{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:57:43Z","timestamp":1789070263010,"version":"build-2803163510"},"reference-count":71,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,19]],"date-time":"2025-01-19T00:00:00Z","timestamp":1737244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"G\u00fcnter Endres Fond","award":["EXC-2049-390688087"],"award-info":[{"award-number":["EXC-2049-390688087"]}]},{"name":"Sonnenfeld-Stiftung","award":["EXC-2049-390688087"],"award-info":[{"award-number":["EXC-2049-390688087"]}]},{"name":"Federal Ministry of Education and Research (Bundesministerium f\u00fcr Bildung und Forschung, BMBF)","award":["EXC-2049-390688087"],"award-info":[{"award-number":["EXC-2049-390688087"]}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["EXC-2049-390688087"],"award-info":[{"award-number":["EXC-2049-390688087"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Epilepsy affects 50 million people worldwide and is drug-resistant in approximately one-third of cases. Even when a structural lesion is identified as the epileptogenic focus, understanding the underlying genetic causes is crucial to guide both counseling and treatment decisions. Both somatic and germline DNA variants may contribute to the lesion itself and\/or influence the severity of symptoms. We therefore used whole exome sequencing (WES) to search for potentially pathogenic somatic DNA variants in brain samples from children with lesional epilepsy who underwent epilepsy surgery. WES was performed on 20 paired DNA samples extracted from both lesional brain tissue and reference tissue from the same patient, such as leukocytes or fibroblasts. The paired WES data were jointly analyzed using GATK Mutect2 to identify somatic single nucleotide variants (SNVs) or insertions\/deletions (InDels), which were subsequently evaluated in silico for their disease-causing potential using MutationTaster2021. We identified known pathogenic somatic variants in five patients (25%) with variant allele frequencies (VAF) ranging from 3\u201335% in the genes MTOR, TSC2, PIK3CA, FGFR1, and PIK3R1 as potential causes of cortical malformations or central nervous system (CNS) tumors. Depending on the VAF, we used different methods such as Sanger sequencing, allele-specific qPCR, or targeted ultra-deep sequencing (amplicon sequencing) to confirm the variant. In contrast to the usually straightforward confirmation of germline variants, the validation of somatic variants is more challenging because current methods have limitations in sensitivity, specificity, and cost-effectiveness. In our study, WES identified additional somatic variant candidates in additional genes with VAFs ranging from 0.7\u20137.0% that could not be validated by an orthogonal method. This highlights the importance of variant validation, especially for those with very low allele frequencies.<\/jats:p>","DOI":"10.3390\/ijms26020815","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T06:53:32Z","timestamp":1737442412000},"page":"815","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Somatic DNA Variants in Epilepsy Surgery Brain Samples from Patients with Lesional Epilepsy"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7048-208X","authenticated-orcid":false,"given":"Jana Marie","family":"Schwarz","sequence":"first","affiliation":[{"name":"Department of Neuropediatrics, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"},{"name":"Center for Chronically Sick Children, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany"},{"name":"German Epilepsy Center for Children and Adolescents, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany"},{"name":"Charit\u00e9 Pediatric Head and Neck Center, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany"},{"name":"German Center for Child and Adolescent Health (DZKJ), Partner Site Berlin, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4622-8695","authenticated-orcid":false,"given":"Lena-Luise","family":"Becker","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"},{"name":"Center for Chronically Sick Children, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany"},{"name":"German Epilepsy Center for Children and Adolescents, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany"},{"name":"Charit\u00e9 Pediatric Head and Neck Center, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany"},{"name":"Institute of Cell and Neurobiology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Wahle","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Fa\u00dfbender","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich-Wilhelm","family":"Thomale","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurosurgery, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Tietze","sequence":"additional","affiliation":[{"name":"Institute of Neuroradiology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7279-2092","authenticated-orcid":false,"given":"Susanne","family":"Morales-Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Knierim","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2824-3891","authenticated-orcid":false,"given":"Markus","family":"Schuelke","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"},{"name":"German Center for Child and Adolescent Health (DZKJ), Partner Site Berlin, 13353 Berlin, Germany"},{"name":"Neurocure Clinical Research Center, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9454-206X","authenticated-orcid":false,"given":"Angela M.","family":"Kaindl","sequence":"additional","affiliation":[{"name":"Department of Neuropediatrics, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, 13353 Berlin, Germany"},{"name":"Center for Chronically Sick Children, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany"},{"name":"German Epilepsy Center for Children and Adolescents, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany"},{"name":"Charit\u00e9 Pediatric Head and Neck Center, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany"},{"name":"German Center for Child and Adolescent Health (DZKJ), Partner Site Berlin, 13353 Berlin, Germany"},{"name":"Institute of Cell and Neurobiology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, Charit\u00e9platz 1, 10117 Berlin, Germany"},{"name":"Institute of Neuroradiology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t Berlin, and Berlin Institute of Health, Augustenburger Platz 1, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"120766","DOI":"10.1016\/j.jns.2023.120766","article-title":"Drug-Resistant Epilepsy: Definition, Pathophysiology, and Management","volume":"452","author":"Mesraoua","year":"2023","journal-title":"J. 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