Genomic and functional characterization of ASD and ID-associated MYT1L mutation

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Recent advances in human genetics have defined hundreds of causal variants for Autism Spectrum Disorder (ASD) and other intellectual and developmental disabilities (IDDs). However, substantial effort is required to define downstream disease processes and thus to guide development of interventions for each one. One such new ASD gene is MYT1L – while mutations in MYT1L have recently become associated with ASD and Intellectual Disability (IDD) in humans, the role of MYT1L in neural cells and circuits is unclear. Thus, here, we propose a comprehensive mechanistic investigation of MYT1L. This project uses both cutting-edge established workflows as well as innovative new approaches to enable in-depth study of MYT1L loss at the molecular, cellular, structural, and behavioral circuit levels. We will utilize two complementary experimental systems, mouse models and human induced pluripotent stem cell (iPSC)-derived neurons, to define MYT1L's normal roles, and to identify the consequences and reversibility of MYT1L loss. We focus initially on a mutation identified in a patient with a MYT1L putative loss-of-function variant who has ASD and ID. In addition to knock-in of this variant into isogenic control PSC lines, we derived iPSC models from this subject, with and without MYT1L variant correction, enabling us to define consistent consequences of MYT1L mutation across human genetic backgrounds. We also developed mouse models targeting the paralogous amino acid, to enable studies of the consequence of MYT1L loss on brain structure, physiology, and behavioral circuit function. Further, cutting-edge gene therapy-like tools developed for both mouse and human models will allow us to investigate the effects of rescuing gene function. Similar landmark experiments profoundly changed the understanding of other neurodevelopmental disorders by demonstrating that a substantial proportion of the phenotype was reversible, thus spurring the development of therapeutics based on rescuing gene expression. Together, the experiments performed here will elucidate the requirements for and mechanisms by which MYT1L controls brain development and function, will determine how these are disrupted by pathogenic MYT1L mutation, and could also chart a course towards MYT1L-targeted therapies.