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ReNU syndrome variants disrupt spliceosome function and alter 5\u2032 splice site selection\n                    <jats:sup>1,4<\/jats:sup>\n                    . Here we performed saturation genome editing (SGE) of\n                    <jats:italic>RNU4-2<\/jats:italic>\n                    to identify the functional and clinical impact of variants across the entire gene. The resulting SGE function scores, derived from variants\u2019 effects on cell fitness, discriminate ReNU syndrome variants from those observed in the population and markedly outperform in silico variant effect prediction. Using these data, we redefine the ReNU syndrome critical region at single-nucleotide resolution, resolve variant pathogenicity for variants of uncertain significance and show that SGE function scores delineate variants by phenotypic severity and the extent of observed splicing disruption. Furthermore, we identify variants affecting function in regions of\n                    <jats:italic>RNU4-2<\/jats:italic>\n                    that are critical for interactions with other spliceosome components. We show that these variants cause a new recessive neurodevelopmental disorder that is distinct from ReNU syndrome. Together, this work defines the landscape of variant function across\n                    <jats:italic>RNU4-2<\/jats:italic>\n                    , providing critical insights for both diagnosis and therapeutic development.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10334-9","type":"journal-article","created":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T15:03:50Z","timestamp":1775660630000},"page":"429-436","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders"],"prefix":"10.1038","volume":"654","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0584-8265","authenticated-orcid":false,"given":"Joachim","family":"De Jonghe","sequence":"first","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"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5095-7539","authenticated-orcid":false,"given":"Ayanfeoluwa","family":"Adedeji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5051-9714","authenticated-orcid":false,"given":"Elsa","family":"Leit\u00e3o","sequence":"additional","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\/0000-0002-7896-0744","authenticated-orcid":false,"given":"Christina M.","family":"Kajba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5503-6292","authenticated-orcid":false,"given":"Benjamin","family":"Cogn\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5593-6920","authenticated-orcid":false,"given":"Yuyang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0260-7020","authenticated-orcid":false,"given":"Alexander J. 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