{"doi":"10.1101/2025.01.06.24317169","title":"De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa","abstract":"ABSTRACT The U4 small nuclear RNA (snRNA) forms a duplex with the U6 snRNA and, together with U5 and ∼30 proteins, is part of the U4/U6.U5 tri-snRNP complex, located at the core of the major spliceosome. Recently, recurrent de novo variants in the U4 RNA, transcribed from the RNU4-2 gene, and in at least two other RNU genes were discovered to cause neurodevelopmental disorder. We detected inherited and de novo heterozygous variants in RNU4-2 (n.18_19insA and n.56T>C) and in four out of the five RNU6 paralogues (n.55_56insG and n.56_57insG) in 135 individuals from 62 families with non-syndromic retinitis pigmentosa (RP), a rare form of hereditary blindness. We show that these variants are recurrent among RP families and invariably cluster in close proximity within the three-way junction (between stem-I, the 5’ stem-loop and stem-II) of the U4/U6 duplex, affecting its natural conformation. Interestingly, this region binds to numerous splicing factors of the tri-snRNP complex including PRPF3, PRPF8 and PRPF31, previously associated with RP as well. The U4 and U6 variants identified seem to affect snRNP biogenesis, namely the U4/U6 di-snRNP, which is an assembly intermediate of the tri-snRNP. Based on the number of positive cases observed, deleterious variants in RNU4-2 and in RNU6 paralogues could be a significant cause of isolated or dominant RP, accounting for up to 1.2% of all undiagnosed RP cases. This study highlights the role of non-coding genes in rare Mendelian disorders and uncovers pleiotropy in RNU4-2 , where different variants underlie neurodevelopmental disorder and RP.","journal":"medRxiv","year":2025,"id":554642,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":56933,"name":"Kim Rodenburg","orcid":"0000-0003-0389-1518","position":1,"is_corresponding":false},{"id":57113,"name":"Zuzana Cvačková","orcid":"0000-0002-7430-2728","position":2,"is_corresponding":false},{"id":57114,"name":"Karolina Kamińska","orcid":"0000-0002-4720-5527","position":3,"is_corresponding":false},{"id":56936,"name":"Suzanne E. de Bruijn","orcid":"0000-0003-2912-9265","position":4,"is_corresponding":false},{"id":56937,"name":"Ana Belén Iglesias-Romero","orcid":"0000-0003-0044-179X","position":5,"is_corresponding":false},{"id":1411746,"name":"Erica G. 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