Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes
- PMID: 40442284
- PMCID: PMC12165836
- DOI: 10.1038/s41588-025-02209-y
Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes
Erratum in
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Publisher Correction: Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes.Nat Genet. 2025 Jul;57(7):1792. doi: 10.1038/s41588-025-02274-3. Nat Genet. 2025. PMID: 40555818 Free PMC article. No abstract available.
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.
© 2025. The Author(s).
Conflict of interest statement
Competing interests: The authors declare no competing interests.
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References
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- García-Muse, T. & Aguilera, A. R loops: from physiological to pathological roles. Cell179, 604–618 (2019). - PubMed
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- 779257/EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
- 223521/Z/21/Z/Wellcome Trust (Wellcome)
- 2009982/Department of Health | National Health and Medical Research Council (NHMRC)
- WT_/Wellcome Trust/United Kingdom
- NIHR203308/DH | National Institute for Health Research (NIHR)
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