ASD modelling in organoids reveals imbalance of excitatory cortical neuron subtypes during early neurogenesis

There is no clear genetic etiology or convergent pathophysiology for autism spectrum disorders (ASD). Using cortical organoids and single-cell transcriptomics, we modeled alterations in the formation of the forebrain between sons with idiopathic ASD and their unaffected fathers in thirteen families. Alterations in the transcriptome suggest that ASD pathogenesis in macrocephalic and normocephalic probands involves an opposite disruption of the balance between the excitatory neurons of the dorsal cortical plate and other lineages such as the early-generated neurons from the putative preplate. The imbalance stemmed from a divergent expression of transcription factors driving cell fate during early cortical development. While we did not find probands genomic variants explaining the observed transcriptomic alterations, a significant overlap between altered transcripts and reported ASD risk genes affected by rare variants suggests a degree of gene convergence between rare forms of ASD and developmental transcriptome in idiopathic ASD.