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Here we describe biallelic\n                      <jats:italic>RNU2\u20102<\/jats:italic>\n                      variants causing a recently reported, severe, recessive DEE.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We screened individuals who have received WGS analyses at the Genomic Medicine Centre Karolinska for Rare Diseases for biallelic\n                      <jats:italic>RNU2\u20102<\/jats:italic>\n                      variants. Deep phenotyping was performed through reviewing entire medical histories and phenotypic traits were transcribed to their corresponding Human Phenotype Ontology (HPO) term. HPO terms were used to generate pairwise phenotypic similarity scores and assess for significantly shared phenotype enrichment in the\n                      <jats:italic>RNU2\u20102<\/jats:italic>\n                      sub\u2010cohort. RNA sequencing analyses were performed in fibroblast and blood tissues to compare splicing events between\n                      <jats:italic>RNU2\u20102<\/jats:italic>\n                      individuals and two independent control groups.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified 14 individuals from nine families with 12 ultra\u2010rare biallelic\n                      <jats:italic>RNU2\u20102<\/jats:italic>\n                      variants clustering in the conserved 5\u2032 domains. Genotype data from 13 of 14 individuals has been reported previously as part of a larger cohort. All individuals presented with a highly concordant, severe DEE, characterized by severe to profound intellectual disability, inability to walk or communicate, hyperkinesia, and refractory seizures. Infantile spasms and tonic seizures were the predominant seizure types and a Lennox\u2013Gastaut syndrome\u2010like phenotype was common. These individuals had a significantly similar phenotypic signature when compared with 703 individuals with complex pediatric epilepsies (two\u2010sided Monte Carlo permutation test,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u2009.005). RNA sequencing analyses showed aberrant splicing, with the most pronounced effects in fibroblast tissues in mutually exclusive exon and alternate 3\u2032 splice\u2010site events, which were not detectable in blood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      We present deep phenotyping data and transcriptomic analyses that provide support for rare, 5\u2032 clustering biallelic\n                      <jats:italic>RNU2\u20102<\/jats:italic>\n                      variants causing this novel, severe DEE. We propose an RNA sequencing methodology on fibroblast tissue for future validation of\n                      <jats:italic>RNU2\u20102<\/jats:italic>\n                      variants.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/epi.70473","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T15:27:27Z","timestamp":1788276447000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phenotypic and transcriptomic characterization of biallelic\n                    <i>RNU2\u20102<\/i>\n                    developmental and epileptic encephalopathy"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4717-8346","authenticated-orcid":false,"given":"Olivia J.","family":"Henry","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Surgery Karolinska Institutet  Stockholm 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