Analysis of 1386 epileptogenic brain lesions reveals association with DYRK1A and EGFR

Nat Commun. 2024 Nov 30;15(1):10429. doi: 10.1038/s41467-024-54911-w.

Abstract

Lesional focal epilepsy (LFE) is a common and severe seizure disorder caused by epileptogenic lesions, including malformations of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT). Understanding the genetic etiology of these lesions can inform medical and surgical treatment. We conducted a somatic variant enrichment mega-analysis in brain tissue from 1386 individuals who underwent epilepsy surgery, including 599 previously unpublished individuals with ultra-deep ( > 1600x) targeted panel sequencing. Here we confirm four known associations (BRAF, SLC35A2, MTOR, PTPN11), support eight associations without prior statistical support (FGFR1, PIK3CA, AKT3, NF1, PTEN, RHEB, KRAS, NRAS), and identify novel associations for two genes, DYRK1A and EGFR. Both novel genes show specific histopathological phenotypes, interact with LFE genes and pathways, and may represent promising candidates as biomarkers and potentially druggable targets.

MeSH terms

  • Adolescent
  • Adult
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Brain / pathology
  • Brain Neoplasms / complications
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Child
  • Dyrk Kinases*
  • Epilepsy / genetics
  • Epilepsy / pathology
  • ErbB Receptors* / genetics
  • ErbB Receptors* / metabolism
  • Female
  • Humans
  • Male
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism
  • Protein-Tyrosine Kinases* / genetics
  • Protein-Tyrosine Kinases* / metabolism
  • Young Adult

Substances

  • ErbB Receptors
  • Dyrk Kinases
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • EGFR protein, human