Missense Variants Predicted to Contribute to Autism Uncovered

Missense Variants Predicted to Contribute to Autism Uncovered

Research led by Baylor College of Medicine scientists predicts that genetic missense variants in 398 genes play a role in autism spectrum disorder.

Many studies have been carried out investigating the genetics of autism and many variants with potential links to the neurological condition uncovered, but it can be hard to predict which variants are truly contribute to the condition and which do not.

“The most commonly mutated genes linked to the syndrome only account for approximately 2% of the cases,” said Olivier Lichtarge, M.D., Ph.D., a professor and group leader at Baylor College of Medicine, who led the research.

“The current thought is that the syndrome results from a very large number of gene mutations, each mutation having a mild effect.”

Lichtarge and colleagues carried out a detailed analysis of whole-exome sequences collected from 2,384 individuals with autism and 1,792 unaffected siblings.

Missense mutations are a type of genetic variant that results in changes to amino acids and therefore proteins that are encoded by the DNA. These changes can range from minor functional changes to complete protein dysfunction in some cases.

In this study, the researchers looked for missense mutations in the genetic data they collected. To assess function and impact of the variants, they used a computational evolutionary action method to predict how each mutation would impact fitness based on protein evolutionary development over time.

The researchers found variants predicted to contribute to autism spectrum disorder (ASD) in 398 genes, some previously identified ads being linked to autism and some newly identified. These variants represented 23 different functional pathways that had higher evolutionary action scores than would be expected by chance. The genes identified mostly have functions involved with neuronal development and activity, as well as other nervous system-related functions.

There was also a relationship between the evolutionary action score of the mutations in the genes linked to ASD and the individual’s IQ. This applied to both previously known and newly discovered genes and variants.  For example, in the new genes, the mutations with higher evolutionary action scores were linked to a 7-point lower IQ in those affected, suggesting they have a genuine biological effect.

“As a result of layering together all these different complementary views of potential functional impact of the mutations on the biology, we could identify a set of genes that clearly related to ASD,” Lichtarge said.

“These genes fell in pathways that were not necessarily surprising, but reassuringly related to neurological function. Some of these genes had been linked to ASD before, but others had not been previously associated with the syndrome.”

This evolutionary analysis method has not been widely used to date, but the research team think it could help other complex disease researchers to narrow down which gene variants are more likely to have a greater impact than others in a variety of different disorders.