TY - JOUR
T1 - Disruptive CHD8 mutations define a subtype of autism early in development
AU - Bernier, Raphael
AU - Golzio, Christelle
AU - Xiong, Bo
AU - Stessman, Holly A.
AU - Coe, Bradley P.
AU - Penn, Osnat
AU - Witherspoon, Kali
AU - Gerdts, Jennifer
AU - Baker, Carl
AU - Vulto-Van Silfhout, Anneke T.
AU - Schuurs-Hoeijmakers, Janneke H.
AU - Fichera, Marco
AU - Bosco, Paolo
AU - Buono, Serafino
AU - Alberti, Antonino
AU - Failla, Pinella
AU - Peeters, Hilde
AU - Steyaert, Jean
AU - Vissers, Lisenka E.L.M.
AU - Francescatto, Ludmila
AU - Mefford, Heather C.
AU - Rosenfeld, Jill A.
AU - Bakken, Trygve
AU - O'Roak, Brian J.
AU - Pawlus, Matthew
AU - Moon, Randall
AU - Shendure, Jay
AU - Amaral, David G.
AU - Lein, Ed
AU - Rankin, Julia
AU - Romano, Corrado
AU - De Vries, Bert B.A.
AU - Katsanis, Elias Nicholas
AU - Eichler, Evan E.
N1 - Funding Information:
This work was supported by the Simons Foundation Autism Research Initiative (SFARI) 303241 and NIH/NIMH R01MH101221 to E.E.E.; by SFARI 239983 and NIH P50MH094268 to N.K.; by a NARSAD Young Investigator Grant from BBRF to C.G.; and by the European Commission: GENCODYS grant 241995 under FP7 and the Dutch Organisation for Health Research and Development (ZON-MW grants 917-86-319 and 912-12-109) to B.B.A.d.V. E.E.E. is an Investigator of the Howard Hughes Medical Institute and is on the scientific advisory board for DNAnexus, Inc. N.K. is a Distinguished Brumley Professor. We thank all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, E. Hanson, D. Grice, A. Klin, R. Kochel, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, and E. Wijsman). We are grateful to D. Raible and H.S. Zimmermann for providing zebrafish resources and for helpful discussions, to T. Brown for help with manuscript preparation, and to J. Huddleston and M. Malig for sequencing support.
PY - 2014/7/17
Y1 - 2014/7/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84904635209&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904635209&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2014.06.017
DO - 10.1016/j.cell.2014.06.017
M3 - Article
C2 - 24998929
AN - SCOPUS:84904635209
SN - 0092-8674
VL - 158
SP - 263
EP - 276
JO - Cell
JF - Cell
IS - 2
ER -
