title: Disruptive CHD8 mutations define a subtype of autism early in development.
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.
authors.affiliation: Department of Psychiatry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bernier
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Christelle
authors.initials: C
authors.lastname: Golzio
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiong
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Stessman
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Coe
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Osnat
authors.initials: O
authors.lastname: Penn
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Kali
authors.initials: K
authors.lastname: Witherspoon
authors.affiliation: Department of Psychiatry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gerdts
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Baker
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Anneke T
authors.initials: AT
authors.lastname: Vulto-van Silfhout
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Janneke H
authors.initials: JH
authors.lastname: Schuurs-Hoeijmakers
authors.affiliation: I.R.C.C.S. Associazione Oasi Maria Santissima, Troina 94018, Italy; Medical Genetics, University of Catania, Catania 95123, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Fichera
authors.affiliation: I.R.C.C.S. Associazione Oasi Maria Santissima, Troina 94018, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bosco
authors.affiliation: I.R.C.C.S. Associazione Oasi Maria Santissima, Troina 94018, Italy.
authors.forename: Serafino
authors.initials: S
authors.lastname: Buono
authors.affiliation: I.R.C.C.S. Associazione Oasi Maria Santissima, Troina 94018, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Alberti
authors.affiliation: I.R.C.C.S. Associazione Oasi Maria Santissima, Troina 94018, Italy.
authors.forename: Pinella
authors.initials: P
authors.lastname: Failla
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, KU Leuven, 3000 Leuven, Belgium; Leuven Autism Research (LAuRes), 3000 Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Peeters
authors.affiliation: 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.
authors.forename: Jean
authors.initials: J
authors.lastname: Steyaert
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Lisenka E L M
authors.initials: LELM
authors.lastname: Vissers
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Francescatto
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.affiliation: Signature Genomics Laboratories, PerkinElmer, Inc., Spokane, WA 99207, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98103, USA.
authors.forename: Trygve
authors.initials: T
authors.lastname: Bakken
authors.affiliation: Molecular & Medical Genetics, Oregon Health & Science University (OHSU), Portland, OR 97208, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98109, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pawlus
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98109, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
authors.forename: Randall
authors.initials: R
authors.lastname: Moon
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Autism Phenome Project, MIND Institute, University of California-Davis, Sacramento, CA 95817, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Amaral
authors.affiliation: Allen Institute for Brain Science, Seattle, WA 98103, USA.
authors.forename: Ed
authors.initials: E
authors.lastname: Lein
authors.affiliation: Peninsula Clinical Genetics Service, Exeter EX1 2ED, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Rankin
authors.affiliation: I.R.C.C.S. Associazione Oasi Maria Santissima, Troina 94018, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Romano
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Bert B A
authors.initials: BBA
authors.lastname: de Vries
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: 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.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000473:pathology; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D041981:Gastrointestinal Tract / Q000294:innervation / Q000503:physiopathology; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D058627:Megalencephaly / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C523331:CHD8 protein, human; C000592497:CHD8 protein, zebrafish; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins