PROJECT SUMMARY Tuberous Sclerosis Complex (TSC) is a genetic syndrome that predisposes patients to tumor formation and is often diagnosed during infancy. Brain lesions, including subependymal giant cell astrocytoma (SEGA) and cortical tubers, occur in ~20% of TSC patients and remain challenging to manage as there is extreme phenotypic heterogeneity. In order to better understand and surveil which patients are likely to develop severe brain lesions and associated treatment-resistant epilepsy, this project aims to understand the genotype-phenotype relationships of TSC. I hypothesize that the severity of tumor burden in TSC patients is associated with (and can be predicted by) mutations in specific genetic modifiers. I aim to (1) characterize genetic modifiers that associate with SEGA and cortical tubers and (2) establish biological consequences of mutations in DNA damage repair genes that we have identified in patients with TSC. The research and training plans here are designed to expose me to translational and clinical research studies, analysis of patient -omics data, implementation of CRISPR/Cas9 genome editing, use of two- and three-dimensional human cell models, and metabolic profiling. These skills and the training I receive in this career phase will be essential for my future career as an independent researcher.