对小核仁RNA基因的系统分析揭示了显性和隐性发育性及癫痫性脑病中的常见变异。
Systematic analysis of snRNA genes reveals frequent variants in dominant and recessive developmental and epileptic encephalopathies.
作者信息
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
机构信息
Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Univ Rouen Normandie, Normandie Univ, Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Abnormalities, Rouen, France.
出版信息
medRxiv. 2025 Sep 4:2025.09.02.25334923. doi: 10.1101/2025.09.02.25334923.
Variants in spliceosomal small nuclear RNA (snRNA) genes (ReNU syndrome), , and 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 and biallelic variants in associated with both dominant and recessive NDDs in 126 individuals from 108 unrelated families. Recessive 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 variant in with an inherited allele, reflecting the high mutability of snRNA genes. Dominant and recessive -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 variants as a frequent cause of NDDs, nearly as prevalent as ReNU syndrome.
剪接体小核RNA（snRNA）基因（ReNU综合征）中的变异最近与显性神经发育障碍（NDDs）相关联，揭示了非编码snRNAs在人类疾病中一个以前被忽视的主要作用。在这里，我们通过国际合作，对一个包含26,911名罕见病患者的法国队列中的200个潜在功能性snRNA基因进行了系统分析。我们在来自108个无关家庭的126名个体中鉴定出与显性和隐性NDDs相关的 和双等位基因变异。隐性 NDD的发病率至少是由n.4G>A和n.35A>G引起的显性NDD的两倍，并且通常源于 中与一个遗传等位基因相关的变异，这反映了snRNA基因的高突变性。显性和隐性 -NDDs具有重叠的临床特征，且癫痫频发。血液转录组学和DNA甲基化分析揭示了对剪接和表观特征的细微、变异特异性影响。我们的研究结果支持影响梯度模型以及显性和隐性遗传之间的连续性，确定 变异是NDDs的常见病因，其患病率几乎与ReNU综合征一样高。
Zotero 插件