ArticleNature genetics2026
Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes.
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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. An erratum has been issued. Cited by 9 papers.
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9citing papers in PubMed
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Who cites it
9 citing papers in PubMed.
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- Article
- 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
- Article
- Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies.Nature genetics · 2026Article
- Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy.Nature genetics · 2026Article
- Systematic analysis of snRNA genes reveals frequentmedRxiv : the preprint server for health sciences · 2025Article
Corrections and comments
- Erratum issued
Authors and funding
98 authors.
Rocio Rius *Centre for Population Genomics, Garvan Institute of Medical Research, UNSW Sydney, Sydney, New South Wales, Australia.ORCID http://orcid.org/0000-0002-9871-3126
Alexander J M Blakes *Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.ORCID http://orcid.org/0000-0002-0260-7020
Yuyang ChenBig Data Institute, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0001-5593-6920
Joachim De JongheThe Genome Function Laboratory, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0003-0584-8265
François LecoquierreBig Data Institute, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0002-9110-1856
Ruebena DawesBig Data Institute, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0003-2135-0117
Benjamin CogneNantes Université, CHU de Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.ORCID http://orcid.org/0000-0002-5503-6292
Hyung Chul KimBig Data Institute, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0001-5877-5456
Javeria R AlviDepartment of Pediatric Neurology, University of Child Health Sciences, The Children's Hospital, Lahore, Pakistan.
Florence AmblardService de Génétique, Génomique et Procréation, CHU Grenoble Alpes, Grenoble, France.
Morad AnsariSouth East Scotland Clinical Genetics Service, NHS lothian, Edinburgh, UK.
Annabelle ArltInstitute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany.
Christina Austin-TseCenter for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Sarah BaerDepartment of Neuropediatrics, ERN EpiCare, French Centre de référence des Épilepsies Rares (CréER), Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Meena BalasubramanianDivision of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK.ORCID http://orcid.org/0000-0003-1488-3695
Elsa V BaltonDepartment of Medicine, University of Washington School of Medicine, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-5699-3895
Giulia BarciaGenomic Medecine of Rare Disease, Necker Hospital, Paris, France.
Ana Beleza-MeirelesClinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London, UK.
Jonathan A BernsteinDepartment of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.ORCID http://orcid.org/0000-0001-5369-346X
Jasmin BeygoInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Pierre BlancLaboratoire SeqOIA, Paris, France.
Nuria C BramswigDepartment of Medical Genetics, Centre of Medical Genetics, University and University Hospital Münster, Münster, Germany.ORCID http://orcid.org/0000-0002-3367-586X
Frederik BraunInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.ORCID http://orcid.org/0000-0002-3601-2746
Daniel BuchzikDepartment of Neuropediatrics, Diak Klinikum Landkreis Schwäbisch Hall, Schwäbisch Hall, Germany.
Daniel G CalameSection of Pediatric Neurology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Jamie CampbellSouth East Scotland Clinical Genetics Service, NHS lothian, Edinburgh, UK.
Charles CouttonService de Génétique, Génomique et Procréation, CHU Grenoble Alpes, Grenoble, France.
Chloe A CunninghamVictorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.ORCID http://orcid.org/0000-0002-2525-1936
Nitsuh DargieDepartment of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
Christel DepienneInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.ORCID http://orcid.org/0000-0002-7212-9554
Katrina M DippleDepartment of Pediatrics, University of Washington, Seattle, WA, USA.
Anne DieuxCHU Lille, ULR7364 - RADEME - Maladies Rares du Développement Embryonnaire, Lille, France.
Abhijit DixitClinical Genetics, Nottingham University Hospitals, Nottingham, UK.ORCID http://orcid.org/0000-0001-9240-0674
Lauren DreyerGenetic Health WA, Perth, Western Australia, Australia.
Haowei DuDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Salima El ChehadehService de Génétique Médicale, Institut de Génétique Médicale D'Alsace, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.ORCID http://orcid.org/0000-0003-1613-6570
Michael FieldGenetics of Learning Disability Service, Hunter Genetics, Waratah, Western Australia, Australia.ORCID http://orcid.org/0000-0001-7455-934X
Lisa J EwansCentre for Clinical Genetics, Sydney Children's Hospitals Network, Sydney, New South Wales, Australia.
