{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T23:09:11Z","timestamp":1780528151658,"version":"3.54.1"},"reference-count":17,"publisher":"Georg Thieme Verlag KG","issue":"03","funder":[{"name":"Verein Zukunftszehner -Spenden f\u00fcr die Zukunft schwerkranker Kinder"},{"name":"Young Hope-Forschungszentrum f\u00fcr Kinder-und Jugendmedizin"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neuropediatrics"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Developmental and epileptic encephalopathy (DEE) is extremely heterogeneous and only 30 to 50% of affected individuals receive a diagnosis upon routine genetic diagnostics. We show that genome sequencing, complemented by optical genome mapping (OGM), resolved an exome-negative case.<\/jats:p>\n                  <jats:p>We performed trio short-read genome sequencing, karyotyping, OGM, and quantitative real-time PCR.<\/jats:p>\n                  <jats:p>In a boy with DEE (severe global developmental delay\/intellectual disability, early-onset, multiple and concurrent seizures, EEG suggestive of Lennox-Gastaut syndrome, dystonic tetraplegia), routine diagnostic testing (karyotyping, array-CGH, and exome sequencing) failed to yield a diagnosis. Genome sequencing detected a de novo translocation that OGM validated and expanded to a complex chromosomal rearrangement (CCR) involving seven breakpoints in chromosomes 5, 9, 12, and 15. The breakpoint on chromosome 15 affected the 5\u2032UTR promotor region of CHD2. Quantitative real-time PCR on RNA from proband-derived lymphoblast cells showed a 40% reduction of CHD2 expression confirming the pathogenicity of the variant.<\/jats:p>\n                  <jats:p>Our case highlights that CCR can underly CHD2-related DEE94 and likely underlie other (genetically unsolved) cases. There is not one technique that can detect all genetic variants. We emphasize the advantage of combining genome sequencing with OGM as a complementary second step in unresolved cases to improve the detection and structural characterization of genetic variation, including CCRs.<\/jats:p>","DOI":"10.1055\/a-2856-1470","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T23:25:32Z","timestamp":1778282732000},"page":"226-231","source":"Crossref","is-referenced-by-count":0,"title":["Unmasking Complex Chromosomal Rearrangement Impacting CHD2 by Genome Sequencing and Optical Genome Mapping in Developmental and Epileptic Encephalopathy\u2014DEE94"],"prefix":"10.1055","volume":"57","author":[{"given":"Robin","family":"Wijngaard","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinelopi","family":"Dragoumi","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Hippokratio General Hospital, Aristotle University, Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4864-9346","authenticated-orcid":false,"given":"Machteld M.","family":"Oud","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia B.","family":"Wortmann","sequence":"first","affiliation":[{"name":"University Children's Hospital, Paracelsus Medical University, Salzburg, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kornelia","family":"Neveling","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"van Beek","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"van de Zande","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron A.","family":"Wevers","sequence":"additional","affiliation":[{"name":"Translational Metabolic Laboratory, Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Zafeiriou","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Hippokratio General Hospital, Aristotle University, Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"194","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"issue":"11","key":"ref1","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/S2352-4642(24)00196-2","article-title":"The expanding field of genetic developmental and epileptic encephalopathies: current understanding and future perspectives","volume":"8","author":"N Specchio","year":"2024","journal-title":"Lancet Child Adolesc Health"},{"issue":"05","key":"ref2","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1111\/epi.17547","article-title":"Genes4Epilepsy: an epilepsy gene resource","volume":"64","author":"K L Oliver","year":"2023","journal-title":"Epilepsia"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"761178","DOI":"10.3389\/fgene.2022.761178","article-title":"A novel variant of the CHD2 gene associated with developmental delay and myoclonic epilepsy","volume":"13","author":"L Zhu","year":"2022","journal-title":"Front Genet"},{"key":"ref4","volume-title":"CHD2-Related Neurodevelopmental Disorders","author":"G L Carvill","year":"1993"},{"issue":"02","key":"ref5","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1177\/1535759720906118","article-title":"A 2020 view on the genetics of developmental and epileptic encephalopathies","volume":"20","author":"H C Happ","year":"2020","journal-title":"Epilepsy Curr"},{"issue":"04","key":"ref6","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1002\/jimd.12507","article-title":"How to proceed after \u201cnegative\u201d exome: a review on genetic diagnostics, limitations, challenges, and emerging new multiomics techniques","volume":"45","author":"S B Wortmann","year":"2022","journal-title":"J Inherit Metab Dis"},{"issue":"01","key":"ref7","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/s41431-022-01185-9","article-title":"The performance of genome sequencing as a first-tier test for neurodevelopmental disorders","volume":"31","author":"B PGH van der Sanden","year":"2023","journal-title":"Eur J Hum Genet"},{"issue":"04","key":"ref8","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1101\/gr.279970.124","article-title":"The additional diagnostic yield of long-read sequencing in undiagnosed rare diseases","volume":"35","author":"G F Del Gobbo","year":"2025","journal-title":"Genome Res"},{"issue":"08","key":"ref9","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1016\/j.ajhg.2021.05.012","article-title":"Optical genome mapping enables constitutional chromosomal aberration detection","volume":"108","author":"T Mantere","year":"2021","journal-title":"Am J Hum Genet"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13039-020-0470-0","article-title":"Chromoanagenesis: a piece of the macroevolution scenario","volume":"13","author":"F Pellestor","year":"2020","journal-title":"Mol Cytogenet"},{"issue":"11","key":"ref11","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1016\/j.tig.2022.06.003","article-title":"Complex genomic rearrangements: an underestimated cause of rare diseases","volume":"38","author":"J Schuy","year":"2022","journal-title":"Trends Genet"},{"issue":"01","key":"ref12","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13073-024-01301-y","article-title":"Genome sequencing as a generic diagnostic strategy for rare disease","volume":"16","author":"G Schobers","year":"2024","journal-title":"Genome Med"},{"issue":"08","key":"ref13","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1016\/j.ajhg.2021.06.001","article-title":"Next-generation cytogenetics: comprehensive assessment of 52 hematological malignancy genomes by optical genome mapping","volume":"108","author":"K Neveling","year":"2021","journal-title":"Am J Hum Genet"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.yebeh.2014.02.005","article-title":"CHD2 mutations in Lennox-Gastaut syndrome","volume":"33","author":"C Lund","year":"2014","journal-title":"Epilepsy Behav"},{"issue":"01","key":"ref15","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13039-022-00600-6","article-title":"Mechanisms of structural chromosomal rearrangement formation","volume":"15","author":"B Burssed","year":"2022","journal-title":"Mol Cytogenet"},{"issue":"01","key":"ref16","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/nbt.1754","article-title":"Integrative genomics viewer","volume":"29","author":"J T Robinson","year":"2011","journal-title":"Nat Biotechnol"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"D1331","DOI":"10.1093\/nar\/gkaf1250","article-title":"The UCSC Genome Browser database: 2026 update","volume":"54","author":"J Casper","year":"2026","journal-title":"Nucleic Acids Res"}],"container-title":["Neuropediatrics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-2856-1470.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T22:39:31Z","timestamp":1780526371000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-2856-1470"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,8]]},"references-count":17,"journal-issue":{"issue":"03","published-online":{"date-parts":[[2026,6,3]]},"published-print":{"date-parts":[[2026,6]]}},"URL":"https:\/\/doi.org\/10.1055\/a-2856-1470","archive":["Portico","CLOCKSS"],"relation":{},"ISSN":["0174-304X","1439-1899"],"issn-type":[{"value":"0174-304X","type":"print"},{"value":"1439-1899","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,8]]}}}