{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T14:07:20Z","timestamp":1790431640791,"version":"4.1.0"},"posted":{"date-parts":[[2025,9,4]]},"group-title":"Genetic and Genomic Medicine","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Variants in spliceosomal small nuclear RNA (snRNA) genes\n                  <jats:italic>RNU4-2<\/jats:italic>\n                  (ReNU syndrome),\n                  <jats:italic>RNU5B-1<\/jats:italic>\n                  , and\n                  <jats:italic>RNU2-2<\/jats:italic>\n                  have recently been linked to dominant neurodevelopmental disorders (NDDs), revealing a major, previously overlooked role for noncoding snRNAs in human disease. Here, we systematically analysed 200 potentially functional snRNA genes in a French cohort comprising 26,911 individuals with rare disorders and through international collaborations. We identify\n                  <jats:italic>de novo<\/jats:italic>\n                  and biallelic variants in\n                  <jats:italic>RNU2-2<\/jats:italic>\n                  associated with both dominant and recessive NDDs in 126 individuals from 108 unrelated families. Recessive\n                  <jats:italic>RNU2-2<\/jats:italic>\n                  NDD is at least twice as frequent as the dominant NDD caused by n.4G&gt;A and n.35A&gt;G, and often arises from a\n                  <jats:italic>de novo<\/jats:italic>\n                  variant in\n                  <jats:italic>trans<\/jats:italic>\n                  with an inherited allele, reflecting the high mutability of snRNA genes. Dominant and recessive\n                  <jats:italic>RNU2-2<\/jats:italic>\n                  -NDDs share overlapping clinical features with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our findings support a gradient-of-impact model and a continuum between dominant and recessive inheritance, establishing\n                  <jats:italic>RNU2-2<\/jats:italic>\n                  variants as a frequent cause of NDDs, nearly as prevalent as ReNU syndrome.\n                <\/jats:p>","DOI":"10.1101\/2025.09.02.25334923","type":"posted-content","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T20:55:16Z","timestamp":1757019316000},"source":"Crossref","is-referenced-by-count":9,"title":["Systematic analysis of snRNA genes reveals frequent\n                  <i>RNU2-2<\/i>\n                  variants in dominant and recessive developmental and epileptic encephalopathies"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5051-9714","authenticated-orcid":false,"given":"Elsa","family":"Leit\u00e3o","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0738-0531","authenticated-orcid":false,"given":"Amandine","family":"Santini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5503-6292","authenticated-orcid":false,"given":"Benjamin","family":"Cogne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Essid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Athanasiadou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christy W.","family":"LaFlamme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Marijon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Bernard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0538-0981","authenticated-orcid":false,"given":"Nicolas","family":"Chatron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Barcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Keren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril","family":"Mignot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perrine","family":"Charles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Besnard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7753-8226","authenticated-orcid":false,"given":"Jean-Madeleine","family":"de Sainte Agathe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edith P. 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