{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T01:44:22Z","timestamp":1791510262622,"version":"4.3.4"},"reference-count":96,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T00:00:00Z","timestamp":1665619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"German Research Council","award":["BL 421\/4-1"],"award-info":[{"award-number":["BL 421\/4-1"]}]},{"name":"German Research Council","award":["NU 50\/13-1"],"award-info":[{"award-number":["NU 50\/13-1"]}]},{"name":"West German Genome Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Understanding the exact molecular mechanisms involved in the aetiology of epileptogenic pathologies with or without tumour activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (&amp;gt;350\u00d7) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants in low-grade epilepsy-associated tumours (7.92 \u00b1 5.65 single-nucleotide variants) than in brain tissue from malformations of cortical development (6.11 \u00b1 4 single-nucleotide variants) or hippocampal sclerosis (5.1 \u00b1 3.04 single-nucleotide variants). Tumour tissues also had the largest number of likely pathogenic variant carrying cells. low-grade epilepsy-associated tumours had the highest proportion of samples with one or more somatic copy-number variants (24.7%), followed by malformations of cortical development (5.4%) and hippocampal sclerosis (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among low-grade epilepsy-associated tumours. For germline variant-associated malformations of cortical development genes such as TSC2, DEPDC5 and PTEN, germline single-nucleotide variants were frequently identified within large loss of heterozygosity regions, supporting the recently proposed \u2018second hit\u2019 disease mechanism in these genes. We detect somatic variants in 12 established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the aetiology of low-grade epilepsy-associated tumours (e.g. BRAF) and malformations of cortical development (e.g. SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with low-grade epilepsy-associated tumours and NRAS Q61 mutated protein with a complex malformation of cortical development 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 identify large recurrent 1q21\u2013q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical-genetic analyses showed that the numbers of somatic single-nucleotide variant across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with low-grade epilepsy-associated tumours. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening and guides future directions for clinical implementation of epilepsy surgery genetics.<\/jats:p>","DOI":"10.1093\/brain\/awac376","type":"journal-article","created":{"date-parts":[[2022,10,13]],"date-time":"2022-10-13T03:16:51Z","timestamp":1665631011000},"page":"1342-1356","source":"Crossref","is-referenced-by-count":69,"title":["The genomic landscape across 474 surgically accessible epileptogenic human brain lesions"],"prefix":"10.1093","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3563-9977","authenticated-orcid":false,"given":"Javier A","family":"L\u00f3pez-Rivera","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University , Cleveland, OH 44195 , USA"},{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195 , USA"},{"name":"Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic , Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Costin","family":"Leu","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195 , USA"},{"name":"Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic , Cleveland, OH 44195 , USA"},{"name":"Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T. , Cambridge, MA 02142 , USA"},{"name":"Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London , London WC1N 3BG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Macnee","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne , 50931 Cologne , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Khoury","sequence":"additional","affiliation":[{"name":"Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic , Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, University Hospital Erlangen , Erlangen 91054 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Coras","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, University Hospital Erlangen , Erlangen 91054 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0074-2480","authenticated-orcid":false,"given":"Katja","family":"Kobow","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, University Hospital Erlangen , Erlangen 91054 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisha","family":"Bhattarai","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195 , USA"},{"name":"Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic , Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0546-5141","authenticated-orcid":false,"given":"Eduardo","family":"P\u00e9rez-Palma","sequence":"additional","affiliation":[{"name":"Universidad del Desarrollo, Centro de Gen\u00e9tica y Gen\u00f3mica, Facultad de Medicina Cl\u00ednica Alemana , Santiago 12438 , Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajo","family":"Hamer","sequence":"additional","affiliation":[{"name":"Epilepsy Center, University Hospital Erlangen , 91054 Erlangen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Brandner","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University Hospital Erlangen , Erlangen 91054 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"R\u00f6ssler","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Medical University Vienna , 1090 Vienna , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2225-8654","authenticated-orcid":false,"given":"Christian G","family":"Bien","sequence":"additional","affiliation":[{"name":"Department of Epileptology (Krankenhaus Mara), Medical School, Bielefeld University , 33617 Bielefeld , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thilo","family":"Kalbhenn","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery - Epilepsy surgery, Evangelisches Klinikum Bethel, Universit\u00e4tsklinikum OWL, Bielefeld University , 33617 Bielefeld , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Pieper","sequence":"additional","affiliation":[{"name":"Center for Pediatric Neurology, Neurorehabilitation and Epileptology, Schoen-Clinic , 83569 Vogtareuth , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Till","family":"Hartlieb","sequence":"additional","affiliation":[{"name":"Center for Pediatric Neurology, Neurorehabilitation and Epileptology, Schoen-Clinic , 83569 Vogtareuth , Germany"},{"name":"Research Institute \u2018Rehabilitation, Transition, Palliation\u2019, PMU Salzburg , 5020 Salzburg , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Butler","sequence":"additional","affiliation":[{"name":"Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic , Cleveland, OH 44195 , 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Medicine in the Helmholtz Association (MDC) , 13125 Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa-Marie","family":"Niestroj","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne , 50931 Cologne , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic , Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5442-4912","authenticated-orcid":false,"given":"Robyn M","family":"Busch","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic , Cleveland, OH 44195 , USA"},{"name":"Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic , Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"N\u00fcrnberg","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne , 50931 Cologne , Germany"},{"name":"Center for Molecular Medicine Cologne (CMMC), University of Cologne, Faculty of Medicine and University Hospital Cologne , 50931 Cologne , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imad","family":"Najm","sequence":"additional","affiliation":[{"name":"Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic , Cleveland, OH 44195 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8676-0788","authenticated-orcid":false,"given":"Ingmar","family":"Bl\u00fcmcke","sequence":"additional","affiliation":[{"name":"Charles Shor Epilepsy Center, Neurological Institute, Cleveland Clinic , Cleveland, OH 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