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Background  Disruptive mutation in the  CHD8  gene is one of the top genetic risk factors in autism spectrum disorders (ASDs). Previous analyses of genome-wide  CHD8  occupancy and reduced expression of  CHD8  by shRNA knockdown in committed neural cells showed that  CHD8  regulates multiple cell processes critical for neural functions, and its targets are enriched with ASD-associated genes.    Methods  To further understand the molecular links between  CHD8  functions and ASD, we have applied the CRISPR/Cas9 technology to knockout one copy of  CHD8  in induced pluripotent stem cells (iPSCs) to better mimic the loss-of-function status that would exist in the developing human embryo prior to neuronal differentiation. We then carried out transcriptomic and bioinformatic analyses of neural progenitors and neurons derived from the  CHD8  mutant iPSCs.    Results  Transcriptome profiling revealed that  CHD8  hemizygosity ( CHD8  +/− ) affected the expression of several thousands of genes in neural progenitors and early differentiating neurons. The differentially expressed genes were enriched for functions of neural development, β-catenin/Wnt signaling, extracellular matrix, and skeletal system development. They also exhibited significant overlap with genes previously associated with autism and schizophrenia, as well as the downstream transcriptional targets of multiple genes implicated in autism. Providing important insight into how  CHD8  mutations might give rise to macrocephaly, we found that seven of the twelve genes associated with human brain volume or head size by genome-wide association studies (e.g.,  HGMA2 ) were dysregulated in  CHD8  +/−  neural progenitors or neurons.    Conclusions  We have established a renewable source of  CHD8  +/−  iPSC lines that would be valuable for investigating the molecular and cellular functions of  CHD8 . Transcriptomic profiling showed that  CHD8  regulates multiple genes implicated in ASD pathogenesis and genes associated with brain volume.    Electronic supplementary material  The online version of this article (doi:10.1186/s13229-015-0048-6) contains supplementary material, which is available to authorized users.

CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment