Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development
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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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The finding of brain overgrowth in this sample of young children with 'idiopathic' ASD is consistent with an emerging literature demonstrating brain overgrowth in genetically-defined ASD subgroups (e.g., 16p11 deletions, CHD8).
“The finding of brain overgrowth in this sample of young children with 'idiopathic' ASD is consistent with an emerging literature demonstrating brain overgrowth in genetically-defined ASD subgroups (e.g., 16p11 deletions 15 , CHD8 16 ).”
From Early brain development in infants at high risk for autism spectrum disorder (2017) · cites this paper as [16]
CHD8 is the gene most frequently affected by ASD-associated rare de novo variation.
“chromodomain helicase DNA-binding protein 8 (CHD8)118, which is the gene most frequently affected by ASD-associated rare de novo variation72,119–121.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [121]
Deep phenotyping of 15 patients with CHD8 mutations led to identification of a proposed ASD subtype.
“Deep phenotyping of 15 patients with CHD8 mutations has led to the identification of a proposed ASD subtype (56)”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [56]
Studies on CHD8 and iPS-derived ASD neurons indicate the dysregulation of proliferation and macrocephaly in ASD could be linked to the disruption of these signaling pathways and shortened G1/S transition.
“Studies on CHD8 and iPS-derived ASD neurons indicate the dysregulation of proliferation and macrocephaly in ASD could be linked to the disruption of these signaling pathways and shortened G1/S transition[54, 55, 57, 94, 183, 192, 193].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [193]
Knock-down of the CHD8 ortholog results in macrocephaly in zebrafish and increased brain weight and volume in mice, phenotypes that reflect clinical observations in subjects with loss-of-function mutations in the gene.
“Knock-down of the CHD8 ortholog results in macrocephaly in zebrafish [32, 343] and increased brain weight and volume [187, 287] in mice, phenotypes that reflect clinical observations in subjects with loss-of-function mutations in the gene [32].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [32]
Dysfunction of the Chd8 complex has been associated with autism, and H4K16 acetylation by this complex is associated with brain aging.
“Dysfunction of this complex has been associated with autism33, and H4K16 acetylation by this complex is associated with brain aging34.”
From Cell type-specific transcriptional programs in mouse prefrontal cortex during adolescence and addiction (2019) · cites this paper as [33]
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Self-citationRecurrent de novo mutations implicate novel genes underlying simplex autism risk
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Self-citationThe ASD Living Biology: from cell proliferation to clinical phenotype
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“Indeed, evidence for the enrichment of ASD genes among genes that are dysregulated in induced pluripotent stem cell (iPSC) models of CHD8 (Sugathan et al., 2014) or FOXP1 (Araujo et al., 2015) was strongest for genes that were dysregulated in trans (i.e., their respective transcripts were differentially expressed in m…”
BackgroundInfluentialGermline Chd8 haploinsufficiency alters brain development in mouse
Gompers, A. L., Su-Feher, L., Ellegood, J., Copping, N. A., Riyadh, M. A., Stradleigh, T. W., Pride, M. C., Schaffler, M. D., Wade, A. A., Catta-Preta, R., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4592 · Cited by 266 · see citing works
The microbiota-gut-brain axis and its potential therapeutic role in autism spectrum disorder
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Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits
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Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling
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The road to precision psychiatry: translating genetics into disease mechanisms
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Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID
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Self-citationInsufficient Evidence for “Autism-Specific” Genes
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A Cross-Disorder Method to Identify Novel Candidate Genes for Developmental Brain Disorders
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Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant mice
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Neocortical neurogenesis and the etiology of autism spectrum disorder
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Cellular phenotypes in human iPSC-derived neurons from a genetic model of autism spectrum disorder
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BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations
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Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications
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Epigenetics of Autism Spectrum Disorder
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“Such genes, in turn, can provide insight into the atypical neurodevelopment 11 underlying ASD, both individually (17, 18) and en masse (5, 10, 19).”
BackgroundGenetic research in autism spectrum disorders
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The clinical presentation caused by truncating <i>CHD8</i> variants
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- Authors
- 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., Francescatto, L., Mefford, H. C., Rosenfeld, J. A., Bakken, T., O’Roak, B. J., Pawlus, M., Moon, R., Shendure, J., Amaral, D. G., Lein, E., Rankin, J., Romano, C., de Vries, B. B. A., Katsanis, N., & Eichler, E. E.
- Affiliations
- University of Washington (US)
- Duke Medical Center (US)
- Radboud University Medical Center (NL)
- University of Catania (IT)
- Oasi Maria SS (IT)
- Universitair Ziekenhuis Leuven (BE)
- Maastricht University Medical Centre (NL)
- Allen Institute for Brain Science (US)
- Oregon Health & Science University (US)
- Howard Hughes Medical Institute (US)
- University of California, Davis (US)
- Corresponding author
- Eichler, Evan E.
- ORCID
- Bernier, Raphael
- Golzio, Christelle
- Xiong, Bo
- Stessman, Holly A.
- Coe, Bradley P.
- Gerdts, Jennifer
- Schuurs-Hoeijmakers, Janneke H.
- Fichera, Marco
- Bosco, Paolo
- Buono, Serafino
- Alberti, Antonino
- Failla, Pinella
- Peeters, Hilde
- Steyaert, Jean
- Vissers, Lisenka E.L.M.
- Mefford, Heather C.
- Rosenfeld, Jill A.
- Bakken, Trygve
- O’Roak, Brian J.
- Pawlus, Matthew
- Moon, Randall
- Shendure, Jay
- Amaral, David G.
- Lein, Ed
- Romano, Corrado
- Katsanis, Nicholas
- Eichler, Evan E.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 158
- Issue
- 2
- Pages
- 263-276
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4136921
- OpenAlex
- W2128300020
- Cited by
- 798
- References
- 67
- Citations by year
- 2026: 50 · 2025: 58 · 2024: 57 · 2023: 51 · 2022: 68 · 2021: 85 · 2020: 84 · 2019: 70 · 2018: 63 · 2017: 76 · 2016: 63 · 2015: 61 · 2014: 11
- FWCI
- 39.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lirias (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (P50MH094268, R01MH101221)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083091)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- CHD8, autism spectrum disorder, ASD subtypes, disruptive mutations, developmental delay, macrocephaly, gastrointestinal motility, enteric neurons, zebrafish model, brain development, genotype-phenotype correlation
- MeSH terms
- Adolescent, Amino Acid Sequence, Animals, Brain, Child, Child Development Disorders, Pervasive, Child, Preschool, DNA-Binding Proteins, Female, Humans, Macaca mulatta, Male, Molecular Sequence Data, Mutation, Transcription Factors, Zebrafish, Sequence Alignment, Zebrafish Proteins, Gastrointestinal Tract, Megalencephaly
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