{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:35:02Z","timestamp":1784280902407,"version":"3.55.0"},"reference-count":8,"publisher":"BMJ","issue":"8","funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP24ek0109760"],"award-info":[{"award-number":["JP24ek0109760"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MHLW Health Labour Sciences Research","award":["23FC1052"],"award-info":[{"award-number":["23FC1052"]}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K14966"],"award-info":[{"award-number":["23K14966"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2025,5,13]]},"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:p>\n                  <jats:italic>RNU4-2<\/jats:italic> encodes U4 small nuclear RNA (snRNA), a non-coding RNA forming the spliceosome complex via the U4\/U6 snRNA duplex. <jats:italic>RNU4-2<\/jats:italic> heterozygous variants cause ReNU syndrome, which is characterised by intellectual disability, developmental delay, epilepsy, short stature and distinctive dysmorphic features. ReNU syndrome accounts for 0.4\u20130.5% of all cases of developmental delay, and <jats:italic>RNU4-2<\/jats:italic> variants are located in the T-loop or stem III region of U4 snRNA, of which approximately 80% are the n.64_65insT variant in the T-loop. We identified four Japanese patients (4.3%) with novel and recurrent <jats:italic>RNU4-2<\/jats:italic> variants from 93 individuals of developmental delay with negative results from exome sequencing. Genotype-phenotype correlations were observed in the present case series and a literature review. T-loop variants manifested severe developmental delay with more than 70% of cases being non-verbal. Stem III region variants resulted in milder developmental delay with fluent speech and nearly normal gross motor development milestones. In addition, we report a patient demonstrating intractable epilepsy with neurological regression harbouring a novel de novo heterozygous <jats:italic>RNU4-2<\/jats:italic> variant (n.66A&gt;G). This report expands the phenotypic spectrum of ReNU syndrome and suggests the presence of phenotypic variability related to variant location.<\/jats:p>","DOI":"10.1136\/jmg-2024-110604","type":"journal-article","created":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T21:30:16Z","timestamp":1748122216000},"page":"531-535","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Genotype-phenotype correlations and phenotypic expansion in a case series of ReNU syndrome associated with <i>RNU4-2<\/i> variants"],"prefix":"10.1136","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8420-6070","authenticated-orcid":false,"given":"Yukiko","family":"Kuroda","sequence":"first","affiliation":[{"name":"Division of Medical Genetics, Kanagawa Children\u2019s Medical Center, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koki","family":"Nagai","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Kanagawa Children\u2019s Medical Center, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Kawai","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Kanagawa Children\u2019s Medical Center, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5590-8126","authenticated-orcid":false,"given":"Takuya","family":"Naruto","sequence":"additional","affiliation":[{"name":"Clinical Research Institute, Kanagawa Children\u2019s Medical Center, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harutaka","family":"Saijou","sequence":"additional","affiliation":[{"name":"Division of Neurology, Kanagawa Children\u2019s Medical Center, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shotaro","family":"Morikawa","sequence":"additional","affiliation":[{"name":"Division of Neurology, Kanagawa Children\u2019s Medical Center, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohide","family":"Goto","sequence":"additional","affiliation":[{"name":"Division of Neurology, Kanagawa Children\u2019s Medical Center, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mutsumi","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Odawara Municipal Hospital, Odawara, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Kurosawa","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Kanagawa Children\u2019s Medical Center, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,5,24]]},"reference":[{"key":"2025101710033225000_62.8.531.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07773-7"},{"key":"2025101710033225000_62.8.531.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03085-5"},{"key":"2025101710033225000_62.8.531.3","doi-asserted-by":"publisher","DOI":"10.1038\/nature14548"},{"key":"2025101710033225000_62.8.531.4","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14628"},{"key":"2025101710033225000_62.8.531.5","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14574"},{"key":"2025101710033225000_62.8.531.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2024.101288"},{"key":"2025101710033225000_62.8.531.7","doi-asserted-by":"crossref","unstructured":"Nava C , Cogne B , Santini A , et al . Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption. Nat Genet 2025;07. doi:10.1038\/s41588-025-02184-4","DOI":"10.1038\/s41588-025-02184-4"},{"key":"2025101710033225000_62.8.531.8","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax3289"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2024-110604","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T17:03:39Z","timestamp":1760720619000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2024-110604"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,24]]},"references-count":8,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,7,21]]},"published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1136\/jmg-2024-110604"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2024-110604","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,24]]}}}