Analysis of R-loop forming regions identifies RNU2-2 and RNU5B-1 as neurodevelopmental disorder genes
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.
Authors
- Sam Griffiths‐Jones (ORCID: https://orcid.org/0000-0001-6043-807X)
- Nora Shannon (ORCID: https://orcid.org/0000-0003-3150-7894)
- Cas Simons (ORCID: https://orcid.org/0000-0003-3147-8042)
- T. Kim (ORCID: https://orcid.org/0009-0001-5303-0444)
- Adam Jackson (ORCID: https://orcid.org/0000-0002-3674-3960)
- Rocío Rius (ORCID: https://orcid.org/0000-0002-9871-3126)
- Alexander J. M. Blakes (ORCID: https://orcid.org/0000-0002-0260-7020)
- Meena Balasubramanian (ORCID: https://orcid.org/0000-0003-1488-3695)
- Raymond T. O’Keefe (ORCID: https://orcid.org/0000-0001-8764-1289)
- Tiong Yang Tan (ORCID: https://orcid.org/0000-0001-8455-7778)
- Siddharth Banka (ORCID: https://orcid.org/0000-0002-8527-2210)
- Jong‐Hee Chae (ORCID: https://orcid.org/0000-0002-9162-0138)
- Jennifer Campbell (ORCID: https://orcid.org/0000-0002-0684-4437)
- Anna de Burca
- Jamie M. Ellingford (ORCID: https://orcid.org/0000-0003-1137-9768)
- Gillian Rice (ORCID: https://orcid.org/0000-0002-4223-0571)
- Melody Redman (ORCID: https://orcid.org/0000-0003-3112-3188)
- David Hunt
- Jungmin Choi (ORCID: https://orcid.org/0000-0002-8614-0973)
- Soo‐Yeon Kim (ORCID: https://orcid.org/0000-0001-8915-3924)
- Seungbok Lee (ORCID: https://orcid.org/0000-0002-3145-8714)
- Juhyeon Hong (ORCID: https://orcid.org/0009-0009-2070-3022)
- Nishi Thaker
Institutions
- Garvan Institute of Medical Research (AU)
- The University of Melbourne (AU)
- Korea University (KR)
- Leeds Teaching Hospitals NHS Trust (GB)
- Manchester Academic Health Science Centre (GB)
- Princess Anne Hospital (GB)
- Seoul National University Hospital (KR)
- Nottingham City Hospital (GB)
- University Hospital Southampton NHS Foundation Trust (GB)
- University of Manchester (GB)
- UNSW Sydney (AU)
- Manchester University NHS Foundation Trust (GB)
- Seoul National University Children's Hospital (KR)
- St Mary's Hospital (GB)
- Victorian Clinical Genetics Services (AU)
- Sheffield Children's NHS Foundation Trust (GB)
- Genomics England (GB)
- Murdoch Children's Research Institute (AU)
- Genomics (United Kingdom) (GB)
- University of Sheffield (GB)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-05-29
- DOI
- https://doi.org/10.1038/s41588-025-02209-y
- Citations
- 16
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 12.90
Funders
- Wellcome
- Wellcome Trust
- Children’s Hospital of Wisconsin Research Institute
- Murdoch Children's Research Institute
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care
- European Commission
- Horizon 2020 Framework Programme
- Manchester Biomedical Research Centre
- Medical Research Council
- National Health and Medical Research Council