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De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.
Chen, Yuyang; Dawes, Ruebena; Kim, Hyung Chul; Ljungdahl, Alicia; Stenton, Sarah L; Walker, Susan; Lord, Jenny; Lemire, Gabrielle; Martin-Geary, Alexandra C; Ganesh, Vijay S; Ma, Jialan; Ellingford, Jamie M; Delage, Erwan; D'Souza, Elston N; Dong, Shan; Adams, David R; Allan, Kirsten; Bakshi, Madhura; Baldwin, Erin E; Berger, Seth I; Bernstein, Jonathan A; Bhatnagar, Ishita; Blair, Ed; Brown, Natasha J; Burrage, Lindsay C; Chapman, Kimberly; Coman, David J; Compton, Alison G; Cunningham, Chloe A; D'Souza, Precilla; Danecek, Petr; Délot, Emmanuèle C; Dias, Kerith-Rae; Elias, Ellen R; Elmslie, Frances; Evans, Care-Anne; Ewans, Lisa; Ezell, Kimberly; Fraser, Jamie L; Gallacher, Lyndon; Genetti, Casie A; Goriely, Anne; Grant, Christina L; Haack, Tobias; Higgs, Jenny E; Hinch, Anjali G; Hurles, Matthew E; Kuechler, Alma; Lachlan, Katherine L; Lalani, Seema R.
Afiliação
  • Chen Y; Big Data Institute, University of Oxford, Oxford, UK.
  • Dawes R; Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Kim HC; Big Data Institute, University of Oxford, Oxford, UK.
  • Ljungdahl A; Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Stenton SL; Big Data Institute, University of Oxford, Oxford, UK.
  • Walker S; Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Lord J; Institute of Developmental and Regenerative Medicine, Department of Paediatrics, University of Oxford, Oxford, UK.
  • Lemire G; Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
  • Martin-Geary AC; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ganesh VS; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Ma J; Genomics England, London, UK.
  • Ellingford JM; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
  • Delage E; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • D'Souza EN; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Dong S; Big Data Institute, University of Oxford, Oxford, UK.
  • Adams DR; Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Allan K; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bakshi M; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Baldwin EE; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Berger SI; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bernstein JA; Genomics England, London, UK.
  • Bhatnagar I; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.
  • Blair E; Division of Evolution, Infection and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, UK.
  • Brown NJ; Human Genetics, Wellcome Sanger Institute, Hinxton, UK.
  • Burrage LC; Big Data Institute, University of Oxford, Oxford, UK.
  • Chapman K; Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Coman DJ; Institute of Developmental and Regenerative Medicine, Department of Paediatrics, University of Oxford, Oxford, UK.
  • Compton AG; Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
  • Cunningham CA; Undiagnosed Disesases Program, National Human Genome Research Institute, Bethesda, MD, USA.
  • D'Souza P; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
  • Danecek P; Department of Clinical Genetics, Liverpool Hospital, Sydney, NSW, Australia.
  • Délot EC; Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Dias KR; Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC, USA.
  • Elias ER; Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA.
  • Elmslie F; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
  • Evans CA; GREGoR Stanford Site, Stanford University School of Medicine, Stanford, CA, USA.
  • Ewans L; Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USA.
  • Ezell K; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
  • Fraser JL; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
  • Gallacher L; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
  • Genetti CA; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
  • Goriely A; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Grant CL; Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA.
  • Haack T; Department of Metabolic Medicine, Queensland Children's Hospital, Brisbane, QLD, Australia.
  • Higgs JE; Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.
  • Hinch AG; School of Medicine, Griffith university, Gold Coast, QLD, Australia.
  • Hurles ME; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
  • Kuechler A; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
  • Lachlan KL; Murdoch Children's Research Institute, Melbourne, VIC, Australia.
  • Lalani SR; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
Nature ; 2024 Jul 11.
Article em En | MEDLINE | ID: mdl-38991538
ABSTRACT
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals where it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologs. Using RNA-sequencing, we show how 5' splice site usage is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 bp region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article