Idiopathic focal epilepsies are increasingly attributed to post-zygotic mutations (i.e., somatic variants), which are typically acquired during fetal development. While somatic variants in epilepsy were previously synonymous with malformations of cortical development and the PI3K-mTOR gene pathway, it is increasingly recognized that pathogenic somatic variation is present in many focal epilepsy types and encompasses variants in new genes and pathways. We recently discovered that mesial temporal lobe epilepsy, which is the most common focal epilepsy in adults and associated with a spectrum of histopathological findings, may be caused by somatic variants that activate Ras-MAPK signaling. However, despite the recent advances only a minority of focal epilepsy cases have a genetic diagnosis. Using novel sequencing approaches such as duplex sequencing and advanced analytics we aim to identify new variants, genes, and pathways that play a causal role in idiopathic focal epilepsies. Additionally, we hope to develop minimally invasive genetic diagnostic strategies that could be incorporated into routine epilepsy management and care.

We showed for the first time that somatic Ras-MAPK variants in the human hippocampus are a likely causal agent for mesial temporal lobe epilepsy with hippocampal sclerosis. Moreover, there is an increasing number of publications reporting new somatic variants and genes in focal epilepsy resections. Using human surgical tissue and model systems, our lab examines the biochemical properties, the molecular pathways, and the neurobiological processes through which somatic variants are involved in epileptogenesis and neural circuit dysfunction. To that end, we use a range of approaches including protein biochemistry, single cell transcriptomics, massively parallel reporter assays, and high throughput electrophysiology and calcium/voltage imaging.

Our group and others have shown that there is an enrichment of oncogenic somatic variants in both typical and diseased brains. While mutations may occur at any part of the genome, genetic variation in the human brain is non-random, suggesting a role for oncogenic somatic variants in brain development through clonal selection. However, very little is known about the origins and the consequences of oncogenic variants in the brain outside of cancer. Our lab in particular is very interested in the role of postnatal neurogenesis in the development of mesial temporal lobe epilepsy and other adolescent- and adult-onset neuropsychiatric diseases. To address this important question, we use novel single cell DNA/RNA sequencing and lineage tracing in the human brain as well as in experimental model systems to investigate the mechanisms of clonal selection in both typical and diseased brains.