Modelling Sifrim-Hitz-Weiss Syndrome Using Mouse Genetics

Abstract

Neurodevelopmental disorders encompass a spectrum of different conditions with both genetic and environmental etiologies. Although rapid progress has been made in deciphering the genetic landscape of these disorders, in most cases, it remains unclear how mutations undermine neurodevelopmental mechanisms. However, increasing identification of risk genes suggests chromatin remodelling is frequently impacted. For instance, de novo variants encoding the chromatin remodeller CHD4 causes Sifrim-Hitz-Weiss syndrome, which manifests as an overgrowth-intellectual disability syndrome. To further understand Chd4’s role during cortical development, we excised the ATPase domain of Chd4 in the germline or specifically in the developing telencephalon, creating three mouse models. Germline heterozygotes presented a slight decrease in brain weight, cortex area and Ctip2+ cells, with females displaying more overt impairments in learning and memory. Telencephalon-specific conditional heterozygotes exhibited slight changes in white matter, increased repetitive movements and altered social behaviours. Telencephalon-specific conditional knockouts presented with decreased brain size, brain weight, and cortex thickness due to decreased upper layer neurons, and anxiety phenotypes. These data reveal an unexpected complexity in the impacts of Chd4 mutations on neurodevelopmental processes and behaviour.