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

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.

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Item Type:	Article
Authors/Creators:	Rius, R. https://orcid.org/0000-0002-9871-3126 Blakes, A.J.M. https://orcid.org/0000-0002-0260-7020 Chen, Y. https://orcid.org/0000-0001-5593-6920 De Jonghe, J. https://orcid.org/0000-0003-0584-8265 Lecoquierre, F. https://orcid.org/0000-0002-9110-1856 Dawes, R. https://orcid.org/0000-0003-2135-0117 Cogne, B. https://orcid.org/0000-0002-5503-6292 Kim, H.C. https://orcid.org/0000-0001-5877-5456 Alvi, J.R. Amblard, F. Ansari, M. Arlt, A. Austin-Tse, C. Baer, S. Balasubramanian, M. https://orcid.org/0000-0003-1488-3695 Balton, E.V. https://orcid.org/0000-0002-5699-3895 Barcia, G. Beleza-Meireles, A. Bernstein, J.A. https://orcid.org/0000-0001-5369-346X Beygo, J. Blanc, P. Bramswig, N.C. https://orcid.org/0000-0002-3367-586X Braun, F. https://orcid.org/0000-0002-3601-2746 Buchzik, D. Calame, D.G. Campbell, J. Coutton, C. Cunningham, C.A. https://orcid.org/0000-0002-2525-1936 Dargie, N. Depienne, C. https://orcid.org/0000-0002-7212-9554 Dipple, K.M. Dieux, A. Dixit, A. https://orcid.org/0000-0001-9240-0674 Dreyer, L. Du, H. El Chehadeh, S. https://orcid.org/0000-0003-1613-6570 Field, M. https://orcid.org/0000-0001-7455-934X Ewans, L.J. Geiger, V. Gibbs, R.A. Glass, I. https://orcid.org/0000-0001-6762-8407 Grunewald, O. Gueguen, P. Haack, T.B. https://orcid.org/0000-0001-6033-4836 Hadj Abdallah, H. Harbuz, R. Helbig, I. https://orcid.org/0000-0001-8486-0558 Horvath, J. Hustinx, A. https://orcid.org/0000-0003-4592-3979 Isidor, B. Jacquemont, M.-L. Jamie, F. Jeanne, M. Kessler, R. Klinkhammer, H. https://orcid.org/0000-0003-3752-1275 Korenke, G.C. Kotzaeridou, U. Krawitz, P. https://orcid.org/0000-0002-3194-8625 Laurie, S. https://orcid.org/0000-0003-3913-5829 Leventer, R.J. https://orcid.org/0000-0003-0362-5607 Levy, R.J. https://orcid.org/0000-0003-0393-6835 Lupski, J.R. https://orcid.org/0000-0001-9907-9246 Marijon, P. https://orcid.org/0000-0002-6694-6873 McGinnis, K.E. Mendez, R. Messaoud, O. https://orcid.org/0000-0003-4547-0180 Nava, C. https://orcid.org/0000-0003-1272-0518 Nizard, M. O’Donnell-Luria, A. O’Leary, M.C. https://orcid.org/0000-0002-8718-4759 Olivieri, S. Parida, A. Pehlivan, D. Prentice, A.J. https://orcid.org/0009-0008-7459-1778 Posey, J.E. https://orcid.org/0000-0003-4814-6765 Reuter, C.M. Satre, V. Schluth-Bolard, C. Smol, T. Sultan, T. Taylor, J. Thauvin-Robinetvin, C. https://orcid.org/0000-0002-4155-139X Thevenon, J. Uebergang, E. https://orcid.org/0000-0003-0305-7822 Ueberberg, S. Vincent-Delorme, C. Wassmer, E. https://orcid.org/0000-0002-2446-1106 Westwood, E. Wheeler, M.T. https://orcid.org/0000-0001-8721-3022 Gulec, E.Y. Vanderver, A. Vossough, A. Sanders, S.J. https://orcid.org/0000-0001-9112-5148 Banka, S. https://orcid.org/0000-0002-8527-2210 Findlay, G.M. https://orcid.org/0000-0002-7767-8608 MacArthur, D.G. Simons, C. https://orcid.org/0000-0003-3147-8042 Whiffin, N. https://orcid.org/0000-0003-1554-6594
Copyright, Publisher and Additional Information:	© The Author(s) 2026. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Genetic testing; Genomics; Medical genetics
Dates:	Submitted: 18 August 2025 Accepted: 25 February 2026 Published (online): 8 April 2026 Published: April 2026
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Funding Information:	Funder Grant number Wellcome Trust Ltd 223521/Z/21/Z
Date Deposited:	16 Apr 2026 08:59
Last Modified:	16 Apr 2026 08:59
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41588-026-02554-6
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:240091

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

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