- Gompers, Andrea L;
- Su-Feher, Linda;
- Ellegood, Jacob;
- Copping, Nycole A;
- Riyadh, M Asrafuzzaman;
- Stradleigh, Tyler W;
- Pride, Michael C;
- Schaffler, Melanie D;
- Wade, A Ayanna;
- Catta-Preta, Rinaldo;
- Zdilar, Iva;
- Louis, Shreya;
- Kaushik, Gaurav;
- Mannion, Brandon J;
- Plajzer-Frick, Ingrid;
- Afzal, Veena;
- Visel, Axel;
- Pennacchio, Len A;
- Dickel, Diane E;
- Lerch, Jason P;
- Crawley, Jacqueline N;
- Zarbalis, Konstantinos S;
- Silverman, Jill L;
- Nord, Alex S
The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8+/del5 mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8+/del5 mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8+/del5 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes and neuroimmune signaling. We identified a co-expression module with peak expression in early brain development featuring dysregulation of RNA processing, chromatin remodeling and cell-cycle genes enriched for promoter binding by Chd8, and we validated increased neuronal proliferation and developmental splicing perturbation in Chd8+/del5 mice. This integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency for brain development.