Rare genetic neurodevelopmental disorders: from basic science to precision medicine

For a proportion of patients with neurodevelopmental disorders (NDDs), DNA testing enables the identification of a rare mutation that is likely to play a major causal role. In such cases, genetic diagnosis of a rare monogenic NDD can have immediate positive impacts on patients and families. However, major barriers remain towards the long-term goal of precision treatments for NDDs based on genetic diagnosis. Chief among these barriers is the lack of basic understanding of the underlying cellular, molecular, and neurodevelopmental impacts of pathogenic patient mutations. Among the forms of monogenic NDDs, there has emerged an unexpectedly strong link with causal mutations that impact gene regulation, or how genes are turned on or off in the right cells at the right time. In this presentation, I will discuss major outstanding questions regarding rare monogenic NDDs, and how basic science research using cellular and animal models can reveal the impact of NDD-associated mutations, focusing on our work on NDD phenotypes caused by rare mutations to the gene CHD8. I will also describe how basic science understanding of the molecular control of gene regulation paired with Cas9/CRISPR technology is driving pre-clinical advancements in precision treatments for monogenic NDDs. Presented by Alex Nord, Ph.D.