{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T23:42:55Z","timestamp":1794008575488,"version":"4.8.0"},"reference-count":19,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000008","name":"Health Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000008","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009408","name":"Fondation Brain Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009408","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005155","name":"Azrieli Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005155","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100023422","name":"Epilepsy Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100023422","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009003","name":"Hotchkiss Brain Institute, University of Calgary","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009003","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012856","name":"Alberta Children's Hospital Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000196","name":"Canada Foundation for Innovation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100030706","name":"Department of Clinical Neurosciences, University of Calgary","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100030706","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Germline variants in\n                    <jats:italic>DEPDC5<\/jats:italic>\n                    are a cause of familial focal epilepsy with variable foci. Affected individuals may have focal cortical dysplasia if a second brain somatic variant occurs. As access to brain tissue is limited, the second somatic hit in the brain is usually presumed if a clear pathogenic germline variant is present. Here, we present a patient with structural focal epilepsy due to focal cortical dysplasia. He underwent epilepsy surgery at age 2\u2009months. Clinical genetic testing revealed a germline variant of uncertain significance (VUS)\n                    <jats:italic>DEPDC5<\/jats:italic>\n                    c.920T&gt;G, p. (Leu307Arg). We hypothesized that if the proband's germline\n                    <jats:italic>DEPDC5<\/jats:italic>\n                    variant was disease\u2010causal, a second somatic variant may be identifiable in affected cortical tissue. DNA was extracted from archived brain formalin\u2010fixed paraffin\u2010embedded tissue and subjected to deep gene panel analysis. This revealed an additional somatic pathogenic variant in\n                    <jats:italic>DEPDC5<\/jats:italic>\n                    , which was confirmed using droplet digital PCR. Identification of the second somatic hit in brain tissue (\n                    <jats:italic>DEPDC5<\/jats:italic>\n                    c.982C&gt;T, p.(Arg328*)) confirmed the two\u2010hit situation in this patient and supported disease causality of the germline variant. In conclusion, testing tissue for somatic variants may be clinically relevant at a patient\u2010specific level if a germline VUS affects a gene where a two\u2010hit mechanism is known.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.a.64204","type":"journal-article","created":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T12:55:07Z","timestamp":1753966507000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification of a Second\u2010Hit Brain Somatic\n                    <scp>\n                      <i>DEPDC5<\/i>\n                    <\/scp>\n                    Variant Supports Causality of a\n                    <scp>\n                      <i>DEPDC5<\/i>\n                    <\/scp>\n                    Germline Variant of Uncertain Significance. Time for a Classification Update?"],"prefix":"10.1002","volume":"197","author":[{"given":"Ala'a","family":"Alsayed","sequence":"first","affiliation":[{"name":"Department of Clinical Neurosciences University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zainab","family":"Hakim","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences University of Calgary  Calgary Alberta Canada"},{"name":"Hotchkiss Brain Institute University of Calgary  Calgary Alberta Canada"},{"name":"Alberta Children's Hospital Research Institute University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Merrikh","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences University of Calgary  Calgary Alberta Canada"},{"name":"Hotchkiss Brain Institute University of Calgary  Calgary Alberta Canada"},{"name":"Alberta Children's Hospital Research Institute University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Khanbabaei","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navprabhjot","family":"Kaur","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Hader","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Soule","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences University of Calgary  Calgary Alberta Canada"},{"name":"Hotchkiss Brain Institute University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Setareh","family":"Ashtiani","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Polanco\u2010Tovar","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morris","family":"Scantlebury","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences University of Calgary  Calgary Alberta Canada"},{"name":"Hotchkiss Brain Institute University of Calgary  Calgary Alberta Canada"},{"name":"Alberta Children's Hospital Research Institute University of Calgary  Calgary Alberta Canada"},{"name":"Department of Pediatrics University of Calgary, Alberta Children's Hospital  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamed","family":"Rahi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology Washington University in St. Louis School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2499-3567","authenticated-orcid":false,"given":"Yang","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology Washington University in St. Louis School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Chan","sequence":"additional","affiliation":[{"name":"Hotchkiss Brain Institute University of Calgary  Calgary Alberta Canada"},{"name":"Alberta Children's Hospital Research Institute University of Calgary  Calgary Alberta Canada"},{"name":"Department of Pathology and Laboratory Medicine, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Arnie Charbonneau Cancer Institute, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan P.","family":"Appendino","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences University of Calgary  Calgary Alberta Canada"},{"name":"Department of Pediatrics University of Calgary, Alberta Children's Hospital  Calgary Alberta Canada"},{"name":"Pediatric Neurology Service, Department of Pediatrics, Jim Pattison Children\u2019s Hospital University of Saskatchewan  Saskatoon Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Pfeffer","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences University of Calgary  Calgary Alberta Canada"},{"name":"Hotchkiss Brain Institute University of Calgary  Calgary Alberta Canada"},{"name":"Department of Medical Genetics, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping Yee Billie","family":"Au","sequence":"additional","affiliation":[{"name":"Alberta Children's Hospital Research Institute University of Calgary  Calgary Alberta Canada"},{"name":"Department of Medical Genetics, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6654-1665","authenticated-orcid":false,"given":"Karl Martin","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences University of Calgary  Calgary Alberta Canada"},{"name":"Hotchkiss Brain Institute University of Calgary  Calgary Alberta Canada"},{"name":"Alberta Children's Hospital Research Institute University of Calgary  Calgary Alberta Canada"},{"name":"Department of Medical Genetics, Cumming School of Medicine University of Calgary  Calgary Alberta Canada"},{"name":"Department of Community Health Sciences University of Calgary  Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,31]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0060-2"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-019-02061-5"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24368"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2021.12.004"},{"key":"e_1_2_10_6_1","unstructured":"ClinGen Sequence Variant Interpretation Working Group.2019.\u201cClinGen Sequence Variant Interpretation Recommendation for in Trans Criterion (PM3)\u2013Version 1.0.\u201dhttps:\/\/clinicalgenome.org\/site\/assets\/files\/3717\/svi_proposal_for_pm3_criterion_\u2010_version_1.pdf."},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2599"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphg.93"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2601"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.braindev.2017.08.003"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.38717"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2023.100947"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI99384"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24126"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.942741"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/jgc4.1646"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12992"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13061"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-020-01273-y"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.64204","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T02:23:15Z","timestamp":1766974995000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.64204"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,31]]},"references-count":19,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/ajmg.a.64204"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.64204","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,31]]},"assertion":[{"value":"2025-04-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e64204"}}