Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes

Abstract

R-loops are DNA–RNA hybrid structures that may promote mutagenesis. However, their contribution to human Mendelian disorders is unexplored. Here we show excess de novo variants in genomic regions that form R-loops (henceforth, ‘R-loop regions’) and demonstrate enrichment of R-loop region variants (RRVs) in ribozyme, snoRNA and snRNA genes, specifically in rare disease cohorts. Using this insight, we report neurodevelopmental disorders (NDDs) caused by rare variants in two major spliceosomal RNA encoding genes, RNU2-2 and RNU5B-1. These, along with the recently described RNU4-2-related ReNU syndrome, provide a genetic explanation for a substantial proportion of individuals with NDDs.

Metadata

Item Type:	Article
Authors/Creators:	Jackson, A. https://orcid.org/0000-0002-3674-3960 Thaker, N. https://orcid.org/0009-0006-7025-8842 Blakes, A. https://orcid.org/0000-0002-0260-7020 Rice, G. https://orcid.org/0000-0002-4223-0571 Griffiths-Jones, S. https://orcid.org/0000-0001-6043-807X Balasubramanian, M. https://orcid.org/0000-0003-1488-3695 Campbell, J. Shannon, N. Choi, J. Hong, J. Hunt, D. de Burca, A. Kim, S.Y. Kim, T. https://orcid.org/0009-0001-5303-0444 Lee, S. Redman, M. Rius, R. Simons, C. Tan, T.Y. https://orcid.org/0000-0001-8455-7778 Ellingford, J. https://orcid.org/0000-0003-1137-9768 O’Keefe, R.T. https://orcid.org/0000-0001-8764-1289 Chae, J.H. Banka, S. https://orcid.org/0000-0002-8527-2210
Copyright, Publisher and Additional Information:	© The Author(s) 2025. 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:	Clinical genetics; Neurodevelopmental disorders
Dates:	Submitted: 3 October 2024 Accepted: 28 April 2025 Published (online): 29 May 2025 Published: June 2025
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 223521/Z/21/Z
Depositing User:	Symplectic Sheffield
Date Deposited:	11 Jun 2025 09:34
Last Modified:	16 Jun 2025 11:42
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41588-025-02209-y
Related URLs:	Dataset Dataset
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:227716