Scholarlink

<p>Small nuclear RNAs (snRNAs) are essential components of the spliceosome. De novo variants in snRNA genes <i>RNU4-2</i> (ReNU syndrome), <i>RNU5B-1</i> and <i>RNU2-2</i> 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 <i>RNU2-2</i> variants in 141 individuals, including 35 with recurrent dominant pathogenic variants and 91 affected members from 73 families with biallelic variants. Recessive <i>RNU2-2</i> 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 <i>RNU2-2</i> 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 <i>RNU2-2</i> variants as a principal contributor to NDDs, nearly as prevalent as ReNU syndrome.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月30日

查看全文
  • Elsa Leitão,
  • Amandine Santini,
  • Benjamin Cogne,
  • Miriam Essid,
  • Maria Athanasiadou,
  • Christy W. LaFlamme,
  • Pierre Marijon,
  • Virginie Bernard,
  • Kevin Jousselin,
  • Nicolas Chatron,
  • Giulia Barcia,
  • Boris Keren,
  • Cyril Mignot,
  • Perrine Charles,
  • Thomas Besnard,
  • Robin Paluch,
  • Jean-Madeleine de Sainte Agathe,
  • Edith P. Almanza Fuerte,
  • Soham Sengupta,
  • Mathieu Milh,
  • Francis Ramond,
  • Talia Allan,
  • Isabelle An,
  • Camila Araujo,
  • 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,
  • Pascal Chambon,
  • Nicole Chemaly,
  • Bertrand Chesneau,
  • Estelle 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,
  • 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,
  • Tobias B. Haack,
  • Nina Härting,
  • Martin Georg Häusler,
  • Solveig Heide,
  • Theresia Herget,
  • Bénédicte Héron,
  • Delphine Héron,
  • Johanna Herwig,
  • Mathilde Heulin,
  • Tess Holling,
  • Clara Houdayer,
  • Bertrand Isidor,
  • Aurélia Jacquette,
  • Louis Januel,
  • Nolwenn Jean-Marçais,
  • Frank J. Kaiser,
  • Sabine Kaya,
  • Chontelle King,
  • Marina Konyukh,
  • Florian Kraft,
  • Jeremias Krause,
  • Rémi Kirstetter,
  • Alma Kuechler,
  • Ingo Kurth,
  • Kerstin Kutsche,
  • Audrey Labalme,
  • Jean-Serene Laloy,
  • Vincent Laugel,
  • Floriane Le Bricquir,
  • Anne-Sophie Lèbre,
  • Marine Lebrun,
  • Eric Leguern,
  • Jonathan Levy,
  • Nico Lieffering,
  • Stanislas Lyonnet,
  • Kevin Lüthy,
  • Sian M. W. Macdonald,
  • Lamisse Mansour-Hendili,
  • Julien Maraval,
  • Iris Marquardt,
  • Carolin Mattausch,
  • Sandra Mercier,
  • Olfa Messaoud,
  • Godelieve Morel,
  • Jérémie Mortreux,
  • Arnold Munnich,
  • Rima Nabbout,
  • Sophie Nambot,
  • Vincent Navarro,
  • Ashana Neale,
  • Laetitia Nguyen,
  • Mathilde Nizon,
  • Frédérique Nowak,
  • Melanie C. O’Leary,
  • Sylvie Odent,
  • Naomi Meave Ojeda,
  • Valérie Olin,
  • Simone Olivieri,
  • Katrin Õunap,
  • Lynn S. Pais,
  • Eleni Panagiotakaki,
  • Olivier Patat,
  • Laurence Perrin-Sabourin,
  • Florence Petit,
  • Christophe Philippe,
  • Amélie Piton,
  • Marc Planes,
  • Céline Poirsier,
  • Antoine Pouzet,
  • Clément Prouteau,
  • Sylvia Quéméner-Redon,
  • Mathilde Renaud,
  • Anne-Claire Richard,
  • Marlène Rio,
  • Clotilde Rivier,
  • Florence Robin-Renaldo,
  • Paul Rollier,
  • Massimiliano Rossi,
  • Agathe Roubertie,
  • Valentin Ruault,
  • Maïlys Rupin-Mas,
  • Pascale Saugier-Veber,
  • Aline Saunier,
  • Russell Saneto,
  • Elisabeth Sarrazin,
  • Catherine Sarret,
  • Elise Schaefer,
  • Caroline Schluth-Bolard,
  • Amy Schneider,
  • Isabell Schumann,
  • Vladimir B. Seplyarskiy,
  • Stephanie Spranger,
  • Thomas Smol,
  • Marc Sturm,
  • Shamil R. Sunyaev,
  • Brian Sperelakis-Beedham,
  • Sarah L. Stenton,
  • Friedrich Stock,
  • Mylène Tharreau,
  • Deniz Torun,
  • Joseph Toulouse,
  • Harshini Thiyagarajah,
  • Stéphanie Valence,
  • Sophie Valleix,
  • Julien Van-Gils,
  • Laurent Villard,
  • Dorothée Ville,
  • Nathalie Villeneuve,
  • Antonio Vitobello,
  • Aurélie Waernessyckle,
  • Jan Wagner,
  • Yvonne Weber,
  • Dagmar Wieczorek,
  • Tom Witkowski,
  • Manya Yadavilli,
  • Tony Yammine,
  • Khaoula Zaafrane-Khachnaoui,
  • Maha S. Zaki,
  • Alban Ziegler,
  • Nuria C. Bramswig,
  • Alban Lermine,
  • Gael Nicolas,
  • Joseph G. Gleeson,
  • Lynette G. Sadleir,
  • Michael S. Hildebrand,
  • Ingrid E. Scheffer,
  • Nicola Whiffin,
  • Anne O’Donnell-Luria,
  • Heather C. Mefford,
  • Pierre Blanc,
  • Julien Thevenon,
  • Camille Charbonnier,
  • Clément Charenton,
  • Christel Depienne,
  • Gaetan Lesca,
  • Caroline Nava

摘要

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.