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There is no clear genetic etiology or convergent pathophysiology for autism spectrum disorders (ASD). Using induced pluripotent stem cell (iPSC)-derived brain organoids and single-cell transcriptomics, we modeled alterations in the formation of the forebrain between sons with ASD and their unaffected fathers in ten families. Relative to fathers, probands with macrocephaly presented an increase in dorsal cortical plate excitatory neurons (EN-DCP) to the detriment of preplate lineages, whereas normocephalic ASD probands presented an opposite decrease in EN-DCP-related gene expression. Both cohorts converged in a dysregulation of outer radial glia genes related to translation. In macrocephalic probands, an increase in progenitor self-renewal genes ID1/ID3 was coupled to a larger pool of cortical progenitors. Furthermore, changes in ID1/ID3 expression were best predictors of ASD clinical severity. We suggest that head circumference reveals a fundamental difference in etiological mechanisms of ASD rooted in alterations in progenitor fate and unbalanced excitatory cortical neuron diversity.

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