{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T14:51:12Z","timestamp":1791471072021,"version":"4.3.4"},"reference-count":47,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["460333672"],"award-info":[{"award-number":["460333672"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["493665037"],"award-info":[{"award-number":["493665037"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Bl421\/4\u20101"],"award-info":[{"award-number":["Bl421\/4\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["NU 50\/13\u20101"],"award-info":[{"award-number":["NU 50\/13\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS117544"],"award-info":[{"award-number":["R01 NS117544"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Malformations of cortical development and low\u2010grade epilepsy\u2010associated tumors often cause drug\u2010resistant lesional focal epilepsy (LFE) amenable to surgical treatment. Genetic testing of resected brain tissue can provide diagnostic and mechanistic information and may eventually support personalized treatment approaches. However, systematic &gt;300\u00d7 whole genome sequencing (GS) of bulk epileptogenic lesions, particularly after nondiagnostic deep exome sequencing and array\u2010based genotyping, has not been evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here, we performed deep GS (&gt;300\u00d7 coverage) on 33 epileptogenic brain lesions from individuals with LFE, selected for lesions with a high prior probability of a genetic finding, all of whom had negative results for candidate germline or somatic variants in previous deep exome sequencing (ES; &gt;350\u00d7 coverage) and array\u2010based genotyping.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified candidate somatic variants in known LFE\u2010associated genes in seven of 33 participants (21%). Two participants had two candidate variants each. In total, three of 33 participants (9%) had variants that could only be detected by GS: two deletions in\n                      <jats:italic>TSC2<\/jats:italic>\n                      , two deletions in\n                      <jats:italic>NPRL3<\/jats:italic>\n                      , and an exonic inversion in\n                      <jats:italic>FGFR1<\/jats:italic>\n                      . Three individuals had germline polymorphisms that may represent modulators or risk factors. Exploratory mutational signature analysis revealed clocklike signatures and a correlation between mutational signatures, age at seizure onset, and histopathology, indicating an age\u2010related mechanism of mutation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>Deep GS establishes the feasibility of genome\u2010wide profiling at a depth relevant to low\u2010variant allelic frequency mosaicism and reveals candidate variants missed by ES, particularly complex structural variants. As sequencing costs decrease, GS may complement other technologies in somatic variant detection, enabling more widespread clinical implementation of tissue sequencing in epilepsy surgery. Further studies are needed to address the remaining conceptual and technological challenges in somatic variant detection.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi.70526","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T14:02:46Z","timestamp":1791468166000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deep whole genome sequencing of epileptogenic brain lesions"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1596-5599","authenticated-orcid":false,"given":"Christian M.","family":"Bo\u00dfelmann","sequence":"first","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic  Cleveland Ohio USA"},{"name":"Epilepsy Center Neurological Institute, Cleveland Clinic  Cleveland Ohio USA"},{"name":"Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, partner of the European Reference Network EpiCARE University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0598-3301","authenticated-orcid":false,"given":"Costin","family":"Leu","sequence":"additional","affiliation":[{"name":"Epilepsy Center Neurological Institute, Cleveland Clinic  Cleveland Ohio USA"},{"name":"Department of Neurology University of Texas Health Science Center at Houston  Houston Texas USA"},{"name":"Center for Neurogenetics University of Texas Health Science Center at Houston  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3801-1595","authenticated-orcid":false,"given":"Lucas","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Department of Neuropathology partner of the European Reference Network EpiCARE, Universit\u00e4tsklinikum Erlangen, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8617-0913","authenticated-orcid":false,"given":"Roland","family":"Coras","sequence":"additional","affiliation":[{"name":"Department of Neuropathology partner of the European Reference Network EpiCARE, Universit\u00e4tsklinikum Erlangen, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen 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 partner of the European Reference Network EpiCARE, Universit\u00e4tsklinikum Erlangen, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1709-8617","authenticated-orcid":false,"given":"Hajo","family":"Hamer","sequence":"additional","affiliation":[{"name":"Epilepsy Center, partner of the European Reference Network EpiCARE Universit\u00e4tsklinikum Erlangen, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9444-0178","authenticated-orcid":false,"given":"Daniel","family":"Delev","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, partner of the European Reference Network EpiCARE Universit\u00e4tsklinikum Erlangen, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"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, Bethel Epilepsy Center, Medical School OWL, Bielefeld University  Bielefeld Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6249-629X","authenticated-orcid":false,"given":"Thilo","family":"Kalbhenn","sequence":"additional","affiliation":[{"name":"Department of Epileptology Krankenhaus Mara, Bethel Epilepsy Center, Medical School OWL, Bielefeld University  Bielefeld Germany"},{"name":"Department of Neurosurgery (Evangelisches Klinikum Bethel), Medical School Bielefeld University  Bielefeld Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Pieper","sequence":"additional","affiliation":[{"name":"Center