ scores.

This suggested to the researchers that, in people with autism, deleterious variants in essential genes affect social skills in males, while deleterious variants in both essential and non-essential genes affect IQ.

Using RNA-sequencing data from BrainSpan, the researchers gauged the expression of essential and non-essential genes in different parts of the brain at different developmental stages to find 41 distinct co-expression modules. Most essential genes, the researchers found, were expressed early in development, while non-essential genes were expressed later on.

Three of these modules were enriched for potential autism-related genes, the researchers reported. These three modules were also enriched for essential genes and for early expression in fetal brain regions, they noted.

From these three modules, the researchers uncovered 974 essential genes that are co-expressed with known autism candidate genes. Based on a co-expression network of these 974 essential genes, the researchers whittled them down to a set of 29 for priority follow up to examine a potential disease role.

"We provided another way to prioritize autism genes," Xiao Ji, a doctoral student in Bućan's lab, said in a statement. "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."

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