{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T21:58:50Z","timestamp":1791842330573,"version":"4.3.4"},"reference-count":13,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T00:00:00Z","timestamp":1748044800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2025,4,27]]},"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:p>We analysed rare variants in the non-coding <jats:italic>RNU4-2<\/jats:italic> gene as a potential cause of neurodevelopmental disorder (NDD) and intellectual disability (ID) in a large cohort of individuals enriched for parental consanguinity.<\/jats:p>\n               <jats:p>Genome sequencing (GS) data from 22\u2009928 individuals in our Biodatabank were queried for rare, monoallelic variants in <jats:italic>RNU4-2<\/jats:italic>. From these, 4918 patients presented with NDD\/ID. Human Phenotype Ontology (HPO)-encoded clinical information was extracted and analysed using the ontologyX R package.<\/jats:p>\n               <jats:p>Nearly 50% of the 4918 patients with NDD\/ID reported parental consanguinity. Eight relevant heterozygous <jats:italic>RNU4-2<\/jats:italic> variants were identified in 28 patients. n.64_65insT was the most frequently detected variant (20 patients, 71%), while the remaining variants were found in 1 or 2 patients each (n.65A&gt;G, n.66A&gt;G, n.67A&gt;G, n.70T&gt;C, n.76C&gt;T, n.95C&gt;G\u2009and n.135A&gt;C). Four variants are novel or ultra-rare, and two of them are in the 3\u2019 stem loops. HPO-based analysis revealed a consistent syndromic phenotype characterised by NDD, abnormal brain morphology, hypotonia, global developmental delay, microcephaly, seizures, atypical behaviour and facial dysmorphism. <jats:italic>RNU4-2<\/jats:italic> variants accounted for approximately 0.55% of NDD\/ID cases in our full cohort, and 0.25% in the subset of consanguineous patients (all genetic causes included).<\/jats:p>\n               <jats:p>This study underscores the significance of <jats:italic>RNU4-2<\/jats:italic> as a major genetic cause of NDD\/ID, extending its relevance to consanguineous patients, where recessive disorders are often suspected. We advocate for the re-evaluation of existing GS data to uncover potential diagnoses and emphasise the importance of GS as a first-tier diagnostic test.<\/jats:p>","DOI":"10.1136\/jmg-2024-110556","type":"journal-article","created":{"date-parts":[[2025,5,24]],"date-time":"2025-05-24T21:30:21Z","timestamp":1748122221000},"page":"536-539","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["<i>RNU4-2<\/i> monoallelic variants as a leading cause of syndromic neurodevelopmental disorder, including in patients with parental consanguinity"],"prefix":"10.1136","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9544-1877","authenticated-orcid":false,"given":"Aida M","family":"Bertoli-Avella","sequence":"first","affiliation":[{"name":"Centogene GmbH, Rostock, Mecklenburg-Vorpommern, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian A","family":"Ganoza","sequence":"additional","affiliation":[{"name":"Centogene GmbH, Rostock, Mecklenburg-Vorpommern, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Centogene GmbH, Rostock, Mecklenburg-Vorpommern, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Najafi","sequence":"additional","affiliation":[{"name":"Centogene GmbH, Rostock, Mecklenburg-Vorpommern, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel L","family":"Polla","sequence":"additional","affiliation":[{"name":"Centogene GmbH, Rostock, Mecklenburg-Vorpommern, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna","family":"Kandaswamy","sequence":"additional","affiliation":[{"name":"Centogene GmbH, Rostock, Mecklenburg-Vorpommern, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kornelia","family":"Tripolszki","sequence":"additional","affiliation":[{"name":"Centogene GmbH, Rostock, Mecklenburg-Vorpommern, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Bauer","sequence":"additional","affiliation":[{"name":"Centogene GmbH, Rostock, Mecklenburg-Vorpommern, Germany"},{"name":"Pomeranian University Medicine, Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Pinto Basto","sequence":"additional","affiliation":[{"name":"Centogene GmbH, Rostock, Mecklenburg-Vorpommern, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,5,24]]},"reference":[{"key":"2025101712261290000_62.8.536.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0908094"},{"key":"2025101712261290000_62.8.536.2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13394"},{"key":"2025101712261290000_62.8.536.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01242-6"},{"key":"2025101712261290000_62.8.536.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-020-00713-9"},{"key":"2025101712261290000_62.8.536.5","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2314761"},{"key":"2025101712261290000_62.8.536.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03085-5"},{"key":"2025101712261290000_62.8.536.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07773-7"},{"key":"2025101712261290000_62.8.536.8","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/mgg3.262","article-title":"A comprehensive global genotype-phenotype database for rare diseases","volume":"5","author":"Trujillano","year":"2017","journal-title":"Mol Genet Genomic Med"},{"key":"2025101712261290000_62.8.536.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01159-0"},{"key":"2025101712261290000_62.8.536.10","doi-asserted-by":"crossref","DOI":"10.1016\/j.gimo.2023.100833","article-title":"Systematic gene-disease relationship (GDR) curation unveils 61 gene-disease associations and highlights the impact on genetic testing","volume":"1","author":"Zonic","year":"2023","journal-title":"Genet Med Open"},{"key":"2025101712261290000_62.8.536.11","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw763"},{"key":"2025101712261290000_62.8.536.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2022.04.017"},{"key":"2025101712261290000_62.8.536.13","doi-asserted-by":"crossref","DOI":"10.3389\/fgene.2019.01152","article-title":"RNA-Seq Perspectives to Improve Clinical Diagnosis","volume":"10","author":"Marco-Puche","year":"2019","journal-title":"Front Genet"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2024-110556","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T19:26:19Z","timestamp":1760729179000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2024-110556"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,24]]},"references-count":13,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,7,21]]},"published-print":{"date-parts":[[2025,8]]}},"alternative-id":["10.1136\/jmg-2024-110556"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2024-110556","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]]}}}