Newly Identified Microexons Offer Clues to Autism Spectrum Disorder’s Genetic Roots

A newly published study in Nature reveals that several previously unidentified microexons play a role in the development of autism spectrum disorder (ASD). Researchers from the University of Toronto, Sloan Kettering Institute, King’s College London, and the Francis Crick Institute identified hundreds of new microexons associated with ASD and other neurological conditions.

They developed a machine learning approach called MicroExonator to analyze over 100 terabytes of RNA sequencing data. This tool detected over 1,500 microexons, with nearly 300 appearing to be spliced specifically in the brain. These microexons are concentrated in genes linked to critical brain functions, suggesting a potential connection to neurological health.

The scientists explored whether genetic variants in ASD individuals impact these microexons more than in neurotypical individuals. They built a machine learning model to predict the regulatory effects of ASD-associated genetic variants on microexon splicing. The model showed that rare genetic variants have a significant impact on neuronal microexon splicing.

These variants were predominantly found in 85% of autistic individuals who previously lacked a genetic link to autism, providing a genetic diagnosis for them. This finding could help explain the genetic basis of ASD for a significant portion of affected individuals. The researchers believe their work could lead to new therapeutic approaches targeting microexon dysregulation and understanding similar genetic variants in other neurological conditions like schizophrenia and epilepsy.