PubMed · 40950445
Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies.
Abstract
Variants in spliceosomal small nuclear RNA (snRNA) genes RNU4-2 (ReNU syndrome), RNU5B-1, and RNU2-2 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 de novo and biallelic variants in RNU2-2 associated with both dominant and recessive NDDs in 126 individuals from 108 unrelated families. Recessive RNU2-2 NDD is at least twice as frequent as the dominant NDD caused by n.4G>A and n.35A>G, and often arises from a de novo variant in trans with an inherited allele, reflecting the high mutability of snRNA genes. Dominant and recessive RNU2-2-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 RNU2-2 variants as a frequent cause of NDDs, nearly as prevalent as ReNU syndrome.
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Elsa Leitão, Amandine Santini, Benjamin Cogne, Myriam Essid, Maria Athanasiadou, Christy W LaFlamme, Pierre Marijon, Virginie Bernard, Nicolas Chatron, Giulia Barcia, Boris Keren, Cyril Mignot, Perrine Charles, Thomas Besnard, Jean-Madeleine de Sainte Agathe, Edith P Almanza Fuerte, Soham Sengupta, Mathieu Milh, Francis Ramond, Talia Allan, Isabelle An, Camila Araujo, Stephanie Arpin, Christina Austin-Tse, Stéphane Auvin, Sarah Baer, Nadia Bahi-Buisson, Mads Bak, Magalie Barth, Stéphanie Baulac, Nathalie Bednark Weirauch, Matthias Begemann, Mark F Bennett, Uriel Bensabath, Stéphane Bézieau, Rakia Bhouri, Margaux Biehler, Trine Bjørg Hammer, Julie Bogoin, Emilie Bonanno, Simon Boussion, Nuria C Bramswig, Céline Bris, Adelaide Brosseau-Beauvir, Ange-Line Bruel, Julien Buratti, Pascal Chambon, Nicole Chemaly, Bertrand Chesneau, Estelle Colin, Maxime Colmard, Solène Conrad, Thomas Courtin, Louis T Dang, Anne de Saint Martin, Caroline de Vanssay de Blavous Legendre, Anne-Sophie Denommé-Pichon, Stephanie DiTroia, Martine Doco-Fenzy, Christèle Dubourg, Charlotte Dubucs, Stéphanie Ducreux, Louis Dufour, Romain Duquet, Benjamin Durand, Salima El Chehadeh, Miriam Elbracht, Laurence Faivre, Marie Faoucher, Anne Faudet, Sylvie Forlani, Mélanie Fradin, Pauline Gaignard, Benjamin Ganne, Aurore Garde, Justine Géraud, Deepak Gill, Alice Goldenberg, David Grabli, Coraline Grisel, Sophie Gueden, Paul Gueguen, Anne-Marie Guerrot, Agnès Guichet, Nina Härting, Martin Georg Häusler, Solveig Heide, Bénédicte Héron, Delphine Héron, Mathilde Heulin, Clara Houdayer, Bertrand Isidor, Aurélia Jacquette, Louis Januel, Nolwenn Jean-Marçais, Kevin Jousselin, Frank J Kaiser, Sabine Kaya, Chontelle King, Marina Konyukh. 2025-09-04. Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies.. https://doi.org/10.1101/2025.09.02.25334923
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