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MTLE with HS has minimal contribution from germline genetic variation\n                  <jats:sup>3<\/jats:sup>\n                  , and is associated with prior precipitating insults such as prolonged childhood seizures and head trauma\n                  <jats:sup>4\u20136<\/jats:sup>\n                  . Somatic variants in Ras-MAPK pathway genes were recently reported in a few MTLE surgical specimens\n                  <jats:sup>7,8<\/jats:sup>\n                  , 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 &gt;40% of MTLE specimens harboring activating Ras-MAPK variants in\n                  <jats:italic>PTPN11<\/jats:italic>\n                  ,\n                  <jats:italic>NF1<\/jats:italic>\n                  ,\n                  <jats:italic>BRAF<\/jats:italic>\n                  ,\n                  <jats:italic>KRAS<\/jats:italic>\n                  , 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 (&lt;0.5%) variant allele fractions were associated with older seizure onset and HS pathology, supporting a late prenatal or postnatal origin. Ras-MAPK variants in MTLE were enriched in cells derived from hippocampal progenitors\u2014neurons, astrocytes, oligodendrocytes\u2014in line with the known neuronal hyperexcitability and seizures induced by Ras-MAPK overactivation\n                  <jats:sup>9,10<\/jats:sup>\n                  ; in contrast, Alzheimer disease hippocampi exhibited microglial enrichment of Ras-MAPK variants, consistent with prior reports\n                  <jats:sup>11<\/jats:sup>\n                  . Single-nucleus RNA sequencing showed increased expression of Ras-MAPK genes in neurons and upregulation of pathways mediating neurogenesis and neural development in MTLE. Functional validation of novel, recurrent\n                  <jats:italic>PTPN11<\/jats:italic>\n                  variants confirmed gain-of-function, while cellular modeling in induced pluripotent stem cells demonstrated proliferative\/survival advantages for mutant cells in mosaic culture. Overall, our data suggest that somatic Ras-MAPK variants and acquired risk factors may converge on clonal competition in the hippocampus to modulate epilepsy risk.\n                <\/jats:p>","DOI":"10.64898\/2026.01.26.701822","type":"posted-content","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T20:30:16Z","timestamp":1769545816000},"source":"Crossref","is-referenced-by-count":8,"title":["Activating Ras-MAPK pathway variants drive hippocampal clonal competition in human epilepsy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3348-557X","authenticated-orcid":false,"given":"Sattar","family":"Khoshkhoo","sequence":"first","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Harvard Medical School, Boston, MA, USA"},{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, MA, USA"},{"name":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyun","family":"Bae","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, MA, USA"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilan","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, MA, USA"},{"name":"Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashton","family":"Tillett","sequence":"additional","affiliation":[{"name":"Department of Neurology, Mass General Brigham, Harvard Medical School, Boston, MA, USA"},{"name":"Division of Genetics and Genomics, Manton Center for 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