Stratifying SYNGAP1 Mutations to Develop Patient-Specific Targeted Therapeutic Strategies

SYNGAP1 syndrome is a rare genetic condition that can cause intellectual disability, epilepsy, and features of autism. It is linked to changes in a gene called SYNGAP1, which plays a crucial role in brain development and communication between brain cells. However, not all SYNGAP1 mutations have the same effects, and it is still unclear why some individuals are more severely affected than others. In this project, we are using skin cells donated by children with different SYNGAP1 mutations to create lab-grown models of the human brain called cortical organoids. These 3D models allow us to closely study how each mutation affects early brain development and the formation of neural networks. We will measure changes in gene expression, brain cell development, and electrical signaling to better understand how each mutation works. Importantly, we will also test whether a known drug, lovastatin, can improve brain cell function in these models. We will apply the drug at two different stages of brain development to see when it might be most effective. Our goal is to understand the effects of different SYNGAP1 mutations and identify the best time and way to treat them. This research may lead to more personalized treatments for children with SYNGAP1 syndrome and improve our understanding of how the human brain develops.