Disruptive CHD8 mutations define a subtype of autism early in development

Cell. 2014 Jul 17;158(2):263-276. doi: 10.1016/j.cell.2014.06.017.

Raphael Bernier ¹, Christelle Golzio ², Bo Xiong ³, Holly A Stessman ³, Bradley P Coe ³, Osnat Penn ³, Kali Witherspoon ³, Jennifer Gerdts ¹, Carl Baker ³, Anneke T Vulto-van Silfhout ⁴, Janneke H Schuurs-Hoeijmakers ⁴, Marco Fichera ⁵, Paolo Bosco ⁶, Serafino Buono ⁶, Antonino Alberti ⁶, Pinella Failla ⁶, Hilde Peeters ⁷, Jean Steyaert ⁸, Lisenka E L M Vissers ⁴, Ludmila Francescatto ², Heather C Mefford ⁹, Jill A Rosenfeld ¹⁰, Trygve Bakken ¹¹, Brian J O'Roak ¹², Matthew Pawlus ¹³, Randall Moon ¹⁴, Jay Shendure ³, David G Amaral ¹⁵, Ed Lein ¹¹, Julia Rankin ¹⁶, Corrado Romano ⁶, Bert B A de Vries ⁴, Nicholas Katsanis ², Evan E Eichler ¹⁷

Affiliations

1 Department of Psychiatry, University of Washington, Seattle, WA 98195, USA.
2 Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA.
3 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
4 Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
5 I.R.C.C.S. Associazione Oasi Maria Santissima, Troina 94018, Italy; Medical Genetics, University of Catania, Catania 95123, Italy.
6 I.R.C.C.S. Associazione Oasi Maria Santissima, Troina 94018, Italy.
7 Center for Human Genetics, University Hospitals Leuven, KU Leuven, 3000 Leuven, Belgium; Leuven Autism Research (LAuRes), 3000 Leuven, Belgium.
8 Leuven Autism Research (LAuRes), 3000 Leuven, Belgium; Department of Child and Adolescent Psychiatry, KU Leuven, 3000 Leuven, Belgium; Department of Clinical Genetics, Academic Hospital Maastricht, and Research Institute Growth & Development (GROW), Maastricht University, 6200 MD Maastricht, The Netherlands.
9 Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
10 Signature Genomics Laboratories, PerkinElmer, Inc., Spokane, WA 99207, USA.
11 Allen Institute for Brain Science, Seattle, WA 98103, USA.
12 Molecular & Medical Genetics, Oregon Health & Science University (OHSU), Portland, OR 97208, USA.
13 Department of Pharmacology, University of Washington, Seattle, WA 98109, USA.
14 Department of Pharmacology, University of Washington, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
15 Autism Phenome Project, MIND Institute, University of California-Davis, Sacramento, CA 95817, USA.
16 Peninsula Clinical Genetics Service, Exeter EX1 2ED, UK.
17 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA. Electronic address: eee@gs.washington.edu.

PMID: 24998929 DOI: 10.1016/j.cell.2014.06.017

Abstract

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.

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