Autism spectrum disorder (ASD) is a complex condition affecting communication, social interactions, and behavior in approximately 1–2% of people worldwide. While some cases of ASD can be linked to specific genetic changes, most remain unexplained, leaving families and clinicians without clear answers. Recent studies suggest that our current understanding of genes and their functions is incomplete, particularly in specialized cells like neurons. Standard gene databases often overlook subtle differences in how genes are spliced into different forms, potentially missing tens of thousands of unique protein-coding splice isoforms. If these overlooked genetic elements harbor mutations, they could play a hidden role in ASD.
Our project aims to uncover these hidden protein-coding sequences and understand how they might contribute to ASD. We use cutting-edge long-read RNA sequencing and advanced mass spectrometry to map out virtually every possible gene splice isoform in cells developing into neurons. By confirming which isoforms are made into proteins, we can create a vastly improved reference resource of genes expressed in human developing neurons. Using this resource, we will analyze large collections of wholegenome DNA data from families affected by ASD. We will look for rare DNA mutations that fall within these newly identified gene splice isoforms and investigate whether such mutations are more common in individuals with ASD compared to their unaffected relatives or the general population.
Our ultimate goal is to improve genetic diagnoses of ASD by revealing new links between specific mutations and the proteins that help build and maintain healthy neurons. In the long run, a better understanding of these hidden genetic factors could lead to more personalized approaches to diagnosis, treatment, and support for families affected by ASD.
