UCSF

Recent studies have identified over one hundred high-confidence autism spectrum disorder (ASD) genes and several hundred congenital heart disorder (CHD) genes. While CHD has been shown to commonly co-occur with autism spectrum disorder (ASD), the shared molecular mechanisms underlying this comorbidity remain unknown. Recent studies have shown that ASD gene perturbations commonly dysregulate neural progenitor cell (NPC) proliferation and neurogenesis. Our lab first sought to understand the extent to which the broader set of ASD genes are involved in this process and to identify the biological pathways underlying this convergence. Next, we investigated ASD and CHD shared risk by identifying CHD genes that present with a neurogenesis phenotype.

In this dissertation we utilized CROP-Seq to repress a large subset of the known ASD genes in a human in vitro model of cortical neurogenesis. We reinforced neurogenesis and microtubule biology as points of convergence in ASD gene perturbations (Chapter 1). We then investigated shared risk between ASD and CHD by performing a neurogenesis screen involving ASD and CHD genes and determined that a subset of ASD and CHD genes play key roles in neuronal progenitor cell proliferation and are enriched for ciliary biology (Chapter 2). Overall, this work contributes to the growing literature on the developmental pathways disrupted in ASD and CHD.