ArticleNature genetics2026
Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy.
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Article in Nature genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed.
- Whole-genome discovery of pathogenic snRNA variants and efficient extended-exome screening.iScience · 2026Article
- Multiple quality control checkpoints safeguard small nuclear RNA biogenesis and prevent assembly of aberrant spliceosomes.Genes & development · 2026Article
- Guidance for clinical variant classification in genes for spliceosomal small nuclear RNAs.medRxiv : the preprint server for health sciences · 2026Article
- Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder.Nature genetics · 2026Article
- Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes.Nature genetics · 2026Article
- Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies.Nature genetics · 2026Article
- Blood-based RNA-Seq of 5412 individuals with rare disease identifies new candidate diagnoses in the National Genomic Research Library.medRxiv : the preprint server for health sciences · 2026Article
- The human branchpoint-interacting stem-loop sequence and structure regulates U2 snRNA expression, branchpoint recognition, and the transcriptome.Nucleic acids research · 2026Article
- The human branchpoint-interacting stem loop sequence and structure regulates U2 snRNA expression, branchpoint recognition, and transcriptome.bioRxiv : the preprint server for biology · 2025Article
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Authors and funding
62 authors.
Adam Jackson *Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. adam.jackson@manchester.ac.uk.ORCID http://orcid.org/0000-0002-3674-3960
Alexander J M Blakes *Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.ORCID http://orcid.org/0000-0002-0260-7020
Bader AlhaddadLifera Omics, Riyadh, Saudi Arabia.
Olivia J HenryDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.ORCID http://orcid.org/0000-0002-4717-8346
Angelica M Delgado-VegaDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.ORCID http://orcid.org/0000-0002-9865-0591
Elizabeth WallWest Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
Ola AbdelhadiDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Shakti AgrawalBirmingham Children's Hospital, Birmingham, UK.
Khadijah BakurLifera Omics, Riyadh, Saudi Arabia.
Edward BlairOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Angela F BradyNorth West Thames Regional Genetics Service, London North West Healthcare University NHS Trust, Northwick Park Hospital, London, UK.
Helen BrittainWest Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
Kate E ChandlerDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Natasha ClarkeSouth West Thames Centre for Genomics, St George's, Epsom and St Helier University Hospitals and Health Group, London, UK.
Miriana DanelliGenetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Nicholas DrinkallCentral and South Genomic Laboratory Hub, West Midlands Genomics Laboratory, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
Irene DubaDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.ORCID http://orcid.org/0009-0005-4189-8704
Frances ElmslieSouth West Thames Centre for Genomics, St George's, Epsom and St Helier University Hospitals and Health Group, London, UK.ORCID http://orcid.org/0000-0002-2508-9107
Jamie EllingfordDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.ORCID http://orcid.org/0000-0003-1137-9768
Lisa J EwansCentre for Clinical Genetics, Sydney Children's Hospitals Network, Sydney, New South Wales, Australia.
Andrew P FennellMonash Genetics, Monash Health, Melbourne, Victoria, Australia.ORCID http://orcid.org/0000-0001-6744-1810
Gabriella GazdaghWessex Clinical Genetic Service, University Hospital Southampton, Southampton, UK.
Simon P HellerNeurology Department, King's College Hospital, Denmark Hill, London, UK.ORCID http://orcid.org/0000-0001-7335-9266
Anna HammarsjöDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Kristina KarrmanDepartment of Clinical Genetics, Pathology and Molecular Diagnostics, Skåne University Hospital, Lund, Sweden.
Usha KiniOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Nicole LeskoDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Anna LindstrandDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Rebecca MacintoshCentre for Clinical Genetics, Sydney Children's Hospitals Network, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0001-5036-0264
Sahar MansourSouth West Thames Centre for Genomics, St George's, Epsom and St Helier University Hospitals and Health Group, London, UK.
Lara MenziesDepartment of Clinical Genetics, Great Ormond Street Hospital, London, UK.
Kay MetcalfeDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Alison MilhenchGloucestershire Hospitals NHS Foundation Trust, Cheltenham, UK.
Lina NashefNeurology Department, King's College Hospital, Denmark Hill, London, UK.
Raymond T O'KeefeDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.ORCID http://orcid.org/0000-0001-8764-1289
Nadja Pekkola PachecoDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Elizabeth E PalmerCentre for Clinical Genetics, Sydney Children's Hospitals Network, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0003-1844-215X
Amitav ParidaBirmingham Children's Hospital, Birmingham, UK.
Katrina PrescottLeeds Clinical Genomics Service, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
Melody RedmanLeeds Clinical Genomics Service, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
Alessandra RenieriGenetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.ORCID http://orcid.org/0000-0002-0846-9220
Chiara FalleriniGenetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Caterina Lo RizzoGenetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Rani SachdevCentre for Clinical Genetics, Sydney Children's Hospitals Network, Sydney, New South Wales, Australia.
Cas SimonsCentre for Population Genomics, Garvan Institute of Medical Research, UNSW Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0003-3147-8042
Sanjay M SisodiyaResearch Department of Epilepsy, UCL Queen Square Institute of Neurology, London, UK.ORCID http://orcid.org/0000-0002-1511-5893
Helen StewartOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Tommy StödbergDepartment of Child Neurology, Karolinska University Hospital, Stockholm, Sweden.
Benito Banos-PineroOxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Fulya TaylanDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.ORCID http://orcid.org/0000-0002-2907-0235
Huw B ThomasDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.ORCID http://orcid.org/0000-0001-9626-9706
Flavia TinellaGenetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
Samuel WiafeRare Disease Ghana Initiative, Accra, Ghana.
Anna WedellDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Nicola WhiffinBig Data Institute, University of Oxford, Oxford, UK.
Susan WalkerGenomics England, London, UK.ORCID http://orcid.org/0000-0002-5016-6426
Rocio RiusCentre for Population Genomics, Garvan Institute of Medical Research, UNSW Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-9871-3126
Jong Hee ChaeDepartment of Genomic Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
Ann NordgrenDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.ORCID http://orcid.org/0000-0003-3285-4281
Fowzan AlkurayaLifera Omics, Riyadh, Saudi Arabia.ORCID http://orcid.org/0000-0003-4158-341X
Jenny LordSheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, Sheffield, UK.ORCID http://orcid.org/0000-0002-0539-9343
Siddharth BankaDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. siddharth.banka@manchester.ac.uk.ORCID http://orcid.org/0000-0002-8527-2210
Funding
No grant is acknowledged in the PubMed record.
Abstract
Neurodevelopmental disorders (NDDs) affect 2-4% of the population, are predominantly genetic and remain unsolved in ~50% of individuals. We show that rare biallelic variants in RNU2-2 are enriched and over-transmitted in individuals with unresolved NDDs. We define a recessive RNU2-2 syndrome, delineate its unique genetic architecture and show that it manifests clinically as a severe developmental and epileptic encephalopathy. We find that candidate biallelic variants are significantly correlated with reduced U2-2 abundance, implicating compromised transcript stability as a probable pathomechanism. We identify a decreased ratio of U2-2 to its paralog U2-1 as a potential diagnostic biomarker for this condition. We show that the recessive RNU2-2 syndrome is genetically, clinically and mechanistically distinct from the dominant RNU2-2 disorder. Within our cohort, the recessive RNU2-2 syndrome emerges as by far the most frequent recessive NDD, greatly disproportionate to the small genomic footprint of this non-protein-coding gene.
Indexed as
EpilepsyNeurodevelopmental DisordersRNA, Small NuclearAllelesFemaleGenes, RecessiveHumansRNA, Small Nuclear
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