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

Genetic variants in RNU4-2, which is transcribed into the U4 small nuclear RNA component of the major spliceosome, were recently shown to cause ReNU syndrome, a prevalent dominant neurodevelopmental disorder (NDD). These variants almost exclusively arise de novo and cluster within 18 nucleotides of RNU4-2. Here we describe a new recessive NDD associated with homozygous and compound heterozygous variants in RNU4-2. We identify 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site. We characterize the clinical phenotype in 31 individuals, demonstrating that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces. Finally, we find reduced RNU4-2 transcript levels in individuals with the recessive disorder, suggesting a loss-of-function disease mechanism that is distinct from the mechanism underlying ReNU syndrome. Together, these findings expand the genotypic and phenotypic spectrum of RNU4-2-associated NDDs.

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Publication Details

Journal
Nature Genetics
Published
2026-04-01
DOI
https://doi.org/10.1038/s41588-026-02554-6
Citations
2
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
25.30

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article

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

Nitsuh Dargie, James R. Lupski, Abhijit Dixit, Radu Harbuz et al.
2 citations
Nature Genetics
RNA Research and Splicing
25.30
article

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

Nitsuh Dargie, James R. Lupski, Abhijit Dixit, Radu Harbuz, Daniel G. MacArthur, Marie‐Line Jacquemont, Ruebena Dawes, Tobias B. Haack, Christel Thauvin‐Robinet, Florence Amblard, Chloe A Cunningham, Arastoo Vossough, Cas Simons, Lauren Dreyer, Peter Michael Krawitz, Giulia Barcia, Rocío Rius, Nuria C. Bramswig, Olivier Grunewald, Hyung Chul Kim, François Lecoquierre, Christel Depienne, Alexander J. M. Blakes, Hannah Klinkhammer, Meena Balasubramanian, Rebecca J. Levy, Chloe M. Reuter, Kaitlin McGINNIS, Yuyang Chen, Véronique Satre, Annabelle Arlt, Joachim De Jonghe, Caroline Nava, Daniel G. Calame, Morad Ansari, Stephan Sanders, Richard Jacob Leventer, Melanie O’Leary, Urania Kotzaeridou, Riley Kessler, Pierre Marijon, Matthew T. Wheeler, Frederik Braun, Olfa Messaoud, Siddharth Banka, Anne Dieux, Eloise Uebergang, Alexander Hustinx, Sarah Baer, Sandra Ueberberg, Thomas Smol, Ian A. Glass, Nicola Whiffin, Gregory M. Findlay, Steven Laurie, Evangeline Wassmer, Jasmin Beygo, C Vincent-Delorme, Elsa Balton, Tipu Sultan, Jamie Campbell, Ingo Helbig, Jonathan A. Bernstein, Charles Coutton, Benjamin Cogné, Hamza Hadj Abdallah, Amitav Parida, Katrina M. Dipple, Jane Horvath, Daniel Buchzik, Vanessa Geiger, Mevyn Nizard, Simone Olivieri, Salima El Chehadeh, Elif Yilmaz Gulec, Anne O’Donnell-Luria, Anna Jenne Prentice, Rodrigo Mendez, Christina Austin-Tse, Jennifer E. Posey, Caroline Schluth-Bolard, Ana Beleza-Meireles, Haowei Du, Adeline Vanderver, Julien Thevenon, Javeria R. Alvi, Lisa J. Ewans, John Taylor, Bertrand Isidor, Fraser Jamie, Médéric Jeanne, Davut Pehlivan, Paul Gueguen, Richard A. Gibbs, Pierre Blanc, Emma Westwood, G. Christoph Korenke
article en
2 citations

Abstract

Genetic variants in RNU4-2, which is transcribed into the U4 small nuclear RNA component of the major spliceosome, were recently shown to cause ReNU syndrome, a prevalent dominant neurodevelopmental disorder (NDD). These variants almost exclusively arise de novo and cluster within 18 nucleotides of RNU4-2. Here we describe a new recessive NDD associated with homozygous and compound heterozygous variants in RNU4-2. We identify 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site. We characterize the clinical phenotype in 31 individuals, demonstrating that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces. Finally, we find reduced RNU4-2 transcript levels in individuals with the recessive disorder, suggesting a loss-of-function disease mechanism that is distinct from the mechanism underlying ReNU syndrome. Together, these findings expand the genotypic and phenotypic spectrum of RNU4-2-associated NDDs.

