Biallelic variants in the non-coding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes

作者：Rocío Rius, Alexander J. M. Blakes, Yuyang Chen, Joachim De Jonghe, Javeria Raza Alvi, Florence Amblard, Christina Austin‐Tse, Sarah Baer, Meena Balasubramanian, Elsa Balton, Giulia Barcia, Jonathan A. Bernstein, Pierre Blanc, Daniel Buchzik, Daniel G. Calame, Benjamin Cogné, Charles Coutton, Chloe A Cunningham, Nitsuh Dargie, Christel Depienne, Katrina M. Dipple, Anne Dieux, Abhijit Dixit, Lauren Dreyer, Haowei Du, Salima El Chehadeh, Michael Field, Vanessa Geiger, Richard A. Gibbs, Ian A. Glass, Olivier Grunewald, Paul Guéguen, Tobias B. Haack, Hamza Hadj Abdallah, Radu Harbuz, Bertrand Isidor, Marie‐Line Jacquemont, Médéric Jeanne, Georg Christoph Korenke, Urania Kotzaeridou, Richard J. Leventer, James R. Lupski, Pierre Marijon, Kaitlin E McGinnis, Rodrigo Mendez, Olfa Messaoud, Caroline Nava, Mevyn Nizard, Anne O’Donnell‐Luria, M. O'Leary, Simone Olivieri, Amitav Parida, Davut Pehli̇van, Jennifer E. Posey, Chloe M. Reuter, Véronique Satre, Caroline Schluth‐Bolard, Thomas Smol, Tipu Sultan, Christel Thauvin‐Robinet, Julien Thévenon, Eloise Uebergang, Catherine Vincent‐Delorme, Evangeline Wassmer, Matthew T. Wheeler, Elif Yılmaz Güleç, Adeline Vanderver, Arastoo Vossough, Stephan Sanders, Siddharth Banka, Gregory M. Findlay, Daniel G. MacArthur, Cas Simons, Nicola Whiffin · 发表于：medRxiv · 年份：2025 · DOI：10.1101/2025.08.13.25333306 · 被引用次数：5 · 研究领域：RNA regulation and disease、RNA modifications and cancer、RNA Research and Splicing

ABSTRACT Genetic variants in RNU4-2 , which encodes U4, a key non-coding small nuclear RNA (snRNA) component of the major spliceosome, were recently shown to cause a prevalent neurodevelopmental disorder (NDD) called ReNU syndrome. These variants, which almost exclusively arise de novo , act in a dominant fashion and are clustered within 18 nucleotides (nt) in the centre of RNU4-2 . Here we describe a novel recessive NDD associated with homozygous and compound heterozygous variants in RNU4-2 . We identified 32 individuals with biallelic variants outside of the 18 nt ReNU syndrome region, that cluster within other functionally important elements of U4, including the Stem II region, the k-turn motif, and the Sm protein binding site. We characterise the clinical phenotype in 27 of these individuals, demonstrating that the recessive disorder is clinically distinct from dominant ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces. Together, these findings expand the genotypic and phenotypic spectrum of RNU4-2 -associated NDDs.