ArticleNature genetics2025
Mutations in the small nuclear RNA gene RNU2-2 cause a severe neurodevelopmental disorder with prominent epilepsy.
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Article in Nature genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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45 citing papers in PubMed.
- Genome sequencing for the diagnosis of intellectual disability as a paradigm for rare diseases in the French healthcare setting: the prospective DEFIDIAG study.Genome medicine · 2025Trial
- Genetic developmental and epileptic encephalopathies in adulthood: Gaps in evidence and care.Epilepsia open · 2026Review
- Integrative and systematic genomic approaches to improve diagnosis in rare and undiagnosed diseases: results from the RareBoost project.European journal of human genetics : EJHG · 2026Article
- Genetic Diagnosis in Epilepsy: Implications for Clinical Management.Current neurology and neuroscience reports · 2026Review
- Prenatal Phenotypic Features of Five Fetal Cases With RNU4ATAC-Associated Microcephalic Osteodysplastic Primordial Dwarfism Type I.Prenatal diagnosis · 2026Article
- 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
- Beyond the gene: isoform diversity as a key contributor to human brain disorders.Current opinion in genetics & development · 2026Review
- Best practice recommendations for bioinformatics approaches applied to high-throughput sequencing for rare disease and cancer diagnosis within the UK National Health Service.Journal of medical genetics · 2026Article
- Beyond Coding Variants: RNA-Level Mechanisms in Human Disease and Precision Therapeutics.Genes · 2026Review
- Article
- Biallelic RNU2-2-related neurodevelopmental disorder presenting as Lennox-Gastaut syndrome.Acta neurologica Belgica · 2026Article
- Monoallelic and biallelic RNU4-2 variants in neurodevelopmental disorders.Journal of human genetics · 2026Article
- Article
- LSM7 coordinates scaRNA-mediated snRNA modification to ensure spliceosome fidelity and spermatogonial stem cell differentiation.Cell death and differentiation · 2026Article
- Dysfunction of a SET3-like complex underlies a family of related neurological disorders.Nature communications · 2026Article
- Genome sequencing boosts diagnostic yield for the developmental and epileptic encephalopathies.medRxiv : the preprint server for health sciences · 2026Article
- Population-Based Study of Drug-Resistant Epilepsy Before Age Two: Predominance of Developmental and Epileptic Encephalopathies.Neurology international · 2026Article
- Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder.Nature genetics · 2026Article
Corrections and comments
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Authors and funding
52 authors.
Daniel GreeneDepartment of Medicine, University of Cambridge, Cambridge, UK.
Koenraad De WispelaereDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0003-1946-3024
Jon LeesBristol Medical School, University of Bristol, Bristol, UK.
Marta Codina-SolàDepartment of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Brynjar O JenssondeCODE genetics/Amgen Inc., Reykjavik, Iceland.
Emma HalesNIHR BioResource, Cambridge University Hospitals, Cambridge, UK.
Andrea KatrineczNIHR BioResource, Cambridge University Hospitals, Cambridge, UK.
Esther Nieto MolinaAndalusian Platform for Computational Medicine, Andalusian Public Foundation Progress and Health-FPS, Seville, Spain.
Sonia PascoalNIHR BioResource, Cambridge University Hospitals, Cambridge, UK.
Rolph PfundtDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Rachel SchotDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.ORCID http://orcid.org/0000-0001-9578-4095
Marta Sevilla PorrasCIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Frank SleutelsDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.ORCID http://orcid.org/0000-0001-6813-5209
Irene ValenzuelaDepartment of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain.ORCID http://orcid.org/0000-0003-2350-6058
Robin WijngaardDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
Ignacio Arroyo CarreraPediatric Department, Hospital San Pedro de Alcántara, Cáceres, Spain.
Giles AttonWessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Didac Casas-AlbaClinical Genetics Department and Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain.
Deirdre DonnellyDepartment of Medical Genetics, Belfast City Hospital, Belfast, UK.
Anna Duat RodríguezCIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Bárbara Fernández GarozGenetics Department, Hospital Niño Jesús, Madrid, Spain.
Nicola FouldsWessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Deyanira García-Navas NúñezPediatric Department, Hospital San Pedro de Alcántara, Cáceres, Spain.
Elena González AlguacilCIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Joanna JarvisClinical Genetics Unit, Birmingham Women's Hospital, Birmingham, UK.
Sarina G KantDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Irene Madrigal BajoCIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Antonio F Martinez-MonsenyClinical Genetics Department and Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain.
