Elsa Leitão, Amandine Santini, Benjamin Cogne, Miriam Essid, Maria Athanasiadou, Christy W. LaFlamme, Pierre Marijon, Virginie Bernard, Kévin Jousselin, Nicolas Chatron, Giulia Barcia, Boris Keren, Cyril Mignot, P. Charles, T. Besnard, Robin Paluch, Jean‐Madeleine de Sainte Agathe, Edith P. Almanza Fuerte, Soham Sengupta, Mathieu Milh, Francis Ramond, Talia Allan, Isabelle An, Camila Araújo, Stéphanie Arpin, Christina Austin-Tse, Stéphane Auvin, Sarah Baer, Nadia Bahi-Buisson, Mads Bak, Magalie Barth, Stéphanie Baulac, Nathalie Bednarek-Weirauch, Matthias Begemann, Mark F. Bennett, Uriel Bensabath, Stéphane Bézieau, Rakia Bhouri, Margaux Biehler, Trine Bjørg Hammer, Julie Bogoin, Emilie Bonanno, Simon Boussion, Céline Bris, Adelaide Brosseau-Beauvir, Ange-Line Bruel, Audrey Briand-Suleau, Julien Buratti, Tristan Celse, P. Chambon, Nicole Chémaly, Bertrand Chesneau, E. Colin, Maxime Colmard, Cindy Colson, Solène Conrad, Thomas Courtin, Isabelle Creveaux, Anne-Charlotte Cullier, Louis T. Dang, Anne de Saint Martin, Caroline de Vanssay de Blavous Legendre, Bénédicte Demeer, Anne-Sophie Denommé-Pichon, Philine Diekhoff, Stephanie DiTroia, Martine Doco-Fenzy, C. 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, J Géraud, Deepak Gill, Alice Goldenberg, David Grabli, Coraline Grisel, Sophie Guéden, Paul Gueguen, Anne-Marie Guerrot, Agnès Guichet, Tobias B. Haack, Nina Härting, Martin Häusler, Solveig Heide, Theresia Herget, Bénédicte Héron, Delphine Héron, J. Herwig
Small nuclear RNAs (snRNAs) are essential components of the spliceosome. De novo variants in snRNA genes RNU4-2 (ReNU syndrome), RNU5B-1 and RNU2-2 have been linked to dominant neurodevelopmental disorders (NDDs), revealing a large unexpected contribution of noncoding RNA genes to genetic diseases. Here, through international collaborations, we analyze systematically 200 potentially functional snRNA genes in a French cohort of 34,329 people with rare disorders. We report RNU2-2 variants in 141 individuals, including 35 with recurrent dominant pathogenic variants and 91 affected members from 73 families with biallelic variants. Recessive RNU2-2 NDD is at least twice as frequent as the dominant form and often involves a de novo variant in trans with an inherited allele, consistent with 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 results support a gradient-of-impact model bridging dominant and recessive inheritance, and establish RNU2-2 variants as a principal contributor to NDDs, nearly as prevalent as ReNU syndrome.