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https://repository.monashhealth.org/monashhealthjspui/handle/1/58111| Title: | Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy. | Authors: | Chae J.H.;Blakes A.J.M.;Alhaddad B.;Henry O.J.;Delgado-Vega A.M.;Wall E.;Abdelhadi O.;Agrawal S.;Bakur K.;Blair E.;Brady A.F.;Brittain H.;Chandler K.E.;Clarke N.;Danelli M.;Drinkall N.;Duba I.;Elmslie F.;Ellingford J.;Ewans L.J.;Gazdagh G.;Heller S.P.;Hammarsjo A.;Karrman K.;Kini U.;Lesko N.;Lindstrand A.;Macintosh R.;Mansour S.;Menzies L.;Metcalfe K.;Milhench A.;Nashef L.;O'Keefe R.T.;Pacheco N.P.;Palmer E.E.;Parida A.;Prescott K.;Redman M.;Renieri A.;Fallerini C.;Rizzo C.L.;Sachdev R.;Simons C.;Sisodiya S.M.;Stewart H.;Stodberg T.;Banos-Pinero B.;Taylan F.;Thomas H.B.;Tinella F.;Wiafe S.;Wedell A.;Whiffin N.;Walker S.;Rius R.;Fennell A.P. ;Nordgren A.;Alkuraya F.;Lord J.;Banka S.;Jackson A. | Monash Health Department(s): | Genetics Monash University - School of Clinical Sciences at Monash Health |
Institution: | (Ewans) Genomics and Inherited Diseases Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia (Ewans, Macintosh, Palmer, Sachdev) Discipline of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia (Fennell) Monash Genetics, Monash Health, Melbourne, VIC, Australia (Fennell) Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, VIC, Australia (Gazdagh) Wessex Clinical Genetic Service, University Hospital Southampton, Southampton, United Kingdom (Gazdagh) Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom (Heller, Nashef) Neurology Department, King's College Hospital, Denmark Hill, London, United Kingdom (Karrman) Department of Clinical Genetics, Pathology and Molecular Diagnostics, Skane University Hospital, Lund, Sweden (Mansour) Cardiovascular and Genomics Research Institute, City St George's University of London, London, United Kingdom (Menzies) Department of Clinical Genetics, Great Ormond Street Hospital, London, United Kingdom (Menzies) Department of Genomics and Genetic Medicine, University College London, London, United Kingdom (Milhench) Gloucestershire Hospitals NHS Foundation Trust, Cheltenham, United Kingdom (Prescott, Redman) Leeds Clinical Genomics Service, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom (Renieri, Fallerini) Medical Genetics, University of Siena, Siena, Italy (Renieri, Fallerini) Med Biotech Hub and Competence Centre, Department of Medical Biotechnologies, University of Siena, Siena, Italy (Simons, Rius) Centre for Population Genomics, Garvan Institute of Medical Research, UNSW Sydney, Sydney, NSW, Australia (Simons, Rius) Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia (Sisodiya) Research Department of Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom (Sisodiya) Chalfont Centre for Epilepsy, Chalfont Saint Peter, United Kingdom (Stodberg) Department of Child Neurology, Karolinska University Hospital, Stockholm, Sweden (Stodberg) Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden (Banos-Pinero) Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom (Wiafe) Rare Disease Ghana Initiative, Accra, Ghana (Wiafe) Fred N Binkah School of Public Health, University of Health and Allied Sciences, Ho, Ghana (Wiafe) Ga East Municipal Hospital, Ghana Health Services, Accra, Ghana (Whiffin) Big Data Institute, University of Oxford, Oxford, United Kingdom (Whiffin) Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (Whiffin) Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States (Rius) Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia (Chae) Department of Genomic Medicine, Seoul National University Hospital, Seoul, South Korea (Chae) Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, South Korea (Nordgren) Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden (Nordgren) Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (Alkuraya) Department of Translational Genomics (Genomic Medicine Centre of Excellence (GMCoE)), King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia (Alkuraya) College of Medicine, Alfaisal University, Riyadh, Saudi Arabia (Lord) Sheffield Institute for Translational Neuroscience (SITraN), The University of Sheffield, Sheffield, United Kingdom (Drinkall) Central and South Genomic Laboratory Hub, West Midlands Genomics Laboratory, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, United Kingdom (Danelli, Renieri, Fallerini, Rizzo, Tinella) Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy (Clarke, Elmslie, Mansour) South West Thames Centre for Genomics, St George's, Epsom and St Helier University Hospitals and Health Group, London, United Kingdom (Duba, Lesko, Wedell) Center for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden (Brady) North West Thames Regional Genetics Service, London North West Healthcare University NHS Trust, Northwick Park Hospital, London, United Kingdom (Blair, Kini, Stewart) Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom (Agrawal, Parida) Birmingham Children's Hospital, Birmingham, United Kingdom (Wall, Brittain) West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, United Kingdom (Delgado-Vega, Hammarsjo, Lindstrand, Pacheco, Nordgren) Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden (Henry, Delgado-Vega, Duba, Hammarsjo, Lesko, Lindstrand, Pacheco, Taylan, Wedell, Nordgren) Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden (Alhaddad, Bakur, Alkuraya) Lifera Omics, Riyadh, Saudi Arabia (Jackson, Blakes, Abdelhadi, Chandler, Metcalfe, Banka) Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, United Kingdom (Jackson, Blakes, Abdelhadi, Chandler, Ellingford, Metcalfe, O'Keefe, Thomas, Banka) Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom (Brady) Imperial College London, London, United Kingdom (Ellingford, Walker) Genomics England, London, United Kingdom (Ewans, Macintosh, Palmer, Sachdev) Centre for Clinical Genetics, Sydney Children's Hospitals Network, Sydney, NSW, Australia |
Issue Date: | 7-Apr-2026 | Copyright year: | 2026 | Publisher: | Nature Research | Place of publication: | United States | Publication information: | Nature Genetics. (no pagination), 2026. Date of Publication: 2026. | Journal: | Nature Genetics | 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.Copyright © The Author(s) 2026. | DOI: | https://dx.doi.org/10.1038/s41588-026-02551-9 | PubMed URL: | 41912933 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/58111 | Type: | Article In Press |
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