Shane McKeeDepartment of Medical Genetics, Belfast City Hospital, Belfast, UK.ORCID http://orcid.org/0000-0002-1772-0106
Nelmar Valentina Ortiz CabreraCIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Laia Rodríguez-Revenga BodiCIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Andrea Sariego JamardoNeuropediatric Department, Pediatric Service, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
Kari StefanssondeCODE genetics/Amgen Inc., Reykjavik, Iceland.ORCID http://orcid.org/0000-0003-1676-864X
Patrick SulemdeCODE genetics/Amgen Inc., Reykjavik, Iceland.
Mohnish SuriClinical Genetics, Nottingham University Hospital NHS Trust, Nottingham, UK.
Clara Van KarnebeekDepartments of Pediatrics and Human Genetics, Emma Center for Personalized Medicine, Amsterdam Gastro-Enterology Endocrinology Metabolism, Amsterdam University Medical Centers, Amsterdam, the Netherlands.ORCID http://orcid.org/0000-0002-2648-8337
Pradeep VasudevanClinical Genetics, University Hospitals of Leicester NHS Trust, Leicester, UK.ORCID http://orcid.org/0009-0002-6095-2030
Ana Isabel Vega PajaresGenetics Department, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Valdecilla (IDIVAL), Santander, Spain.
Ángel CarracedoCIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Marc EngelenDepartment of Pediatric Neurology, Amsterdam University Medical Centers, Amsterdam, the Netherlands.ORCID http://orcid.org/0000-0002-5346-8497
Pablo LapunzinaCIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Natasha P MorganNIHR BioResource, Cambridge University Hospitals, Cambridge, UK.
Beatriz MorteCIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Patrick RumpDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.ORCID http://orcid.org/0000-0003-4059-0247
Kathy StirrupsNIHR BioResource, Cambridge University Hospitals, Cambridge, UK.ORCID http://orcid.org/0000-0002-6823-3252
Eduardo F TizzanoDepartment of Clinical and Molecular Genetics, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Tahsin Stefan BarakatDepartment of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands.ORCID http://orcid.org/0000-0003-1231-1562
Michael O'DonoghueNeurology, Nottingham University Hospital NHS Trust, Nottingham, UK.
Luis Alberto Pérez-JuradoCIBER-ER (Biomedical Network Research Center for Rare Diseases), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
Kathleen FresonDepartment of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium.ORCID http://orcid.org/0000-0002-4381-2442
Andrew D MumfordBristol Medical School, University of Bristol, Bristol, UK.
Ernest TurroDepartment of Medicine, University of Cambridge, Cambridge, UK. ernest.turro@mssm.edu.ORCID http://orcid.org/0000-0002-1820-6563
Funding
Integrative analysis of whole genomes and transcriptomes from multiple cell types in rare disease patientsR01HL161365 · NHLBI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Ernest Turro · 2023 to 2026
$2.6MBayesian genetic association analysis of all rare diseases in the Kids First cohortR03HD111492 · NICHD · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI TURRO, ERNEST · 2023 to 2024
$338kNHLBI NIH HHS R01 HL161365NICHD NIH HHS R03 HD111492U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) R03HD111492U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01HL161365Wellcome Trust
Abstract
The major spliceosome includes five small nuclear RNA (snRNAs), U1, U2, U4, U5 and U6, each of which is encoded by multiple genes. We recently showed that mutations in RNU4-2, the gene that encodes the U4-2 snRNA, cause one of the most prevalent monogenic neurodevelopmental disorders. Here, we report that recurrent germline mutations in RNU2-2 (previously known as pseudogene RNU2-2P), a 191-bp gene that encodes the U2-2 snRNA, are responsible for a related disorder. By genetic association, we identified recurrent de novo single-nucleotide mutations at nucleotide positions 4 and 35 of RNU2-2 in nine cases. We replicated this finding in 16 additional cases, bringing the total to 25. We estimate that RNU2-2 syndrome has a prevalence of ~20% that of RNU4-2 syndrome. The disorder is characterized by intellectual disability, autistic behavior, microcephaly, hypotonia, epilepsy and hyperventilation. All cases display a severe and complex seizure phenotype. We found that U2-2 and canonical U2-1 were similarly expressed in blood. Despite mutant U2-2 being expressed in patient blood samples, we found no evidence of missplicing. Our findings cement the role of major spliceosomal snRNAs in the etiologies of neurodevelopmental disorders.
Indexed as
EpilepsyNeurodevelopmental DisordersRNA, Small NuclearAdolescentChildChild, PreschoolFemaleGerm-Line MutationHumansIntellectual DisabilityMaleMicrocephalyMutationPseudogenesRNA, Small Nuclear
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