Characterizing the Neural Phenotype of CHD8 and CHD8-Regulated Targets

Oral Presentation
Thursday, May 2, 2019: 2:06 PM
Room: 516ABC (Palais des congres de Montreal)
C. M. Hudac1, J. Gerdts1, T. Turner2, E. E. Eichler3, S. J. Webb1 and R. Bernier1, (1)Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, (2)University of Washington, Seattle, WA, (3)Department of Genome Science, University of Washington, Seattle, WA

CHD8 is one of the most commonly identified genes in ASD with the most prevalent recurrent de novo mutation rate in ASD cohorts and present a strong genetically-defined subtype of ASD (Bernier et al., 2014). Given the regulatory effects of CHD8 on other neurodevelopmental genes (Cotney et al., 2015), recent evidence indicates that individuals with disruptive ASD-risk mutations to genes that are targeted by CHD8 exhibit a shared phenotype. Little is known about the human neural phenotype; however, Chd8 haploinsufficient mice exhibit altered auditory functional connectivity (Suetterlin et al., 2018), which may suggest issues in processing auditory information.


We sought to characterize the neural phenotype associated with CHD8 and genes regulated by CHD8, and predicted a shared neural phenotype.


Participants (N=106, see Table 1) were grouped based upon genetic and diagnostic etiology: CHD8, Target, Non-Target, No Event ASD (i.e., no known disruptive genetic event), and Typically-Development (TYP). CHD8 target versus non-target functional gene groups were dichotomized based on prior research (Cotney et al., 2015). A passive auditory oddball EEG experiment (Hudac et al., 2018) measured attention and speed of habituation as reflected by the central N1 (60-140 ms). Multilevel analyses (SAS 9.4) tested group differences in condition (i.e., deviant tone vs. repeated tone) and habituation (i.e., the rate of decreasing P3a amplitude).


N1 amplitudes revealed the predicted pattern, F(4, 2400) = 2.89, p =.021, such that auditory deviance was larger in CHD8 and Target groups, relative to Non-Target group, p’s <.036, but not the No Event ASD group, p = .78. These effects were in part driven by the overall large N1 response of the Non-Target group (~8 µV) relative to the other groups (~6.5 µV). Notably, neither the CHD8 or Target groups differed from the No Event (i.e., “idiopathic” ASD) group, p’s > .15. There were no significant omnibus effects of habituation. However, pairwise comparisons indicated unique patterns of deviance (trial level p’s < .05, LSD), such that the CHD8 group exhibited early effects (before trial 40) and the Target group exhibited later effects (after trial 20).


Children with disruptive CHD8 mutations share a similar neural phenotype to children with a disruptive mutation to a gene targeted by CHD8. Critically, this shared phenotype is distinct from genes not targeted by CHD8, which suggests a potential converging genetic mechanism associated with CHD8 that may have implications for an array of high-confidence ASD risk genes. We will discuss these implications and the potential for the distinct habituation patterns as they pertain evidence of overconnectivity in Chd8 mice.

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