Vanessa GeigerGenetikum, MVZ genetikum GmbH, Neu-Ulm, Germany.
Richard A GibbsDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Ian GlassDepartment of Pediatrics, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0001-6762-8407
Olivier GrunewaldU1172-LilNCog-Lille Neuroscience & Cognition, CHU de Lille, Lille, France.
Paul GueguenLaboratoire SeqOIA, Paris, France.
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, Eberhard Karls University, Tübingen, Germany.ORCID http://orcid.org/0000-0001-6033-4836
Hamza Hadj AbdallahGenomic Medecine of Rare Disease, Necker Hospital, Paris, France.
Radu HarbuzService de Génétique, Génomique et Procréation, CHU Grenoble Alpes, Grenoble, France.
Ingo HelbigThe Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0001-8486-0558
Judit HorvathDepartment of Medical Genetics, Centre of Medical Genetics, University and University Hospital Münster, Münster, Germany.
Alexander HustinxInstitute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0003-4592-3979
Bertrand IsidorService de Génétique Médicale, Institut de Génétique Médicale D'Alsace, Centre Hospitalier Universitaire de Nantes, Nantes, France.
Marie-Line JacquemontService de Génétique, CHRU de Tours, Tours, France.
Fraser JamieRare Disease Institute, Division of Genetics and Metabolism and Center for Genetic Medicine Research, Children's National Hospital, Washington, DC, USA.
Médéric JeanneService de Génétique, CHRU de Tours, Tours, France.
Riley KesslerDivision of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Hannah KlinkhammerInstitute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0003-3752-1275
G Christoph KorenkeDepartment of Neuropediatrics, University Children's Hospital, Klinikum Oldenburg, Oldenburg, Germany.
Urania KotzaeridouDepartment of Pediatrics I, Division of Pediatric Neurology and Metabolic Medicine, Medical Faculty of Heidelberg, Heidelberg, Germany.
Peter KrawitzInstitute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0002-3194-8625
Steven LaurieCentro Nacional de Análisis Genómico (CNAG), Baldiri Reixac 4, Barcelona, Spain.ORCID http://orcid.org/0000-0003-3913-5829
Richard J LeventerDepartment of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.ORCID http://orcid.org/0000-0003-0362-5607
Rebecca J LevyDivision of Child Neurology, Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.ORCID http://orcid.org/0000-0003-0393-6835
James R LupskiTexas Children's Hospital, Houston, TX, USA.ORCID http://orcid.org/0000-0001-9907-9246
Pierre MarijonLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0002-6694-6873
Kaitlin E McGinnisGenetic Health WA, Perth, Western Australia, Australia.
Rodrigo MendezCardiovascular Medicine, Stanford University, Stanford, CA, USA.
Olfa MessaoudCenter for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-4547-0180
Caroline NavaLaboratoire SeqOIA, Paris, France.ORCID http://orcid.org/0000-0003-1272-0518
Mevyn NizardGenomic Medecine of Rare Disease, Necker Hospital, Paris, France.
Anne O'Donnell-LuriaCenter for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Melanie C O'LearyCenter for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-8718-4759
Simone OlivieriInstitute of Medical Genetics and Applied Genomics, Eberhard Karls University, Tübingen, Germany.
Amitav ParidaDepartment of Paediatric Neurology, Birmingham Women's and Children's Hospital Foundation Trust, Birmingham, UK.
Davut PehlivanSection of Pediatric Neurology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Anna Jenne PrenticeThe Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA, USA.ORCID http://orcid.org/0009-0008-7459-1778
Jennifer E PoseyDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.ORCID http://orcid.org/0000-0003-4814-6765
Chloe M ReuterDepartment of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Véronique SatreService de Génétique, Génomique et Procréation, CHU Grenoble Alpes, Grenoble, France.
Caroline Schluth-BolardGCS AURAGEN, Lyon, France.
Thomas SmolCHU Lille, ULR7364 - RADEME - Maladies Rares du Développement Embryonnaire, Lille, France.
Tipu SultanDepartment of Pediatric Neurology, University of Child Health Sciences, The Children's Hospital, Lahore, Pakistan.
John TaylorDepartment of Radiology, NHS lothian, Edinburgh, UK.
