Our study provides a framework for studying normal human brain development and its disorders. Using iPSC-derived cortical organoids that recapitulate human first trimester telencephalic development, we performed genome-wide transcriptome analysis in four families affected by idiopathic ASD. The affected individuals do not share any obvious underlying genomic alterations, but all express a phenotypic trait that confers increased symptom severity, macrocephaly. Despite the heterogeneity in genotypes, we were able to identify perturbations in coherent programs of gene expression and associated features of altered neurodevelopment, namely upregulation of cell proliferation, unbalanced inhibitory neuron differentiation, and exuberant synaptic development.
