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De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.
Chen, Yuyang; Dawes, Ruebena; Kim, Hyung Chul; Stenton, Sarah L; Walker, Susan; Ljungdahl, Alicia; Lord, Jenny; Ganesh, Vijay S; Ma, Jialan; Martin-Geary, Alexandra C; Lemire, Gabrielle; D'Souza, Elston N; Dong, Shan; Ellingford, Jamie M; Adams, David R; Allan, Kirsten; Bakshi, Madhura; Baldwin, Erin E; Berger, Seth I; Bernstein, Jonathan A; Brown, Natasha J; Burrage, Lindsay C; Chapman, Kimberly; Compton, Alison G; Cunningham, Chloe A; D'Souza, Precilla; Délot, Emmanuèle C; Dias, Kerith-Rae; Elias, Ellen R; Evans, Carey-Anne; Ewans, Lisa; Ezell, Kimberly; Fraser, Jamie L; Gallacher, Lyndon; Genetti, Casie A; Grant, Christina L; Haack, Tobias; Kuechler, Alma; Lalani, Seema R; Leitão, Elsa; Fevre, Anna Le; Leventer, Richard J; Liebelt, Jan E; Lockhart, Paul J; Ma, Alan S; Macnamara, Ellen F; Maurer, Taylor M; Mendez, Hector R; Montgomery, Stephen B; Nassogne, Marie-Cécile.
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.
  • Stenton SL; Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Walker S; Big Data Institute, University of Oxford, Oxford, UK.
  • Ljungdahl A; Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Lord J; 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.
  • Martin-Geary AC; 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, USA.
  • D'Souza EN; Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
  • Dong S; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ellingford JM; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Adams DR; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Allan K; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bakshi M; Big Data Institute, University of Oxford, Oxford, UK.
  • Baldwin EE; Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Berger SI; Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Bernstein JA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Brown NJ; Big Data Institute, University of Oxford, Oxford, UK.
  • Burrage LC; Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Chapman K; 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, USA.
  • Cunningham CA; Genomics England, London, UK.
  • D'Souza P; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.
  • Délot EC; Division of Evolution, Infection and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicines and Health, University of Manchester, Manchester, UK.
  • Dias KR; Undiagnosed Disesases Program, National Human Genome Research Institute, Bethesda, MD, USA.
  • Elias ER; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
  • Evans CA; Department of Clinical Genetics, Liverpool Hospital, Sydney, NSW, Australia.
  • Ewans L; Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Ezell K; Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC, USA.
  • Fraser JL; Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA.
  • Gallacher L; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
  • Genetti CA; GREGoR Stanford Site, Stanford University School of Medicine, Stanford, CA, USA.
  • Grant CL; Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA, USA.
  • Haack T; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
  • Kuechler A; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
  • Lalani SR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Leitão E; Division of Genetics and Metabolism, Children's National Hospital, Washington, DC, USA.
  • Fevre AL; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
  • Leventer RJ; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
  • Liebelt JE; Murdoch Children's Research Institute, Melbourne, VIC, Australia.
  • Lockhart PJ; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
  • Ma AS; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
  • Macnamara EF; Undiagnosed Disesases Program, National Human Genome Research Institute, Bethesda, MD, USA.
  • Maurer TM; Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC, USA.
  • Mendez HR; Neuroscience Research Australia, Sydney, NSW, Australia.
  • Montgomery SB; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
  • Nassogne MC; Department of Pediatrics, Children's Hospital Colorado, Aurora, CO, USA.
medRxiv ; 2024 Apr 09.
Article em En | MEDLINE | ID: mdl-38645094
ABSTRACT
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Increasingly, 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 novel 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 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Revista: MedRxiv Ano de publicação: 2024 Tipo de documento: Article
Texto completo
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PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Revista: MedRxiv Ano de publicação: 2024 Tipo de documento: Article