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 <i>PTPN11</i>, <i>NF1</i>, <i>BRAF</i>, <i>KRAS</i>, and twelve genes not previously associated with focal epilepsy. This evidence concerns the gene PTPN11 and focal epilepsy.