Thus, the early acceleration in the cell cycle, overproduction of GABA neurons and synaptic overgrowth may be antecedents of the aberrant trajectory of cortical development found in children with ASD. Neuropathological studies found an increased number of neurons (Courchesne et al., 2011), increased number of cortical minicolumns (Casanova et al., 2002) and synapses (Hutsler and Zhang, 2010; Tang et al., 2014) in unselected cases of ASD, suggesting increased production of cortical neurons. A macroscopic increase in HC, found in 15–20% of ASD cases, confers a poorer outcome in ASD (Chaste et al., 2013; Chawarska et al., 2011; Lainhart et al., 2006), suggesting that they represent the extreme of a continuum. Support for this hypothesis comes from the finding that in our patient cohort there is a correlation between the extent of change in gene expression in organoids and degree of patient’s macrocephaly and symptom severity. The finding that altered gene expression does not correlate with HC in the unaffected fathers, despite the fathers having the same degree of macrocephaly, suggests that the macrocephaly in the fathers and in the probands
