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

Christian M. Boßelmann, Costin Leu, Tobias Brünger, Lucas Hoffmann, Sara Baldassari, Mathilde Chipaux, Roland Coras, Katja Kobow, Hajo Hamer, Daniel Delev, Karl Rössler, Christian G. Bien, Thilo Kalbhenn, Tom Pieper, Till Hartlieb, Kerstin Becker, Lisa Ferguson, Robyn M. Busch, Stéphanie Baulac, Peter Nürnberg, Imad Najm, Ingmar Blümcke and Dennis Lal ()
Additional contact information
Christian M. Boßelmann: Cleveland Clinic
Tobias Brünger: The University of Texas Health Science Center at Houston
Lucas Hoffmann: Friedrich-Alexander-Universität Erlangen-Nürnberg
Sara Baldassari: Hôpital de la Pitié Salpêtrière
Mathilde Chipaux: Rothschild Foundation Hospital
Roland Coras: Friedrich-Alexander-Universität Erlangen-Nürnberg
Katja Kobow: Friedrich-Alexander-Universität Erlangen-Nürnberg
Hajo Hamer: Friedrich-Alexander-Universität Erlangen-Nürnberg
Daniel Delev: Friedrich-Alexander-Universität Erlangen-Nürnberg
Karl Rössler: Vienna General Hospital
Christian G. Bien: Bielefeld University
Thilo Kalbhenn: Bielefeld University
Tom Pieper: Vogtareuth
Till Hartlieb: Vogtareuth
Kerstin Becker: University of Cologne
Lisa Ferguson: Cleveland Clinic
Robyn M. Busch: Cleveland Clinic
Stéphanie Baulac: Hôpital de la Pitié Salpêtrière
Peter Nürnberg: University of Cologne
Imad Najm: Cleveland Clinic
Ingmar Blümcke: Cleveland Clinic
Dennis Lal: Cleveland Clinic

Nature Communications, 2024, vol. 15, issue 1, 1-10

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mega-analysis in brain tissue from 1386 individuals who underwent epilepsy surgery, including 599 previously unpublished individuals with ultra-deep ( 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

Date: 2024
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DOI: 10.1038/s41467-024-54911-w

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