Christel Thauvin-RobinetUniversité Bourgogne Europe - CHU Dijon Bourgogne - Inserm U1231 CTM GAD, Centre de Référence des maladies neurogénétiques, Laboratoire de Génomique Médicale, Dijon, France.ORCID http://orcid.org/0000-0002-4155-139X
Julien ThevenonService de Génétique, Génomique et Procréation, CHU Grenoble Alpes, Grenoble, France.
Eloise UebergangMurdoch Children's Research Institute, Melbourne, Victoria, Australia.ORCID http://orcid.org/0000-0003-0305-7822
Sandra UeberbergInstitute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Catherine Vincent-DelormeClinique de Génétique, Hôpital Jeanne de Flandre, CHU de Lille, Lille, France.
Evangeline WassmerBirmingham Children's Hospital, Birmingham, UK.ORCID http://orcid.org/0000-0002-2446-1106
Emma WestwoodNHS Education for Scotland, NHS Scotland, Edinburgh, UK.
Matthew T WheelerCardiovascular Medicine, Stanford University, Stanford, CA, USA.ORCID http://orcid.org/0000-0001-8721-3022
Elif Yilmaz GulecDepartment of Medical Genetics, Istanbul Medeniyet University Medical School, Istanbul, Turkey.
Adeline VanderverDivision of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Arastoo VossoughDepartment of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Stephan J SandersInstitute of Developmental and Regenerative Medicine, Department of Paediatrics, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0001-9112-5148
Siddharth BankaManchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.ORCID http://orcid.org/0000-0002-8527-2210
Gregory M FindlayThe Genome Function Laboratory, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0002-7767-8608
Daniel G MacArthurCentre for Population Genomics, Garvan Institute of Medical Research, UNSW Sydney, Sydney, New South Wales, Australia.
Cas SimonsCentre for Population Genomics, Garvan Institute of Medical Research, UNSW Sydney, Sydney, New South Wales, Australia. cas.simons@populationgenomics.org.au.ORCID http://orcid.org/0000-0003-3147-8042
Nicola WhiffinBig Data Institute, University of Oxford, Oxford, UK. nwhiffin@well.ox.ac.uk.ORCID http://orcid.org/0000-0003-1554-6594
Funding
Child Neurologist Career Development Program (CNCDP)K12NS098482 · NINDS · HUGO W. MOSER RES INST KENNEDY KRIEGER · PI SCHLAGGAR, BRADLEY L · 2016 to 2025
$26.2MStanford Mendelian Genomics Research CenterU01HG011762 · NHGRI · STANFORD UNIVERSITY · PI Jonathan Adam Bernstein, Stephen Montgomery · 2021 to 2026
$16.7MBroad Institute Mendelian Genomic Research CenterU01HG011755 · NHGRI · BROAD INSTITUTE, INC. · PI Anne O'Donnell-Luria, MICHAEL E TALKOWSKI · 2021 to 2026
$14.6MFrequency of variants of unknown significance by ancestry groups in the All of Us Research Program cohortU01HG011758 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI RICHARD A GIBBS, JAMES R. LUPSKI · 2021 to 2026
$13.8MCenter for Undiagnosed Diseases at StanfordU01NS134358 · NINDS · STANFORD UNIVERSITY · PI Jonathan Adam Bernstein, HOLLY K TABOR · 2023 to 2026
$3.1MPacific Northwest Undiagnosed Diseases Network Clinical SiteU01NS134355 · NINDS · UNIVERSITY OF WASHINGTON · PI ELIZABETH ELOYCE BLUE, Katrina M Dipple · 2023 to 2026
$3.0MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MDepartment of Health | National Health and Medical Research Council (NHMRC) 2009982NHGRI NIH HHS R01 HG009141NHGRI NIH HHS U01 HG011755NHGRI NIH HHS U01 HG011758NHGRI NIH HHS U01 HG011762NINDS NIH HHS K12 NS098482NINDS NIH HHS U01 NS134355NINDS NIH HHS U01 NS134358Wellcome Trust CC2190Wellcome Trust (Wellcome) 223521/Z/21/ZWellcome Trust (Wellcome) 305292/Z/23/Z
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.
Indexed as
Neurodevelopmental DisordersRNA, Small NuclearRNA, UntranslatedWhite MatterAllelesChildChild, PreschoolFemaleGenes, RecessiveHumansMalePhenotypeRNA, Small NuclearRNA, Untranslated
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