Disruptive CHD8 mutations define a subtype of autism early in development.

Autism spectrum disorder (ASD) is a heterogeneousdisease in which efforts to define subtypes behav-iorally have met with limited success. Hypothesiz-ing that genetically based subtype identificationmay prove more productive, we resequenced theASD-associated gene CHD8 in 3,730 children withdevelopmental delay or ASD. We identified a totalof 15 independent mutations; no truncating eventswere identified in 8,792 controls, including 2,289 un-affectedsiblings.InadditiontoahighlikelihoodofanASD diagnosis among patients bearing CHD8 muta-tions, characteristics enriched in this group includedmacrocephaly, distinct faces, and gastrointestinalcomplaints. chd8 disruption in zebrafish recapitu-lates features of the human phenotype, includingincreased head size as a result of expansion of theforebrain/midbrain and impairment of gastrointes-tinal motility due to a reduction in postmitotic entericneurons. Our findings indicate that CHD8 disrup-tions define a distinct ASD subtype and reveal unex-pected comorbidities between brain developmentand enteric innervation.