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De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome

Author

Listed:
  • Yuyang Chen

    (University of Oxford
    University of Oxford)

  • Ruebena Dawes

    (University of Oxford
    University of Oxford)

  • Hyung Chul Kim

    (University of Oxford
    University of Oxford)

  • Alicia Ljungdahl

    (University of Oxford
    University of California San Francisco)

  • Sarah L. Stenton

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Susan Walker

    (Genomics England)

  • Jenny Lord

    (University of Sheffield)

  • Gabrielle Lemire

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Alexandra C. Martin-Geary

    (University of Oxford
    University of Oxford)

  • Vijay S. Ganesh

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Harvard Medical School)

  • Jialan Ma

    (Broad Institute of MIT and Harvard)

  • Jamie M. Ellingford

    (Genomics England
    Manchester University NHS Foundation Trust
    University of Manchester)

  • Erwan Delage

    (Wellcome Sanger Institute)

  • Elston N. D’Souza

    (University of Oxford
    University of Oxford)

  • Shan Dong

    (University of Oxford
    University of California San Francisco)

  • David R. Adams

    (National Human Genome Research Institute)

  • Kirsten Allan

    (Murdoch Children’s Research Institute)

  • Madhura Bakshi

    (Liverpool Hospital)

  • Erin E. Baldwin

    (University of Utah School of Medicine)

  • Seth I. Berger

    (Children’s National Research Institute
    Children’s National Hospital)

  • Jonathan A. Bernstein

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Ishita Bhatnagar

    (Oxford University Hospitals NHS Foundation Trust)

  • Ed Blair

    (Oxford University Hospitals NHS Foundation Trust)

  • Natasha J. Brown

    (Murdoch Children’s Research Institute
    University of Melbourne)

  • Lindsay C. Burrage

    (Baylor College of Medicine)

  • Kimberly Chapman

    (Children’s National Hospital)

  • David J. Coman

    (Queensland Children’s Hospital
    University of Queensland
    Griffith university)

  • Alison G. Compton

    (Murdoch Children’s Research Institute
    University of Melbourne
    Murdoch Children’s Research Institute)

  • Chloe A. Cunningham

    (Murdoch Children’s Research Institute
    University of Melbourne)

  • Precilla D’Souza

    (National Human Genome Research Institute)

  • Petr Danecek

    (Wellcome Sanger Institute)

  • Emmanuèle C. Délot

    (Children’s National Research Institute)

  • Kerith-Rae Dias

    (Neuroscience Research Australia
    University of New South Wales)

  • Ellen R. Elias

    (Children’s Hospital Colorado
    University of Colorado)

  • Frances Elmslie

    (St George’s University Hospitals NHS Foundation Trust)

  • Care-Anne Evans

    (Neuroscience Research Australia
    Prince of Wales Hospital)

  • Lisa Ewans

    (University of New South Wales
    Sydney Children’s Hospitals Network
    Garvan Institute of Medical Research)

  • Kimberly Ezell

    (Vanderbilt University Medical Center)

  • Jamie L. Fraser

    (Children’s National Research Institute
    Children’s National Hospital)

  • Lyndon Gallacher

    (Murdoch Children’s Research Institute
    University of Melbourne)

  • Casie A. Genetti

    (Harvard Medical School
    Harvard Medical School)

  • Anne Goriely

    (University of Oxford
    NIHR Biomedical Research Centre)

  • Christina L. Grant

    (Children’s National Hospital)

  • Tobias Haack

    (University of Tübingen
    University of Tübingen)

  • Jenny E. Higgs

    (Liverpool Women’s Hospital)

  • Anjali G. Hinch

    (University of Oxford)

  • Matthew E. Hurles

    (Wellcome Sanger Institute)

  • Alma Kuechler

    (University Duisburg-Essen)

  • Katherine L. Lachlan

    (University Hospital Southampton NHS Trust
    Southampton University)

  • Seema R. Lalani

    (Baylor College of Medicine)

  • François Lecoquierre

    (Department of Genetics and Reference Center for Developmental Disorders)

  • Elsa Leitão

    (University Duisburg-Essen)

  • Anna Le Fevre

    (Murdoch Children’s Research Institute)

  • Richard J. Leventer

    (University of Melbourne
    Murdoch Children’s Research Institute
    Royal Children’s Hospital)

  • Jan E. Liebelt

    (Women’s and Children’s Hospital
    Repromed)

  • Sarah Lindsay

    (Wellcome Sanger Institute)

  • Paul J. Lockhart

    (University of Melbourne
    Murdoch Children’s Research Institute)

  • Alan S. Ma

    (Sydney Children’s Hospitals Network Westmead
    University of Sydney)

  • Ellen F. Macnamara

    (National Human Genome Research Institute)

  • Sahar Mansour

    (St George’s University Hospitals NHS Foundation Trust)

  • Taylor M. Maurer

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Hector R. Mendez

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Kay Metcalfe

    (Health Innovation Manchester)

  • Stephen B. Montgomery

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Mariya Moosajee

    (UCL Institute of Ophthalmology
    The Francis Crick Institute
    Moorfields Eye Hospital NHS Foundation Trust)

  • Marie-Cécile Nassogne

    (UCLouvain
    UCLouvain)

