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

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. Ellingford, Erwan Delage, Elston N. D’Souza, Shan Dong, David R. Adams, Kirsten Allan, Madhura Bakshi, Erin E. Baldwin, Seth I. Berger, Jonathan A. Bernstein, Ishita Bhatnagar, Ed Blair, Natasha J. Brown, Lindsay C. Burrage, Kimberly Chapman, David J. Coman, Alison G. Compton, Chloe A. Cunningham, Precilla D’Souza, Petr Danecek, Emmanuèle C. Délot, Kerith-Rae Dias, Ellen R. Elias, Frances Elmslie, Care-Anne Evans, Lisa Ewans, Kimberly Ezell, Jamie L. Fraser, Lyndon Gallacher, Casie A. Genetti, Anne Goriely, Christina L. Grant, Tobias Haack, Jenny E. Higgs, Anjali G. Hinch, Matthew E. Hurles, Alma Kuechler, Katherine L. Lachlan, Seema R. Lalani, François Lecoquierre, Elsa Leitão, Anna Le Fevre, Richard J. Leventer, Jan E. Liebelt, Sarah Lindsay, Paul J. Lockhart, Alan S. Ma, Ellen F. Macnamara, Sahar Mansour, Taylor M. Maurer, Hector R. Mendez, Kay Metcalfe, Stephen B. Montgomery, Mariya Moosajee, Marie-Cécile Nassogne, Serena Neumann, Michael O’Donoghue, Melanie O’Leary, Elizabeth E. Palmer, Nikhil Pattani, John Phillips, Georgia Pitsava, Ryan Pysar, Heidi L. Rehm, Chloe M. Reuter, Nicole Revencu, Angelika Riess, Rocio Rius, Lance Rodan, Tony Roscioli, Jill A. Rosenfeld, Rani Sachdev, Charles J. Shaw-Smith, Cas Simons, Sanjay M. Sisodiya, Penny Snell, Laura St Clair, Zornitza Stark, Helen S. Stewart, Tiong Yang Tan, Natalie B. Tan, Suzanna E. L. Temple, David R. Thorburn, Cynthia J. Tifft, Eloise Uebergang, Grace E. VanNoy, Pradeep Vasudevan, Eric Vilain, David H. Viskochil, Laura Wedd, Matthew T. Wheeler, Susan M. White, Monica Wojcik, Lynne A. Wolfe, Zoe Wolfenson, Caroline F. Wright, Changrui Xiao, David Zocche, John L. Rubenstein, Eirene Markenscoff-Papadimitriou, Sebastian M. Fica, Diana Baralle, Christel Depienne, Daniel G. MacArthur, Joanna M. M. Howson, Stephan J. Sanders, Anne O’Donnell-Luria and Nicola Whiffin ()
Additional contact information
Yuyang Chen: University of Oxford
Ruebena Dawes: University of Oxford
Hyung Chul Kim: University of Oxford
Alicia Ljungdahl: University of Oxford
Sarah L. Stenton: Broad Institute of MIT and Harvard
Susan Walker: Genomics England
Jenny Lord: University of Sheffield
Gabrielle Lemire: Broad Institute of MIT and Harvard
Alexandra C. Martin-Geary: University of Oxford
Vijay S. Ganesh: Broad Institute of MIT and Harvard
Jialan Ma: Broad Institute of MIT and Harvard
Jamie M. Ellingford: Genomics England
Erwan Delage: Wellcome Sanger Institute
Elston N. D’Souza: University of Oxford
Shan Dong: University of Oxford
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
Jonathan A. Bernstein: 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
Lindsay C. Burrage: Baylor College of Medicine
Kimberly Chapman: Children’s National Hospital
David J. Coman: Queensland Children’s Hospital
Alison G. Compton: Murdoch Children’s Research Institute
Chloe A. Cunningham: Murdoch Children’s Research Institute
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
Ellen R. Elias: Children’s Hospital Colorado
Frances Elmslie: St George’s University Hospitals NHS Foundation Trust
Care-Anne Evans: Neuroscience Research Australia
Lisa Ewans: University of New South Wales
Kimberly Ezell: Vanderbilt University Medical Center
Jamie L. Fraser: Children’s National Research Institute
Lyndon Gallacher: Murdoch Children’s Research Institute
Casie A. Genetti: Harvard Medical School
Anne Goriely: University of Oxford
Christina L. Grant: Children’s National Hospital
Tobias Haack: 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
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
Jan E. Liebelt: Women’s and Children’s Hospital
Sarah Lindsay: Wellcome Sanger Institute
Paul J. Lockhart: University of Melbourne
Alan S. Ma: Sydney Children’s Hospitals Network Westmead
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
Hector R. Mendez: Stanford University School of Medicine
Kay Metcalfe: Health Innovation Manchester
Stephen B. Montgomery: Stanford University School of Medicine
Mariya Moosajee: UCL Institute of Ophthalmology
Marie-Cécile Nassogne: 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
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
Heidi L. Rehm: Broad Institute of MIT and Harvard
Chloe M. Reuter: Stanford University School of Medicine
Nicole Revencu: Université Catholique de Louvain
Angelika Riess: University of Tübingen
Rocio Rius: University of Melbourne
Lance Rodan: Harvard Medical School
Tony Roscioli: Neuroscience Research Australia
Jill A. Rosenfeld: Baylor College of Medicine
Rani Sachdev: University of New South Wales
Charles J. Shaw-Smith: Royal Devon University Hospital
Cas Simons: Garvan Institute of Medical Research and UNSW Sydney
Sanjay M. Sisodiya: UCL Queen Square Institute of Neurology
Penny Snell: Murdoch Children’s Research Institute
Laura St Clair: Sydney Children’s Hospitals Network Westmead
Zornitza Stark: Murdoch Children’s Research Institute
Helen S. Stewart: Oxford University Hospitals NHS Foundation Trust
Tiong Yang Tan: Murdoch Children’s Research Institute
Natalie B. Tan: Murdoch Children’s Research Institute
Suzanna E. L. Temple: Liverpool Hospital
David R. Thorburn: 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
Matthew T. Wheeler: Stanford University School of Medicine
Susan M. White: Murdoch Children’s Research Institute
Monica Wojcik: 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
Christel Depienne: University Duisburg-Essen
Daniel G. MacArthur: Garvan Institute of Medical Research and UNSW Sydney
Joanna M. M. Howson: Novo Nordisk Research Centre
Stephan J. Sanders: University of Oxford
Anne O’Donnell-Luria: Broad Institute of MIT and Harvard
Nicola Whiffin: University of Oxford

Nature, 2024, vol. 632, issue 8026, 832-840

Abstract: 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.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-07773-7 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:632:y:2024:i:8026:d:10.1038_s41586-024-07773-7

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-07773-7

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().