Chromodomain helicase DNA-binding protein 8 (CHD8) was identified as a leading autism spectrum disorder (ASD) candidate gene by whole-exome sequencing and subsequent targeted-sequencing studies. De novo loss-of-function mutations were identified in 12 individuals with ASD and zero controls, accounting for a highly significant association. Small interfering RNA-mediated knockdown of CHD8 in human neural progenitor cells followed by RNA sequencing revealed that CHD8 insufficiency results in altered expression of 1715 genes, including both protein-coding and noncoding RNAs. Among the 10 most changed transcripts, 4 (40%) were noncoding RNAs. The transcriptional changes among protein-coding genes involved a highly interconnected network of genes that are enriched in neuronal development and in previously identified ASD candidate genes. These results suggest that CHD8 insufficiency may be a central hub in neuronal development and ASD risk.

Importance Variation in child responses to adversity creates a clinical challenge to identify children most resilient or susceptible to later risk for disturbances in cognition and health. Advances in establishing scalable biomarkers can lead to early identification and mechanistic understanding of the association of early adversity with neurodevelopment. Objectives To examine whether maternal reports of stress are associated with patterns in resting electroencephalography at 2 months of age and whether unique electroencephalographic profiles associated with risk and resiliency factors can be identified. Design, Setting, and Participants For this cohort study, a population-based sample of 113 mother-infant dyads was recruited from January 1, 2016, to March 1, 2018, during regularly scheduled pediatric visits before infants were 2 months of age from 2 primary care clinics in Boston, Massachusetts, and Los Angeles, California, that predominantly serve families from low-income backgrounds. Data are reported from a single time point, when infants were aged 2 months, of an ongoing cohort study longitudinally following the mother-infant dyads. Exposures Maternal reported exposure to stressful life events and perceived stress. Main Outcomes and Measures Spectral power (absolute and relative) in different frequency bands (Δ, θ, low and high α, β, and γ) from infant resting electroencephalography (EEG) and EEG profiles across frequency bands determined by latent profile analysis. Results Of 113 enrolled infants, 70 (mean [SD] age, 2.42 [0.37] months; 35 girls [50%]) provided usable EEG data. In multivariable hierarchical linear regressions, maternal perceived stress was significantly and negatively associated with absolute β (β = −0.007; 95% CI, −0.01 to −0.001; semipartialr = −0.25) and γ power (β = −0.008; 95% CI, −0.01 to −0.002; semipartialr = −0.28). Maternal educational level was significantly and positively associated with power in high α, β, and γ bands after adjusting for covariates (high school: γ: β = 0.108; 95% CI, 0.014-0.203; semipartialr = −0.236; associate’s degree or higher: high α: β = 0.133; 95% CI, 0.018-0.248; semipartialr=0.241; β: β = 0.167; 95% CI, 0.055-0.279; semipartialr = 0.309; and γ: β = 0.183; 95% CI, 0.066-0.299; semipartialr = 0.323). Latent profile analysis identified 2 unique profiles for absolute and relative power. Maternal perceived stress (β = 0.13; 95% CI, 0.01-0.25; adjusted odds ratio [AOR], 1.14; 95% CI, 1.01-1.28) and maternal educational level (high school: β = 3.00; 95% CI, 0.35-5.65; AOR, 20.09; 95% CI, 1.42-283.16; associate’s degree or higher: β = 4.12; 95% CI, 1.45-6.79; AOR, 61.56; 95% CI, 4.28-885.01) were each associated with unique profile membership. Conclusions and Relevance These findings suggest that unique contributions of caregiver stress and maternal educational level on infant neurodevelopment are detectable at 2 months; EEG might be a promising tool to identify infants most susceptible to parental stress and to reveal mechanisms by which neurodevelopment is associated with adversity. Additional studies validating subgroups across larger cohorts with different stressors and at different ages are required before use at the individual level in clinical settings.