UC San Diego

Alternative splicing plays important role in brain development, however its global contribution to human neurodevelopmental diseases (NDD) has not been fully investigated. Here, we examined the relationship between splicing isoform expression and de novo loss-of-function mutations implicated in autism. We constructed isoform transcriptome of the developing human brain, and observed better resolution and stronger signals at the isoform-level compared to the gene-level transcriptome. We identified differentially expressed isoforms and isoform co-expression modules enriched in autism loss-of-function mutations. These isoforms have higher prenatal expression, are enriched in microexons, and are co-expressed with a unique set of partners. We experimentally test the impact of splice site mutations in five NDD risk genes, including SCN2A, DYRK1A and BTRC, and demonstrate exon skipping. Furthermore, our results suggest that the splice site mutation in BTRC reduces its translational efficiency, likely impacting Wnt signaling through impaired degradation of β-catenin. We propose that functional effect of mutations associated with human diseases should be investigated at isoform- rather than gene-level resolution.