Full-length isoform transcriptome of developing human brain provides new insights into autism

Summary 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 relationships between full-length splicing isoforms expression in the brain and de novo loss-of-function mutations identified in the patients with NDDs. We analyzed the full-length isoform transcriptome of the developing human brain and observed differentially expressed isoforms and isoform co-expression modules undetectable by gene-level analyses. These isoforms were enriched in loss-of-function mutations and microexons, co-expressed with a unique set of partners, and had higher prenatal expression. We experimentally tested the impact of splice site mutations in five NDD risk genes, including SCN2A, DYRK1A and BTRC, and demonstrated exon skipping. Furthermore, our results suggest that the splice site mutation in BTRC reduces 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 the isoform-rather than the gene-level resolution. Highlights Differential isoform expression analysis of the human brain transcriptome reveals neurodevelopmental processes and pathways undetectable by differential gene expression analyses. Splicing isoforms impacted by neurodevelopmental disease (NDD) risk mutations exhibit higher prenatal expression, are enriched in microexons and are involved in neuronal-related functions. Isoform co-expression network analysis identifies modules with splicing and synaptic functions that are enriched in NDD mutations. Splice site mutations impacting NDD risk genes cause exon skipping and produce novel isoforms with altered biological properties. Functional impact of mutations should be investigated at the full-length isoform-level rather than the gene-level resolution