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<p>The major spliceosome contains five small nuclear RNAs (snRNAs; U1, U2, U4, U5 and U6) essential for splicing. Variants in <i>RNU4-2</i>, encoding U4, cause a neurodevelopmental disorder called ReNU syndrome. We investigated de novo variants in 50 snRNA-encoding genes in a French cohort of 23,649 individuals with rare disorders and gathered additional cases through international collaborations. Altogether, we identified 145 previously unreported probands with (likely) pathogenic variants in <i>RNU4-2</i> and 21 individuals with de novo and/or recurrent variants in <i>RNU5B-1</i> and <i>RNU5A-1</i>, encoding U5. Pathogenic variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. <i>RNU4-2</i> variants mainly localize to two structures, the stem III and T-loop/quasi-pseudoknot, which position the U6 ACAGAGA box for 5′ splice site recognition and associate with different phenotypic severity. <i>RNU4-2</i> variants result in specific defects in alternative 5′ splice site usage and methylation patterns (episignatures) that correlate with variant location and clinical severity. This study establishes <i>RNU5B-1</i> as a neurodevelopmental disorder gene, suggests <i>RNU5A-1</i> as a strong candidate and highlights the role of de novo variants in snRNAs.</p>

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Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption

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  • 发表日期：

    2025年5月16日

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  • Caroline Nava,
  • Benjamin Cogne,
  • Amandine Santini,
  • Elsa Leitão,
  • François Lecoquierre,
  • Yuyang Chen,
  • Sarah L. Stenton,
  • Thomas Besnard,
  • Solveig Heide,
  • Sarah Baer,
  • Abhilasha Jakhar,
  • Sonja Neuser,
  • Boris Keren,
  • Anne Faudet,
  • Sylvie Forlani,
  • Marie Faoucher,
  • Kevin Uguen,
  • Konrad Platzer,
  • Alexandra Afenjar,
  • Jean-Luc Alessandri,
  • Stephanie Andres,
  • Chloé Angelini,
  • Bernard Aral,
  • Benoit Arveiler,
  • Tania Attie-Bitach,
  • Marion Aubert Mucca,
  • Guillaume Banneau,
  • Tahsin Stefan Barakat,
  • Giulia Barcia,
  • Stéphanie Baulac,
  • Claire Beneteau,
  • Fouzia Benkerdou,
  • Virginie Bernard,
  • Stéphane Bézieau,
  • Dominique Bonneau,
  • Marie-Noelle Bonnet-Dupeyron,
  • Simon Boussion,
  • Odile Boute,
  • Elise Brischoux-Boucher,
  • Samantha J. Bryen,
  • Julien Buratti,
  • Tiffany Busa,
  • Almuth Caliebe,
  • Yline Capri,
  • Kévin Cassinari,
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  • Camille Cenni,
  • Pascal Chambon,
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  • John Christodoulou,
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  • Alissa M. D’Gama,
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  • Andrée Delahaye-Duriez,
  • Julian Delanne,
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  • Stephan Drukewitz,
  • Véronique Duboc,
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  • Yannis Duffourd,
  • David Dyment,
  • Salima El Chehadeh,
  • Monique Elmaleh,
  • Laurence Faivre,
  • Samuel Fennelly,
  • Hanna Fischer,
  • Mélanie Fradin,
  • Camille Galludec Vaillant,
  • Benjamin Ganne,
  • Jamal Ghoumid,
  • Himanshu Goel,
  • Zeynep Gokce-Samar,
  • Alice Goldenberg,
  • Romain Gonfreville Robert,
  • Svetlana Gorokhova,
  • Louise Goujon,
  • Victoria Granier,
  • Mathilde Gras,
  • John M. Greally,
  • Bianca Greiten,
  • Paul Gueguen,
  • Anne-Marie Guerrot,
  • Saurav Guha,
  • Anne Guimier,
  • Tobias B. Haack,
  • Hamza Hadj Abdallah,
  • Yosra Halleb,
  • Radu Harbuz,
  • Madeleine Harris,
  • Julia Hentschel,
  • Bénédicte Héron,
  • Marc-Phillip Hitz,
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  • Vincent Jadas,
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  • Ryan Lamont,
  • Vincent Laugel,
  • Steven Laurie,
  • Julie L. Lauzon,
  • Louis Lebreton,
  • Marine Lebrun,
  • Marine Legendre,
  • Eric Leguern,
  • Daphné Lehalle,
  • Elodie Lejeune,
  • Gaetan Lesca,
