Activating Ras-MAPK pathway variants drive hippocampal clonal competition in human epilepsy

Abstract Mesial ( a.k.a., medial) temporal lobe epilepsy (MTLE) is the most common focal epilepsy 1,2 and, in drug-resistant cases, is treated by surgical removal of the anterior temporal lobe, which often shows neuronal loss and gliosis consistent with hippocampal sclerosis (HS) 2 . MTLE with HS has minimal contribution from germline genetic variation 3 , and is associated with prior precipitating insults such as prolonged childhood seizures and head trauma 4–6 . Somatic variants in Ras-MAPK pathway genes were recently reported in a few MTLE surgical specimens 7,8 , but their prevalence, clinical relevance, and underlying biological mechanisms remain unknown. Targeted duplex sequencing of hippocampal DNA from 462 surgical resections revealed significant enrichment of deleterious somatic variants in MTLE versus controls, with >40% of MTLE specimens harboring activating Ras-MAPK variants in PTPN11 , NF1 , BRAF , KRAS , and twelve genes not previously associated with focal epilepsy. Eight Ras-MAPK genes showed positive clonal selection in MTLE. Increased somatic variant burden predicted worse surgical outcome. Somatic Ras-MAPK variants at ultra-low (