Faculty, Staff and Student Publications

Language

English

Publication Date

11-30-2024

Journal

Nature Communications

DOI

10.1038/s41467-024-54911-w

PMID

39616148

PMCID

PMC11608322

PubMedCentral® Posted Date

11-30-2024

PubMedCentral® Full Text Version

Post-print

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enrichment mega-analysis in brain tissue from 1386 individuals who underwent epilepsy surgery, including 599 previously unpublished individuals with ultra-deep ( 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.

Keywords

Humans, ErbB Receptors, Dyrk Kinases, Protein-Tyrosine Kinases, Protein Serine-Threonine Kinases, Male, Female, Brain, Adult, Adolescent, Epilepsy, Child, Young Adult, Brain Neoplasms, Epilepsy, Disease genetics

Published Open-Access

yes

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