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

Autor: Boßelmann CM; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA., Leu C; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.; Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London, UK.; Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.; Center for Neurogenetics, The University of Texas Health Science Center at Houston, Houston, TX, USA., Brünger T; Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.; Center for Neurogenetics, The University of Texas Health Science Center at Houston, Houston, TX, USA.; Cologne Center for Genomics (CCG), University of Cologne, Cologne, DE, Germany., Hoffmann L; Department of Neuropathology, Partner of the European Reference Network (ERN) EpiCARE, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Baldassari S; Institut du Cerveau-Paris Brain Institute-ICM, Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, F-75013, Paris, France., Chipaux M; Department of Pediatric Neurosurgery, Rothschild Foundation Hospital, 75019, Paris, France., Coras R; Department of Neuropathology, Partner of the European Reference Network (ERN) EpiCARE, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Kobow K; Department of Neuropathology, Partner of the European Reference Network (ERN) EpiCARE, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Hamer H; Epilepsy Center, EpiCARE Partner, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Delev D; Department of Neurosurgery, EpiCARE Partner, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Rössler K; Department of Neurosurgery, EpiCARE Partner, Medical University of Vienna, Vienna General Hospital, Vienna, Austria., Bien CG; Department of Epileptology, Krankenhaus Mara, Bethel Epilepsy Center, Medical School OWL, Bielefeld University, Bielefeld, Germany., Kalbhenn T; Department of Epileptology, Krankenhaus Mara, Bethel Epilepsy Center, Medical School OWL, Bielefeld University, Bielefeld, Germany.; Department of Neurosurgery (Evangelisches Klinikum Bethel), Medical School, Bielefeld University, Bielefeld, Germany., Pieper T; Center for Pediatric Neurology, Neurorehabilitation, and Epileptology, Schoen-Clinic, Vogtareuth, Rosenheim, Germany., Hartlieb T; Center for Pediatric Neurology, Neurorehabilitation, and Epileptology, Schoen-Clinic, Vogtareuth, Rosenheim, Germany.; Paracelsus Medical University, Salzburg, Austria., Becker K; Cologne Center for Genomics (CCG), University of Cologne, Cologne, DE, Germany., Ferguson L; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA., Busch RM; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA., Baulac S; Institut du Cerveau-Paris Brain Institute-ICM, Sorbonne Université, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, F-75013, Paris, France., Nürnberg P; Cologne Center for Genomics (CCG), University of Cologne, Cologne, DE, Germany.; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany., Najm I; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA., Blümcke I; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.; Department of Neuropathology, Partner of the European Reference Network (ERN) EpiCARE, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Lal D; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. dennis.lal@uth.tmc.edu.; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. dennis.lal@uth.tmc.edu.; Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA. dennis.lal@uth.tmc.edu.; Center for Neurogenetics, The University of Texas Health Science Center at Houston, Houston, TX, USA. dennis.lal@uth.tmc.edu.; Cologne Center for Genomics (CCG), University of Cologne, Cologne, DE, Germany. dennis.lal@uth.tmc.edu.; Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T, Cambridge, MA, USA. dennis.lal@uth.tmc.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Nov 30; Vol. 15 (1), pp. 10429. Date of Electronic Publication: 2024 Nov 30.
DOI: 10.1038/s41467-024-54911-w
Abstrakt: 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.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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