{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T01:44:29Z","timestamp":1791510269239,"version":"4.3.4"},"reference-count":48,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T00:00:00Z","timestamp":1655942400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["K01 HG011062"],"award-info":[{"award-number":["K01 HG011062"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Epilepsia"],"published-print":{"date-parts":[[2022,8]]},"abstract":"Abstract<\/jats:title>\n \n Objective<\/jats:title>\n Epilepsy\u2010associated developmental lesions, including malformations of cortical development and low\u2010grade developmental tumors, represent a major cause of drug\u2010resistant seizures requiring surgical intervention in children. Brain\u2010restricted somatic mosaicism has been implicated in the genetic etiology of these lesions; however, many contributory genes remain unidentified.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We enrolled 50 children who were undergoing epilepsy surgery into a translational research study. Resected tissue was divided for clinical neuropathologic evaluation and genomic analysis. We performed exome and RNA sequencing to identify somatic variation and we confirmed our findings using high\u2010depth targeted DNA sequencing.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n We uncovered candidate disease\u2010causing somatic variation affecting 28 patients (56%), as well as candidate germline variants affecting 4 patients (8%). In agreement with previous studies, we identified somatic variation affecting solute carrier family 35 member A2 (\n SLC35A2<\/jats:italic>\n ) and mechanistic target of rapamycin kinase (\n MTOR<\/jats:italic>\n ) pathway genes in patients with focal cortical dysplasia. Somatic gains of chromosome 1q were detected in 30% (3 of 10) of patients with Type I focal cortical dysplasia (FCD)s. Somatic variation in mitogen\u2010activated protein kinase (\n MAPK)<\/jats:italic>\n pathway genes (i.e., fibroblast growth factor receptor 1 [\n FGFR1<\/jats:italic>\n ],\n FGFR2<\/jats:italic>\n , B\u2010raf proto\u2010oncogene, serine\/threonine kinase [\n BRAF<\/jats:italic>\n ], and KRAS proto\u2010oncogene, GTPase [\n KRAS<\/jats:italic>\n ]) was associated with low\u2010grade epilepsy\u2010associated developmental tumors. RNA sequencing enabled the detection of somatic structural variation that would have otherwise been missed, and which accounted for more than one\u2010half of epilepsy\u2010associated tumor diagnoses. Sampling across multiple anatomic regions revealed that somatic variant allele fractions vary widely within epileptogenic tissue. Finally, we identified putative disease\u2010causing variants in genes not yet associated with focal cortical dysplasia.\n <\/jats:p>\n <\/jats:sec>\n \n Significance<\/jats:title>\n These results further elucidate the genetic basis of structural brain abnormalities leading to focal epilepsy in children and point to new candidate disease genes.<\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/epi.17323","type":"journal-article","created":{"date-parts":[[2022,6,10]],"date-time":"2022-06-10T11:27:33Z","timestamp":1654860453000},"page":"1981-1997","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Detection of brain somatic variation in epilepsy\u2010associated developmental lesions"],"prefix":"10.1111","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1051-9100","authenticated-orcid":false,"given":"Tracy A.","family":"Bedrosian","sequence":"first","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"},{"name":"Department of Pediatrics The Ohio State University College of Medicine Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine E.","family":"Miller","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia E.","family":"Grischow","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"Schieffer","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"},{"name":"Department of Pathology The Ohio State University College of Medicine Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"LaHaye","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyojung","family":"Yoon","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony R.","family":"Miller","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Navarro","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse","family":"Westfall","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Leraas","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Choi","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Williamson","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Fitch","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Kelly","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"White","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"},{"name":"Department of Pediatrics The Ohio State University College of Medicine Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy","family":"Lee","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"},{"name":"Department of Pediatrics The Ohio State University College of Medicine Columbus Ohio USA"},{"name":"Department of Pathology The Ohio State University College of Medicine Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"McGrath","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine E.","family":"Cottrell","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Magrini","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"},{"name":"Department of Pediatrics The Ohio State University College of Medicine Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Leonard","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Nationwide Children's Hospital Columbus Ohio USA"},{"name":"Department of Neurosurgery The Ohio State University College of Medicine Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Pindrik","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Nationwide Children's Hospital Columbus Ohio USA"},{"name":"Department of Neurosurgery The Ohio State University College of Medicine Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ammar","family":"Shaikhouni","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Nationwide Children's Hospital Columbus Ohio USA"},{"name":"Department of Neurosurgery The Ohio State University College of Medicine Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R.","family":"Bou\u00e9","sequence":"additional","affiliation":[{"name":"Department of Pathology The Ohio State University College of Medicine Columbus Ohio USA"},{"name":"Department of Pathology and Laboratory Medicine Nationwide Children's Hospital Columbus Ohio USA"},{"name":"Division of Anatomy, Department of Biomedical Education & Anatomy The Ohio State University College of Medicine Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana L.