{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T04:00:57Z","timestamp":1793678457195,"version":"4.5.1"},"reference-count":54,"publisher":"Springer Science and Business Media LLC","issue":"8026","license":[{"start":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T00:00:00Z","timestamp":1720656000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T00:00:00Z","timestamp":1720656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2024,8,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes\n                    <jats:sup>1<\/jats:sup>\n                    . Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA\n                    <jats:italic>RNU4-2<\/jats:italic>\n                    as a syndromic NDD gene.\n                    <jats:italic>RNU4-2<\/jats:italic>\n                    encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4\/U6.U5 tri-snRNP complex of the major spliceosome\n                    <jats:sup>2<\/jats:sup>\n                    . We identify an 18\u2009base pair region of\n                    <jats:italic>RNU4-2<\/jats:italic>\n                    mapping to two structural elements in the U4\/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that\n                    <jats:italic>RNU4-2<\/jats:italic>\n                    is highly expressed in the developing human brain, in contrast to\n                    <jats:italic>RNU4-1<\/jats:italic>\n                    and other U4 homologues. Using RNA sequencing, we show how 5\u2032 splice-site use is systematically disrupted in individuals with\n                    <jats:italic>RNU4-2<\/jats:italic>\n                    variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18\u2009base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.\n                  <\/jats:p>","DOI":"10.1038\/s41586-024-07773-7","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T12:02:18Z","timestamp":1720699338000},"page":"832-840","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":161,"title":["De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome"],"prefix":"10.1038","volume":"632","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5593-6920","authenticated-orcid":false,"given":"Yuyang","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2135-0117","authenticated-orcid":false,"given":"Ruebena","family":"Dawes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5877-5456","authenticated-orcid":false,"given":"Hyung Chul","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Ljungdahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4071-449X","authenticated-orcid":false,"given":"Sarah 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