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medRxiv : the preprint server for health sciences · 2025

Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies.

СтатьяПрепринтНазвание и аннотация: Перевод в очереди
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Leitão Elsa, Santini Amandine, Cogne Benjamin, Essid Myriam, Athanasiadou Maria, LaFlamme Christy W, Marijon Pierre, Bernard Virginie, Chatron Nicolas, Barcia Giulia, Keren Boris, Mignot Cyril, Charles Perrine, Besnard Thomas, de Sainte Agathe Jean-Madeleine, Fuerte Edith P Almanza, Sengupta Soham, Milh Mathieu, Ramond Francis, Allan Talia, An Isabelle, Araujo Camila, Arpin Stephanie, Austin-Tse Christina, Auvin Stéphane, Baer Sarah, Bahi-Buisson Nadia, Bak Mads, Barth Magalie, Baulac Stéphanie, Weirauch Nathalie Bednark, Begemann Matthias, Bennett Mark F, Bensabath Uriel, Bézieau Stéphane, Bhouri Rakia, Biehler Margaux, Hammer Trine Bjørg, Bogoin Julie, Bonanno Emilie, Boussion Simon, Bramswig Nuria C, Bris Céline, Brosseau-Beauvir Adelaide, Bruel Ange-Line, Buratti Julien, Chambon Pascal, Chemaly Nicole, Chesneau Bertrand, Colin Estelle, Colmard Maxime, Conrad Solène, Courtin Thomas, Dang Louis T, de Saint Martin Anne, de Vanssay de Blavous Legendre Caroline, Denommé-Pichon Anne-Sophie, DiTroia Stephanie, Doco-Fenzy Martine, Dubourg Christèle, Dubucs Charlotte, Ducreux Stéphanie, Dufour Louis, Duquet Romain, Durand Benjamin, Chehadeh Salima El, Elbracht Miriam, Faivre Laurence, Faoucher Marie, Faudet Anne, Forlani Sylvie, Fradin Mélanie, Gaignard Pauline, Ganne Benjamin, Garde Aurore, Géraud Justine, Gill Deepak, Goldenberg Alice, Grabli David, Grisel Coraline, Gueden Sophie, Gueguen Paul, Guerrot Anne-Marie, Guichet Agnès, Härting Nina, Häusler Martin Georg, Heide Solveig, Héron Bénédicte, Héron Delphine, Heulin Mathilde, Houdayer Clara, Isidor Bertrand, Jacquette Aurélia, Januel Louis, Jean-Marçais Nolwenn, Jousselin Kevin, Kaiser Frank J, Kaya Sabine, King Chontelle, Konyukh Marina, Kraft Florian, Krause Jeremias, Kirstetter Rémi, Kuechler Alma, Kurth Ingo, Labalme Audrey, Laloy Jean-Serene, Laugel Vincent, Bricquir Floriane Le, Lèbre Anne-Sophie, Lebrun Marine, Leguern Eric, Levy Jonathan, Lieffering Nico, Lyonnet Stanislas, Lüthy Kevin, Macdonald Sian, Mansour-Hendili Lamisse, Maraval Julien, Mattausch Carolin, Messaoud Olfa, Morel Godelieve, Mortreux Jérémie, Munnich Arnold, Nabbout Rima, Nambot Sophie, Navarro Vincent, Neale Ashana, Nguyen Laetitia, Nizon Mathilde, Nowak Frédérique, O'Leary Melanie C, Odent Sylvie, Ojeda Naomi Meave, Olin Valerie, Õunap Katrin, Pais Lynn S, Paluch Robin, Panagiotakaki Eleni, Patat Olivier, Perrin-Sabourin Laurence, Petit Florence, Philippe Christophe, Piton Amélie, Planes Marc, Poirsier Céline, Pouzet Antoine, Prouteau Clément, Quéméner-Redon Sylvia, Renaud Mathilde, Richard Anne-Claire, Rio Marlène, Rivier Clotilde, Robin-Renaldo Florence, Rollier Paul, Rossi Massimiliano, Roubertie Agathe, Rupin Mailys, Saugier-Veber Pascale, Saneto Russell, Sarrazin Elisabeth, Schaefer Elise, Schluth-Bolard Caroline, Schneider Amy, Schumann Isabell, Seplyarskiy Vladimir, Smol Thomas, Sunyaev Shamil, Sperelakis-Beedham Brian, Stenton Sarah L, Stock Friedrich, Tharreau Mylene, Torun Deniz, Toulouse Joseph, Thiyagarajah Harshini, Valence Stéphanie, Valleix Sophie, Villard Laurent, Ville Dorothée, Villeneuve Nathalie, Vitobello Antonio, Waernessyckle Aurélie, Weber Yvonne, Wieczorek Dagmar, Witkowski Tom, Yadavilli Manya, Yammine Tony, Zaafrane-Khachnaoui Khaoula, Zaki Maha S, Ziegler Alban, Lermine Alban, Nicolas Gael, Gleeson Joseph G, Sadleir Lynette G, Hildebrand Michael S, Scheffer Ingrid E, Whiffin Nicola, O'Donnell-Luria Anne, Mefford Heather C, Blanc Pierre, Thevenon Julien, Charbonnier Camille, Charenton Clément, Depienne Christel, Lesca Gaetan, Nava Caroline

Аннотация

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.

ИП Урсолов Владлен Сергеевич

ИНН 500118482352 · ОГРНИП 314500117700049

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