Abstracts

The Genomic Landscape Across More Than 1000 Surgically Accessible Epileptogenic Human Brain Lesions

Abstract number : 3.112
Submission category : 2. Translational Research / 2C. Biomarkers
Year : 2022
Submission ID : 2204668
Source : www.aesnet.org
Presentation date : 12/5/2022 12:00:00 PM
Published date : Nov 22, 2022, 05:26 AM

Authors :
Costin Leu, PhD – Cleveland Clinic; Javier López-Rivera, PhD – Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, US; Marie Macnee, PhD – Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany; Jean Khoury, MD – Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, US; Lucas Hoffmann, MD – Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany; Roland Coras, MD – Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany; Katja Kobow, PhD – Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany; Nisha Bhattarai, PhD – Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, US; Eduardo Pérez-Palma, PhD – Universidad del Desarrollo, Centro de Genética y Genómica, Facultad de Medicina Clínica Alemana. Santiago 7610658, Chile; Hajo Hamer, MD – Epilepsy Center, University Hospital Erlangen, Erlangen, Germany; Sebastian Brandner, MD – Department of Neurosurgery, University Hospital Erlangen, Erlangen, Germany; Karl Rössler, MD – Department of Neurosurgery, Medical University Vienna, Vienna, Austria; Christian Bien, MD – Department of Epileptology (Krankenhaus Mara), Medical School, Bielefeld University, Bielefeld, Germany; Thilo Kalbhenn, MD – Department of Neurosurgery - Epilepsy surgery, Evangelisches Klinikum Bethel, Universitätsklinikum OWL, Bielefeld University, Bielefeld, Germany; Tom Pieper, MS – Center for Pediatric Neurology, Neurorehabilitation, and Epileptology, Schoen-Clinic, Vogtareuth, Germany; Till Hartlieb, MD – Center for Pediatric Neurology, Neurorehabilitation, and Epileptology, Schoen-Clinic, Vogtareuth, Germany; Elizabeth Butler, PA – Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, US; Giulio Genovese, PhD – Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T, Cambridge, MA 02142, US; Kerstin Becker, PhD – Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany; Janine Altmüller, PhD – Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany; Lisa-Marie Niestroj, PhD – Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany; Lisa Ferguson, MA – Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, US; Robyn Busch, PhD – Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, US; Peter Nürnberg, PhD – Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany; Imad Najm, MD – Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, US; Ingmar Blümcke, PhD – Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany; Dennis Lal, PhD – Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, US

This abstract has been invited to present during the Basic Science Poster Highlights poster session

Rationale: Understanding the exact molecular mechanisms involved in the etiology of epileptogenic pathologies with or without tumor activity is essential for improving the treatment of drug-resistant focal epilepsy.

Methods: At the time of the conference, we will present a joint/meta-analysis of the enrichment of somatic genetic variants in epileptogenic brain lesions that were deep sequenced to discover novel lesion-gene associations and explore the genotype-phenotype association of genetically defined lesion subtypes. In preliminary analyses, we characterized the landscape of somatic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing ( >350×) and whole-genome genotyping.

Results: Across the exome, we observed a larger number of somatic single-nucleotide variants (SNV) in low-grade epilepsy-associated tumors (LEAT) than in brain tissue from malformations of cortical development (MCD) or hippocampal sclerosis (HS). Tumor tissues also had the largest number of likely pathogenic variant carrying cells. LEAT had the highest proportion of samples with one or more somatic copy number variants (CNV; 24.7%), followed by MCD (5.4%) and HS (4.1%). Recurring somatic whole chromosome duplications affecting chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among LEAT. For germline variant-associated MCD genes such as TSC2, DEPDC5, and PTEN, germline SNV were frequently identified within large loss of heterozygosity regions, supporting the recently proposed "second hit" disease mechanism in these genes. We detect somatic variants in twelve established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the etiology of LEAT (e.g., BRAF) and MCD (e.g., SLC35A2 and MTOR). We also identified novel significant associations: PTPN11 with LEAT and NRAS Q61 mutated protein with a complex MCD characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We observed a large recurrent 1q21-q44 duplication affecting AKT3 as associated with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion.

Conclusions: In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions and informs the design of gene panels for clinical diagnostic screening. Genotype-phenotype analysis that informs care will emerge with increasing numbers of genetically delineated lesion subtypes.

Funding: IB and PN received research funding from the German Research Council (DFG, grant agreement numbers BL 421/4-1 and NU 50/13-1). Sequencing was facilitated by the DFG-funded West German Genome Center (WGGC).
Translational Research