Here, we have taken the approach of directly modeling early cortical development in probands with idiopathic ASD. We focused on individuals with increased head/brain size (macrocephaly), as this is one of the most consistently replicated ASD phenotypes (Courchesne et al., 2001) and confers poorer clinical outcomes ASD (Chaste et al., 2013; Chawarska et al., 2011; Lainhart et al., 2006). Using induced pluripotent stem cells (iPSCs) obtained from affected families, we have produced telencephalic organoids that recapitulate transcriptional programs present in mid-fetal human cortical development. Transcriptome and cellular phenotype analyses in this model identified unexpected differences in cell cycle time and synaptic growth, as well as an imbalance in GABA/glutamate neuronal differentiation in patients as compared to their unaffected family members.