  • Serena Neumann

    (Vanderbilt University Medical Center)

  • Michael O’Donoghue

    (Nottingham University Hospitals NHS Trust)

  • Melanie O’Leary

    (Broad Institute of MIT and Harvard)

  • Elizabeth E. Palmer

    (University of New South Wales
    Sydney Children’s Hospitals Network)

  • Nikhil Pattani

    (St George’s University Hospitals NHS Foundation Trust)

  • John Phillips

    (Vanderbilt University Medical Center)

  • Georgia Pitsava

    (University of California Irvine)

  • Ryan Pysar

    (University of New South Wales
    Sydney Children’s Hospitals Network
    The Children’s Hospital at Westmead)

  • Heidi L. Rehm

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Chloe M. Reuter

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Nicole Revencu

    (Université Catholique de Louvain)

  • Angelika Riess

    (University of Tübingen)

  • Rocio Rius

    (University of Melbourne
    Garvan Institute of Medical Research and UNSW Sydney
    Murdoch Children’s Research Institute)

  • Lance Rodan

    (Harvard Medical School)

  • Tony Roscioli

    (Neuroscience Research Australia
    University of New South Wales
    Prince of Wales Hospital)

  • Jill A. Rosenfeld

    (Baylor College of Medicine)

  • Rani Sachdev

    (University of New South Wales
    Sydney Children’s Hospitals Network)

  • Charles J. Shaw-Smith

    (Royal Devon University Hospital)

  • Cas Simons

    (Garvan Institute of Medical Research and UNSW Sydney
    Murdoch Children’s Research Institute)

  • Sanjay M. Sisodiya

    (UCL Queen Square Institute of Neurology
    UK and Chalfont Centre for Epilepsy)

  • Penny Snell

    (Murdoch Children’s Research Institute)

  • Laura St Clair

    (Sydney Children’s Hospitals Network Westmead)

  • Zornitza Stark

    (Murdoch Children’s Research Institute
    University of Melbourne)

  • Helen S. Stewart

    (Oxford University Hospitals NHS Foundation Trust)

  • Tiong Yang Tan

    (Murdoch Children’s Research Institute
    University of Melbourne)

  • Natalie B. Tan

    (Murdoch Children’s Research Institute)

  • Suzanna E. L. Temple

    (Liverpool Hospital
    University of New South Wales)

  • David R. Thorburn

    (Murdoch Children’s Research Institute
    University of Melbourne
    Murdoch Children’s Research Institute)

  • Cynthia J. Tifft

    (National Human Genome Research Institute)

  • Eloise Uebergang

    (Murdoch Children’s Research Institute)

  • Grace E. VanNoy

    (Broad Institute of MIT and Harvard)

  • Pradeep Vasudevan

    (Leicester Royal Infirmary)

  • Eric Vilain

    (University of California Irvine)

  • David H. Viskochil

    (University of Utah School of Medicine)

  • Laura Wedd

    (Garvan Institute of Medical Research and UNSW Sydney
    Murdoch Children’s Research Institute)

  • Matthew T. Wheeler

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Susan M. White

    (Murdoch Children’s Research Institute
    University of Melbourne)

  • Monica Wojcik

    (Harvard Medical School
    Harvard Medical School
    Harvard Medical School)

  • Lynne A. Wolfe

    (National Human Genome Research Institute)

  • Zoe Wolfenson

    (National Human Genome Research Institute)

  • Caroline F. Wright

    (University of Exeter)

  • Changrui Xiao

    (University of California Irvine)

  • David Zocche

    (Northwick Park and St Mark’s Hospitals)

  • John L. Rubenstein

    (University of California San Francisco)

  • Eirene Markenscoff-Papadimitriou

    (University of California San Francisco)

  • Sebastian M. Fica

    (University of Oxford)

  • Diana Baralle

    (University of Southampton
    University Hospital Southampton NHS Foundation Trust)

  • Christel Depienne

    (University Duisburg-Essen)

  • Daniel G. MacArthur

    (Garvan Institute of Medical Research and UNSW Sydney
    Murdoch Children’s Research Institute)

  • Joanna M. M. Howson

    (Novo Nordisk Research Centre)

  • Stephan J. Sanders

    (University of Oxford
    University of California San Francisco)

  • Anne O’Donnell-Luria

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Harvard Medical School)

  • Nicola Whiffin

    (University of Oxford
    University of Oxford
    Broad Institute of MIT and Harvard)

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 base pair 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 in whom 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 homologues. Using RNA sequencing, we show how 5′ splice-site use 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 base pair 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.

Suggested Citation

  • Yuyang Chen & Ruebena Dawes & Hyung Chul Kim & Alicia Ljungdahl & Sarah L. Stenton & Susan Walker & Jenny Lord & Gabrielle Lemire & Alexandra C. Martin-Geary & Vijay S. Ganesh & Jialan Ma & Jamie M. E, 2024. "De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome," Nature, Nature, vol. 632(8026), pages 832-840, August.
    • Handle: RePEc:nat:nature:v:632:y:2024:i:8026:d:10.1038_s41586-024-07773-7
    DOI: 10.1038/s41586-024-07773-7
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