Nature GeneticsVol. 58(4)
Broad Institute (US), Université de Tours (FR), Boston Children's Hospital (US), Centre National de la Recherche Scientifique (FR), National Health Service Scotland (GB), Royal Children's Hospital (AU), NHS Lothian (GB), Nottingham University Hospitals NHS Trust (GB), Children's Hospital of Philadelphia (US), Centre for Human Genetics (GB), Children's National (US), University of Bonn (DE), Harvard University (US), Garvan Institute of Medical Research (AU), Université de Pau et des Pays de l'Adour (FR), Inserm (FR), The University of Melbourne (AU), Aston University (GB), Zimmer Biomet (Netherlands) (NL), Université de Bourgogne (FR), University of California, San Francisco (US), Baylor College of Medicine (US), Guy's and St Thomas' NHS Foundation Trust (GB), University of Washington (US), Université Paris Cité (FR), Heidelberg University (DE), Université de Lille (FR), NHS Education for Scotland (GB), Centre Hospitalier Universitaire de Grenoble (FR), Government of Western Australia Department of Health (AU), The Francis Crick Institute (GB), University Hospital Heidelberg (DE), Open Data Institute (GB), University of Health Sciences Lahore (PK), University of Manchester (GB), Centre Hospitalier Universitaire de Lille (FR), Centre Hospitalier Universitaire de Nantes (FR), UNSW Sydney (AU), Sorbonne Université (FR), University of Oxford (GB), Institut de génétique et de biologie moléculaire et cellulaire (FR), Massachusetts General Hospital (US), München Klinik Schwabing (DE), Manchester University NHS Foundation Trust (GB), Centre Hospitalier Universitaire de Tours (FR), Assistance Publique – Hôpitaux de Paris (FR), Hunter Genetics (AU), Birmingham Children's Hospital (GB), Heidelberger Institut für Radioonkologie (DE), University Hospital Münster (DE), Hôpital Jeanne de Flandre (FR), Genetikum (DE), Normandie Université (FR), St Mary's Hospital (GB), Klinikum Oldenburg (DE), Victorian Clinical Genetics Services (AU), Laboratoire National de Référence (MA), Sheffield Children's NHS Foundation Trust (GB), Centre Hospitalier d'Arras (FR), Brotman Baty Institute (US), Stanford Medicine (US), Istanbul Eye Hospital (TR), Centro Nacional de Análisis Genómico (ES), Institut du Thorax (FR), Hôpitaux Universitaires de Strasbourg (FR), Texas Children's Hospital (US), Sydney Children’s Hospitals Network (AU), Murdoch Children's Research Institute (AU), Center for Genomic Science (IT), Institut du Cerveau (FR), Birmingham Women’s and Children’s NHS Foundation Trust (GB), Génétique Médicale & Génomique Fonctionelle (FR), Institut des Maladies Génétiques Imagine (FR), Istanbul Medeniyet University (TR), University of Duisburg-Essen (DE), Université de Rouen Normandie (FR), Université de Strasbourg (FR), Universitat de Barcelona (ES), Cochrane (GB), University of Pennsylvania (US), University of Tübingen (DE), Université Grenoble Alpes (FR), University of Sheffield (GB), Stanford University (US), Nantes Université (FR)
Silicon Valley Community Foundation, Wellcome, Wellcome Trust, Francis Crick Institute, Children’s Hospital of Wisconsin Research Institute, Broad Institute, Murdoch Children's Research Institute, Australian Government, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, European Commission, Lister Institute of Preventive Medicine, Deutsche Forschungsgemeinschaft, Department of Health and Aged Care, Australian Government, Novo Nordisk, National Institutes of Health, Manchester Biomedical Research Centre, Medical Research Council, National Health and Medical Research Council, National Institute of Neurological Disorders and Stroke
Openalex Percentile: Top 0%
RNA Research and Splicing
25.30
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