  • Marion Lesieur-Sebellin,
  • Jonathan Levy,
  • Agnès Linglart,
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  • Kevin Lüthy,
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  • Jean-Louis Mandel,
  • Lamisse Mansour-Hendili,
  • Julien Marcadier,
  • Victor Marin,
  • Henri Margot,
  • Valentine Marquet,
  • Angèle May,
  • Johannes A. Mayr,
  • Catherine Meridda,
  • Vincent Michaud,
  • Caroline Michot,
  • Gwenael Nadeau,
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  • Laetitia Nguyen,
  • Mathilde Nizon,
  • Frédérique Nowak,
  • Sylvie Odent,
  • Valerie Olin,
  • Ikeoluwa A. Osei-Owusu,
  • Matthew Osmond,
  • Katrin Õunap,
  • Laurent Pasquier,
  • Sandrine Passemard,
  • Melissa Pauly,
  • Olivier Patat,
  • Marine Pensec,
  • Laurence Perrin-Sabourin,
  • Florence Petit,
  • Christophe Philippe,
  • Marc Planes,
  • Annapurna Poduri,
  • Céline Poirsier,
  • Antoine Pouzet,
  • Bradley Prince,
  • Clément Prouteau,
  • Aurora Pujol,
  • Caroline Racine,
  • Mélanie Rama,
  • Francis Ramond,
  • Kara Ranguin,
  • Margaux Raway,
  • André Reis,
  • Mathilde Renaud,
  • Nicole Revencu,
  • Anne-Claire Richard,
  • Lucile Riera-Navarro,
  • Rocio Rius,
  • Diana Rodriguez,
  • Agustí Rodriguez-Palmero,
  • Sophie Rondeau,
  • Annika Roser-Unruh,
  • Christelle Rougeot Jung,
  • Hana Safraou,
  • Véronique Satre,
  • Pascale Saugier-Veber,
  • Clément Sauvestre,
  • Elise Schaefer,
  • Wanqing Shao,
  • Ina Schanze,
  • Jan-Ulrich Schlump,
  • Agatha Schlüter Martin,
  • Caroline Schluth-Bolard,
  • Sarah Schuhmann,
  • Christopher Schröder,
  • Monisha Sebastin,
  • Sabine Sigaudy,
  • Malte Spielmann,
  • Marta Spodenkiewicz,
  • Laura St Clair,
  • Julie Steffann,
  • Radka Stoeva,
  • Harald Surowy,
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  • Annick Toutain,
  • Frédéric Tran Mau-Them,
  • Astrid Unterlauft,
  • Julien Van-Gils,
  • Clémence Vanlerberghe,
  • Georgia Vasileiou,
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  • André Verdel,
  • Alain Verloes,
  • Yoann Vial,
  • Cédric Vignal,
  • Marie Vincent,
  • Catherine Vincent-Delorme,
  • Aline Vincent-Devulder,
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  • Marjolaine Willems,
  • Khaoula Zaafrane-Khachnaoui,
  • Pia Zacher,
  • Lena Zeltner,
  • Alban Ziegler,
  • Wojciech P. Galej,
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  • Kym M. Boycott,
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  • Nicolas Chatron,
  • Amélie Piton,
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  • Matias Wagner,
  • Rami Abou Jamra,
  • Delphine Héron,
  • Cyril Mignot,
  • Pierre Blanc,
  • Anne O’Donnell-Luria,
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  • Camille Charbonnier,
  • Clément Charenton,
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  • Christel Depienne

摘要

The major spliceosome contains five small nuclear RNAs (snRNAs; U1, U2, U4, U5 and U6) essential for splicing. Variants in RNU4-2, encoding U4, cause a neurodevelopmental disorder called ReNU syndrome. We investigated de novo variants in 50 snRNA-encoding genes in a French cohort of 23,649 individuals with rare disorders and gathered additional cases through international collaborations. Altogether, we identified 145 previously unreported probands with (likely) pathogenic variants in RNU4-2 and 21 individuals with de novo and/or recurrent variants in RNU5B-1 and RNU5A-1, encoding U5. Pathogenic variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. RNU4-2 variants mainly localize to two structures, the stem III and T-loop/quasi-pseudoknot, which position the U6 ACAGAGA box for 5′ splice site recognition and associate with different phenotypic severity. RNU4-2 variants result in specific defects in alternative 5′ splice site usage and methylation patterns (episignatures) that correlate with variant location and clinical severity. This study establishes RNU5B-1 as a neurodevelopmental disorder gene, suggests RNU5A-1 as a strong candidate and highlights the role of de novo variants in snRNAs.