Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behav-iorally have met with limited success. Hypothesiz-ing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 un-affected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 muta-tions, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitu-lates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointes-tinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disrup-tions define a distinct ASD subtype and reveal unex-pected comorbidities between brain development and enteric innervation. INTRODUCTION