Raphael Bernier, Christelle Golzio, Bo Xiong, Holly A. Stessman, Bradley P. Coe, Osnat Penn, Kali Witherspoon, Jennifer Gerdts, Carl Baker, Anneke T. Vulto-van Silfhout, Janneke H. Schuurs-Hoeijmakers, Marco Fichera, Paolo Bosco, Serafino Buono, Antonino Alberti, Pinella Failla, Hilde Peeters, Jean Steyaert, Lisenka E.L.M. Vissers, Ludmila Francescatto, Heather C. Mefford, Jill A. Rosenfeld, Trygve Bakken, Brian J. O’Roak, Matthew Pawlus, Randall Moon, Jay Shendure, David G. Amaral, Ed Lein, Julia Rankin, Corrado Romano, Bert B.A. de Vries, Nicholas Katsanis, Evan E. Eichler

Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing 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 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.