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R.","family":"Pierson","sequence":"additional","affiliation":[{"name":"Department of Pathology The Ohio State University College of Medicine Columbus Ohio USA"},{"name":"Department of Pathology and Laboratory Medicine Nationwide Children's Hospital Columbus Ohio USA"},{"name":"Division of Anatomy, Department of Biomedical Education & Anatomy The Ohio State University College of Medicine Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard K.","family":"Wilson","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"},{"name":"Department of Pediatrics The Ohio State University College of Medicine Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam P.","family":"Ostendorf","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The Ohio State University College of Medicine Columbus Ohio USA"},{"name":"Division of Pediatric Neurology Nationwide Children's Hospital Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine R.","family":"Mardis","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"},{"name":"Department of Pediatrics The Ohio State University College of Medicine Columbus Ohio USA"},{"name":"Department of Neurosurgery The Ohio State University College of Medicine Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel C.","family":"Koboldt","sequence":"additional","affiliation":[{"name":"The Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research Institute at Nationwide Children's Hospital Columbus Ohio USA"},{"name":"Department of Pediatrics The Ohio State University College of Medicine Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,6,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2017.08.010"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2010.02777.x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2016.173"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-020-00904-x"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-019-02061-5"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25243"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000294"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3824"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0172-x"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-016-1549-x"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-016-1646-x"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0577-x"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx699"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.09.004"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.806"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.4161\/fly.19695"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2514"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.129684.111"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000460"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab173"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-021-08094-z"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-02043-x"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noab106"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-020-01085-3"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02228-5"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38108"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty897"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007774"},{"issue":"2","key":"e_1_2_10_32_1","first-page":"3170","article-title":"Loss of Shp2 within radial glia is associated with cerebral cortical dysplasia, glial defects of cerebellum and impaired sensorymotor development in newborn mice","volume":"17","author":"Zhu Y","year":"2018","journal-title":"Mol Med Rep"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2866-14.2015"},{"issue":"3","key":"e_1_2_10_34_1","first-page":"2226","article-title":"eEF2K\/eEF2 pathway controls the excitation\/inhibition balance and susceptibility to epileptic seizures","volume":"27","author":"Heise C","year":"2017","journal-title":"Cereb Cortex"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2002.6799"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2011.03.008"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1129947"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2599"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.50815"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI99384"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000006567"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24547"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2020.05.001"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2015.08.005"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12476"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.03.010"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.05.031"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddab366"}],"container-title":["Epilepsia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.17323","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/epi.17323","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/epi.17323","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T12:42:15Z","timestamp":1692276135000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/epi.17323"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,23]]},"references-count":48,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2022,8]]}},"alternative-id":["10.1111\/epi.17323"],"URL":"https:\/\/doi.org\/10.1111\/epi.17323","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.12.06.21267079","asserted-by":"object"}]},"ISSN":["0013-9580","1528-1167"],"issn-type":[{"value":"0013-9580","type":"print"},{"value":"1528-1167","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,23]]},"assertion":[{"value":"2022-02-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}