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We show that rare biallelic variants in\n                    <jats:italic>RNU2-2<\/jats:italic>\n                    are enriched and over-transmitted in individuals with unresolved NDDs. We define a recessive\n                    <jats:italic>RNU2-2<\/jats:italic>\n                    syndrome, delineate its unique genetic architecture and show that it manifests clinically as a severe developmental and epileptic encephalopathy. We find that candidate biallelic variants are significantly correlated with reduced U2-2 abundance, implicating compromised transcript stability as a probable pathomechanism. We identify a decreased ratio of U2-2 to its paralog U2-1 as a potential diagnostic biomarker for this condition. We show that the recessive\n                    <jats:italic>RNU2-2<\/jats:italic>\n                    syndrome is genetically, clinically and mechanistically distinct from the dominant\n                    <jats:italic>RNU2-2<\/jats:italic>\n                    disorder. Within our cohort, the recessive\n                    <jats:italic>RNU2-2<\/jats:italic>\n                    syndrome emerges as by far the most frequent recessive NDD, greatly disproportionate to the small genomic footprint of this non-protein-coding gene.\n                  <\/jats:p>","DOI":"10.1038\/s41588-026-02551-9","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T09:04:07Z","timestamp":1774861447000},"page":"798-809","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy"],"prefix":"10.1038","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3674-3960","authenticated-orcid":false,"given":"Adam","family":"Jackson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0260-7020","authenticated-orcid":false,"given":"Alexander J. 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