{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T01:44:25Z","timestamp":1791510265096,"version":"4.3.4"},"reference-count":81,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T00:00:00Z","timestamp":1650412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"crossref","award":["R01-NS094596"],"award-info":[{"award-number":["R01-NS094596"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"crossref","award":["R01-NS114122"],"award-info":[{"award-number":["R01-NS114122"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"crossref","award":["R01-NS089552"],"award-info":[{"award-number":["R01-NS089552"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Institute for Clinical and Translational Research"},{"DOI":"10.13039\/100006474","name":"Columbia University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006474","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006823","name":"Boston Children\u2019s Hospital","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006823","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Javits Award","award":["NINDS R37-NS125632"],"award-info":[{"award-number":["NINDS R37-NS125632"]}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n\u2009=\u200916), focal cortical dysplasia type I and related phenotypes (n\u2009=\u200948), focal cortical dysplasia type II (n\u2009=\u200944), or focal cortical dysplasia type III (n\u2009=\u200915). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P\u2009=\u20090.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.<\/jats:p>","DOI":"10.1093\/brain\/awac117","type":"journal-article","created":{"date-parts":[[2022,3,24]],"date-time":"2022-03-24T17:40:42Z","timestamp":1648143642000},"page":"2704-2720","source":"Crossref","is-referenced-by-count":87,"title":["Somatic variants in diverse genes leads to a spectrum of focal cortical malformations"],"prefix":"10.1093","volume":"145","author":[{"given":"Dulcie","family":"Lai","sequence":"first","affiliation":[{"name":"Division of Pharmacology and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meethila","family":"Gade","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9912-4163","authenticated-orcid":false,"given":"Edward","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Radiology, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Yong","family":"Koh","sequence":"additional","affiliation":[{"name":"Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children\u2019s Hospital , Boston, MA 02115 , USA"},{"name":"Epilepsy Genetics Program, Department of Neurology, Boston Children\u2019s Hospital and Harvard Medical School , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole M","family":"Walley","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne F","family":"Buckley","sequence":"additional","affiliation":[{"name":"Department of Pathology, Duke University Medical Center , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tristan T","family":"Sands","sequence":"additional","affiliation":[{"name":"Institute for Genomic Medicine, Columbia University Medical Center , New York, NY 10032 , USA"},{"name":"Department of Neurology, Columbia University Medical Center , New York, NY 10032 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cigdem I","family":"Akman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Columbia University Medical Center , New York, NY 10032 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0363-8715","authenticated-orcid":false,"given":"Mohamad A","family":"Mikati","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Duke University , Durham, NC 27708 , USA"},{"name":"Division of Pediatric Neurology, Duke University Medical Center , Durham, NC 27710 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9695-3564","authenticated-orcid":false,"given":"Guy M","family":"McKhann","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Columbia University, New York Presbyterian Hospital , New York, NY 10032 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E","family":"Goldman","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Columbia University , New York, NY 10032 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Canoll","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology, Columbia University , New York, NY 10032 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allyson L","family":"Alexander","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Colorado School of Medicine , Aurora, CO 80045 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen L","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Neurology, University of Colorado School of Medicine , Aurora, CO 80045 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gretchen K","family":"Von Allmen","sequence":"additional","affiliation":[{"name":"Department of Neurology, McGovern Medical School , Houston, TX 77030 , USA"},{"name":"Division of Child Neurology, Department of Pediatrics, McGovern Medical School , Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Rodziyevska","sequence":"additional","affiliation":[{"name":"Division of Child Neurology, Department of Pediatrics, McGovern Medical School , Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenakshi B","family":"Bhattacharjee","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, McGovern Medical School , Houston, TX 77030 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hart G W","family":"Lidov","sequence":"additional","affiliation":[{"name":"Department of Pathology, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannes","family":"Vogel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stanford University, School of Medicine , Stanford, CA 94305 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2651-4603","authenticated-orcid":false,"given":"Gerald A","family":"Grant","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Lucile Packard Children\u2019s Hospital at Stanford, School of Medicine , Stanford, CA 94305 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda E","family":"Porter","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurological Sciences, Stanford University, School of Medicine, Stanford , CA 94305 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annapurna H","family":"Poduri","sequence":"additional","affiliation":[{"name":"Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children\u2019s Hospital , Boston, MA 02115 , USA"},{"name":"Epilepsy Genetics Program, Department of Neurology, Boston Children\u2019s Hospital and Harvard Medical School , Boston, MA 02115 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter B","family":"Crino","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Maryland School of Medicine , Baltimore, MD 21201 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7268-8559","authenticated-orcid":false,"given":"Erin L","family":"Heinzen","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599 , USA"},{"name":"Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,20]]},"reference":[{"issue":"2","key":"2022102718183107700_awac117-B1","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1055\/s-2007-973750","article-title":"A classification scheme for malformations of cortical development","volume":"27","author":"Barkovich","year":"1996","journal-title":"Neuropediatrics"},{"issue":"Pt 5","key":"2022102718183107700_awac117-B2","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1093\/brain\/aws019","article-title":"A developmental and genetic classification for malformations of cortical development: Update 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