Disruptive CHD8 mutations define a subtype of autism early in development

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; Elias Nicholas Katsanis; Evan E. Eichler

doi:10.1016/j.cell.2014.06.017

Disruptive CHD8 mutations define a subtype of autism early in development

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 FrancescattoHeather 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, Elias Nicholas Katsanis, Evan E. Eichler^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

547 Scopus citations

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.

Original language	English (US)
Pages (from-to)	263-276
Number of pages	14
Journal	Cell
Volume	158
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2014.06.017
State	Published - Jul 17 2014

Funding

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.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2014.06.017

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Bernier, R., Golzio, C., Xiong, B., Stessman, H. A., Coe, B. P., Penn, O., Witherspoon, K., Gerdts, J., Baker, C., Vulto-Van Silfhout, A. T., Schuurs-Hoeijmakers, J. H., Fichera, M., Bosco, P., Buono, S., Alberti, A., Failla, P., Peeters, H., Steyaert, J., Vissers, L. E. L. M., ... Eichler, E. E. (2014). Disruptive CHD8 mutations define a subtype of autism early in development. Cell, 158(2), 263-276. https://doi.org/10.1016/j.cell.2014.06.017

@article{f33a5f236ec74b8b9008974b056f4c51,

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.",

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

note = "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. ",

year = "2014",

month = jul,

day = "17",

doi = "10.1016/j.cell.2014.06.017",

language = "English (US)",

volume = "158",

pages = "263--276",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "2",

}

Bernier, R, Golzio, C, Xiong, B, Stessman, HA, Coe, BP, Penn, O, Witherspoon, K, Gerdts, J, Baker, C, Vulto-Van Silfhout, AT, Schuurs-Hoeijmakers, JH, Fichera, M, Bosco, P, Buono, S, Alberti, A, Failla, P, Peeters, H, Steyaert, J, Vissers, LELM, Francescatto, L, Mefford, HC, Rosenfeld, JA, Bakken, T, O'Roak, BJ, Pawlus, M, Moon, R, Shendure, J, Amaral, DG, Lein, E, Rankin, J, Romano, C, De Vries, BBA, Katsanis, EN & Eichler, EE 2014, 'Disruptive CHD8 mutations define a subtype of autism early in development', Cell, vol. 158, no. 2, pp. 263-276. https://doi.org/10.1016/j.cell.2014.06.017

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.

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U2 - 10.1016/j.cell.2014.06.017

DO - 10.1016/j.cell.2014.06.017

M3 - Article

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AN - SCOPUS:84904635209

SN - 0092-8674

VL - 158

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EP - 276

JO - Cell

JF - Cell

IS - 2

ER -

Disruptive CHD8 mutations define a subtype of autism early in development

Abstract

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ASJC Scopus subject areas

UN SDGs

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