De novo SNVs and CNVs, particularly loss-of-function mutations, are significant contributors to ASD risk (21, 59–62). In addition to de novo germline mutations, a substantial number of de novo somatic mutations (i.e., ~5.4% of de novo events) are detected in the blood of ASD patients and are enriched in ASD probands (22). Somatic mosaic mutations also have been identified throughout postmortem ASD brains or, in some instances, in more localized areas in ASD brains (59). Evidence of continuous, widespread cortical mismigration, as seen in some mutant mice, has not been reported in the postmortem ASD brain (63, 64). However, NPCs from a subset of ASD patients with enlarged brain volumes are inherently more proliferative and display abnormal neurogenesis when compared to controls (65, 66). Other ASD patients have focal cortical abnormalities, including disorganized neurons and lamina, polymicrogyria, and other local surface malformations (67). Thus, in addition to specific mutations, additional cell cycles may further affect somatic mutational loads in patients.
