Disruptive CHD8 mutations define a subtype of autism early in development

By R. Bernier, C. Golzio, Bo Xiong, H. Stessman, Bradley P. Coe, Osnat Penn, Kali T. Witherspoon, Jennifer Gerdts, Carl A. Baker, A. V. Silfhout and 24 more. Cell, 2014

750 citations recorded by the source corpus.

Autism spectrum disorder (ASD) is a heterogeneous disease where 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 post-mitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.

Subfields: Cognitive Neuroscience, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/ce651d3f3dfcef96d7e6907c44199d8106562b74

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Citations in the corpus

ATP-dependent chromatin remodeling during mammalian development (2016, background): “…craniofacial and tracheal development (Sperry et al., 2014) CHD8 CHD8 Involved in autism spectrum disorder (Sanders, 2015) and neural development (Bernier et al., 2014; Cotney et al., 2015; Sugathan et al., 2014) CHD9 CHD9 Associates with selective promoters of osteoprogenitors (Shur et al.,…”
Early brain development in infants at high risk for autism spectrum disorder (2017, positive): “Work by Cotney et al. 27 demonstrates the importance of CHD8 in mediating regulatory networks during neurodevelopment, and suggests the potential role of CHD8 in disrupting the proliferation and differentiation of neurons during early human brain development.”
Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015, methodology): “…regulation level, ChIP–seq in induced pluripotent stem cell-derived neurons has been used to define the network of genes regulated by chro-modomain helicase DNA-binding protein 8 ( CHD8 ) 118 , which is the gene most frequently affected by ASD-associated rare de novo variation 72,119–121 .”