CHD8 haploinsufficiency results in delayed neurodevelopment and autistic-like phenotypes in mice

Autism spectrum disorder (ASD) comprises a range of neurodevelopmental disorders characterized by deficits in social interaction and communication as well as by restricted and repetitive behaviours1. ASD has a strong genetic component with high heritability. Exome sequencing analysis has recently identified many de novo mutations in a variety of genes in individuals with ASD, with CHD8, a gene encoding a chromatin remodeler, being most frequently affected2-6. Whether CHD8 mutation is causative for ASD and how it might establish ASD traits have remained unknown, however. Here we show that mice heterozygous for Chd8 mutation manifest macrocephaly and ASD-like behavioural characteristics including increased anxiety, repetitive behaviour, and altered social behaviour. Unexpectedly, CHD8 haploinsufficiency did not result in prominent changes in the expression of a few specific genes but rather gave rise to small but global changes in that of a large number of ASD-related genes in the brain. Gene set enrichment analysis (GSEA) revealed that neurodevelopment is delayed in the mutant embryos. Furthermore, reduced expression of CHD8 resulted in abnormal activation of RE-1 silencing transcription factor (REST), which suppresses the transcription of many neuronal genes, likely accounting for the delay in neurodevelopment in the mutant mice. Our results thus indicate that CHD8 haploinsufficiency is a cause of ASD, with disease pathogenesis likely resulting from abnormal REST activation and a consequent delay in neurodevelopment.