for Pediatric Neurology, Neurorehabilitation, and Epileptology Schoen\u2010Clinic  Rosenheim Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0854-5537","authenticated-orcid":false,"given":"Till","family":"Hartlieb","sequence":"additional","affiliation":[{"name":"Center for Pediatric Neurology, Neurorehabilitation, and Epileptology Schoen\u2010Clinic  Rosenheim Germany"},{"name":"Research Program for Rehabilitation, Transition, and Palliation Paracelsus Medical University  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7897-7181","authenticated-orcid":false,"given":"Kerstin","family":"Becker","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics, Medical Faculty University of Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3577-2257","authenticated-orcid":false,"given":"Lisa","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Epilepsy Center Neurological Institute, Cleveland Clinic  Cleveland Ohio 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 Ohio USA"},{"name":"Epilepsy Center Neurological Institute, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7228-428X","authenticated-orcid":false,"given":"Peter","family":"N\u00fcrnberg","sequence":"additional","affiliation":[{"name":"Cologne Center for Genomics, Medical Faculty University of Cologne  Cologne Germany"},{"name":"Center for Molecular Medicine Cologne University of Cologne, Faculty of Medicine and University Hospital Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5192-2089","authenticated-orcid":false,"given":"Imad","family":"Najm","sequence":"additional","affiliation":[{"name":"Epilepsy Center Neurological Institute, Cleveland Clinic  Cleveland Ohio 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":"Epilepsy Center Neurological Institute, Cleveland Clinic  Cleveland Ohio USA"},{"name":"Department of Neuropathology partner of the European Reference Network EpiCARE, Universit\u00e4tsklinikum Erlangen, Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5173-9636","authenticated-orcid":false,"given":"Dennis","family":"Lal","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic  Cleveland Ohio USA"},{"name":"Epilepsy Center Neurological Institute, Cleveland Clinic  Cleveland Ohio USA"},{"name":"Department of Neurology University of Texas Health Science Center at Houston  Houston Texas USA"},{"name":"Center for Neurogenetics University of Texas Health Science Center at Houston  Houston Texas USA"},{"name":"Cologne Center for Genomics, Medical Faculty University of Cologne  Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2017.3949"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6631a1"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(20)30220\u20109"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eplepsyres.2022.106951"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106208"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.16899"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311\u2010023\u201001395\u2010z"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010024\u201054911\u2010w"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010022\u201001276\u20109"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac376"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1418631112"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26609"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/nan.12462"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2024.3582"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2022.01.001"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2022.07.020"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010018\u20100257\u20103"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17323"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587\u2010022\u201001559\u2010w"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2022.100179"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giad081"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1015"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276\u2010019\u20100277\u20104"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg7492"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwz016"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201021790\u20104"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2011.12.021"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010021\u201003860\u2010z"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592\u2010024\u201002409\u20100"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007556\u20100"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010016\u20101549\u2010x"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1754"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.06.026"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac117"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431\u2010022\u201001213\u20108"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41525\u2010024\u201000396\u2010x"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201006485\u20107"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.inat.2022.101635"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2020.04.004"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2019.01.038"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20181426"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104079"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010018\u20100566\u20104"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3002678"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007753"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431\u2010024\u201001622\u2010x"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi.70526","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/epi.70526","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/epi.70526","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T14:02:48Z","timestamp":1791468168000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/epi.70526"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,8]]},"references-count":47,"alternative-id":["10.1002\/epi.70526"],"URL":"https:\/\/doi.org\/10.1002\/epi.70526","archive":["Portico"],"relation":{},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,8]]},"assertion":[{"value":"2026-08-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"epi.70526"}}