A microexon regulatory code reveals autism-linked genetic variation

Abstract Neuronal microexons are a highly conserved class of alternative splicing events enriched in genes with critical functions in nervous system biology 1,2 . Microexon splicing is often disrupted in the brains of autistic individuals, and mice with microexon deficiencies display autism-like phenotypes 1,3,4 . However, the full landscape of microexons is not known, and the impact of genetic variation on these exons has not been systematically investigated. Here, through extensive transcriptome profiling, we detect hundreds of new microexons, including many with neuronal subtype-specific splicing patterns, and others that activate nonsense-mediated mRNA decay. Using machine learning, we define a sequence code predictive of neuronally spliced microexons and use this to identify critical regulatory elements surrounding the expanded microexon repertoire. This code further reveals genomic variants predicted to alter microexon splicing in individuals affected by autism, with rare variants having the strongest estimated impact. These variants are mostly detected in idiopathic individuals and are associated with autism status. They also converge on synaptic and other autism-linked genes, as well as genes not previously linked to autism. Our results collectively define an expanded repertoire of microexons, delineate their regulatory code, and pinpoint variants predicted to affect their splicing, with implications for the disruption of functions central to neuronal biology and brain disorders.