S Khoshkhoo, Y Wang, Y Chahine, A Tillett, AY Huang, S Robert, B Chhouk, E Kiziltug, C Nelson-Williams, E Stronge, HW Phillips, T Adikari, Z Ye, T Witkowski, D Lai, J Lokan, E Yang, EL Heinzen, E Damisah, H Moradi Chameh, R Coras, B Mathon, V Navarro, F Bielle, S Alexandrescu, A Huttner, I Scheffer, S Berkovic, M Hildebrand, A Poduri, N DeLanerolle, D Spencer, T Valiante, I Blümcke, K Kahle, EA Lee, C Walsh
Mesial temporal lobe epilepsy (MTLE), characterized by seizures arising from the hippocampus, is the most common focal epilepsy subtype in adults with no clear contribution from genetic factors. To evaluate the role of post-zygotic (i.e., somatic) genetic variants in drug-resistant MTLE, we first performed high-coverage whole exome sequencing of hippocampus-derived DNA from 105 surgically-treated MTLE patients and 30 neurotypical individuals. We identified 10 pathogenic somatic variants in MTLE patients all predicted to constitutively activate Ras-MAPK signaling. To assess the burden of low-abundance Ras-MAPK variants in MTLE, we performed duplex gene panel sequencing (depth >1000X) on DNA derived from the hippocampus of 218 surgically-treated MTLE patients and 56 neurotypical individuals. This approach yielded 98 activating somatic Ras-MAPK variants in 81 patients with MTLE (37% of total tested) and no neurotypical controls, overall supporting a significant association (p<1e-5) and a likely causal role for these variants in MTLE pathogenesis. Most variants (n=92, 93%) had cell fractions less than 2%, suggesting a late gestational or early postnatal origin, which may explain the onset of MTLE in adolescence or adulthood. In summary, low-abundance hippocampal somatic variants activating Ras-MAPK signaling may cause MTLE in a significant subset of patients with sporadic, drug-resistant disease.
Epilepsy is a debilitating, chronic neurologic condition, characterized by unprovoked seizures. The most common form of focal epilepsy, mesial temporal lobe epilepsy (MTLE), is described by seizures arising from an important brain structure called the hippocampus and may be drug-resistant in roughly one-third of patients. MTLE is typically not caused by inherited genetic mutations, but somatic mutations that are acquired during brain development may have a role in this disease. To identify somatic mutations that may be associated with MTLE, we extracted DNA from the surgically-removed hippocampus in 218 MTLE patients and 56 deceased donors without neurological diseases. We then sequenced the DNA using a targeted approach that only focused on the protein-coding regions of the human genome. Using this strategy, we identified genetic mutations restricted to the hippocampus in 37% of MTLE patients, specifically in a subset of genes in the Ras-MAPK cell signaling pathway that also play a key role in cancer. Most mutations (93%) were present in less than 2% of cells, suggesting they may have arisen during late fetal development or soon after birth. In summary, low-abundance hippocampal somatic mutations in Ras-MAPK genes may cause MTLE in a significant subset of patients with sporadic, drug-resistant disease.