Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

RNA splicing is highly prevalent in the brain and has strong links to
neuropsychiatric disorders, yet the role of cell-type-specific splicing or
transcript-isoform diversity during human brain development has not been
systematically investigated. Here, we leveraged single-molecule long-read
sequencing to deeply profile the full-length transcriptome of the germinal
zone (GZ) and cortical plate (CP) regions of the developing human
neocortex at tissue and single-cell resolution. We identified 214,516
unique isoforms, of which 72.6% are novel (unannotated in Gencode-v33),
and uncovered a substantial contribution of transcript-isoform diversity,
regulated by RNA binding proteins, in defining cellular identity in the
developing neocortex. We leveraged this comprehensive isoform-centric gene
annotation to re-prioritize thousands of rare de novo risk variants and
elucidate genetic risk mechanisms for neuropsychiatric disorders.