{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T20:43:18Z","timestamp":1790887398050,"version":"4.1.0"},"reference-count":11,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T00:00:00Z","timestamp":1718064000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","award":["09150172110002"],"award-info":[{"award-number":["09150172110002"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2024,10]]},"abstract":"Abstract<\/jats:title>\n \n Despite increasing knowledge of disease\u2010causing genes in human genetics, approximately half of the individuals affected by neurodevelopmental disorders remain genetically undiagnosed. Part of this missing heritability might be caused by genetic variants outside of protein\u2010coding genes, which are not routinely diagnostically investigated. A recent preprint identified de novo variants in the non\u2010coding spliceosomal snRNA gene\n RNU4\u20102<\/jats:italic>\n as a cause of a frequent novel syndromic neurodevelopmental disorder. Here we mined 164 whole genome sequencing (WGS) trios from individuals with neurodevelopmental or multiple congenital anomaly disorders that received diagnostic genomic investigations at our clinic. We identify a recurrent de novo\n RNU4\u20102<\/jats:italic>\n variant (NR_003137.2(\n RNU4\u20102<\/jats:italic>\n ):n.64_65insT) in a 5\u2010year\u2010old girl with severe global developmental delay, hypotonia, microcephaly, and seizures that likely explains her phenotype, given that extensive previous genetic investigations failed to identify an alternative cause. We present detailed phenotyping of the individual obtained during a 5\u2010year follow\u2010up. This includes photographs showing recognizable facial features for this novel disorder, which might allow prioritizing other currently unexplained affected individuals sharing similar facial features for targeted investigations of\n RNU4\u20102<\/jats:italic>\n . This case illustrates the power of re\u2010analysis to solve previously unexplained cases even when a diagnostic genome remains negative.\n <\/jats:p>","DOI":"10.1111\/cge.14574","type":"journal-article","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T03:07:47Z","timestamp":1718075267000},"page":"512-517","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Re\u2010analysis of whole genome sequencing ends a diagnostic odyssey: Case report of an\n RNU4\u20102<\/i>\n related neurodevelopmental disorder"],"prefix":"10.1111","volume":"106","author":[{"given":"Rachel","family":"Schot","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics Erasmus MC University Medical Center Rotterdam The Netherlands"},{"name":"Discovery Unit, Department of Clinical Genetics Erasmus MC University Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1365-2529","authenticated-orcid":false,"given":"Federico","family":"Ferraro","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Erasmus MC University Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert","family":"Geeven","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Erasmus MC University Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2637-9998","authenticated-orcid":false,"given":"Karin E. M.","family":"Diderich","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Erasmus MC University Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1231-1562","authenticated-orcid":false,"given":"Tahsin Stefan","family":"Barakat","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Erasmus MC University Medical Center Rotterdam The Netherlands"},{"name":"Discovery Unit, Department of Clinical Genetics Erasmus MC University Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,11]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2019.00352"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17780"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-020-00974-1"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41525-018-0061-8"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000011655"},{"key":"e_1_2_9_7_1","doi-asserted-by":"crossref","unstructured":"ChenY DawesR KimHC et al.De novo variants in the non\u2010coding spliceosomal snRNA gene RNU4\u20102 are a frequent cause of syndromic neurodevelopmental disorders.medRxiv.2024. doi:10.1101\/2024.04.07.24305438","DOI":"10.1101\/2024.04.07.24305438"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2022.12.015"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.071423.119"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-019-02109-6"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-023-02579-9"},{"key":"e_1_2_9_12_1","doi-asserted-by":"crossref","unstructured":"LesmannH HustinxA MoosaS et al.GestaltMatcher database \u2010 a global reference for the facial phenotypic variability of rare human diseases. medRxiv.2024. doi:10.1101\/2023.06.06.23290887","DOI":"10.1101\/2023.06.06.23290887"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.14574","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T05:57:56Z","timestamp":1725256676000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.14574"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,11]]},"references-count":11,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,10]]}},"alternative-id":["10.1111\/cge.14574"],"URL":"https:\/\/doi.org\/10.1111\/cge.14574","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1111\/CGE.14574\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.14574\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.14574\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.14574\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1111\/CGE.14574\/v2\/response1","asserted-by":"object"}]},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,11]]},"assertion":[{"value":"2024-05-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}