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

Yuyang Chen(Centre for Human Genetics), Ruebena Dawes(Centre for Human Genetics), Hyung Chul Kim(Centre for Human Genetics), Alicia Ljungdahl(University of California, San Francisco), Sarah L. Stenton(Broad Institute), Susan Walker(Genomics England), Jenny Lord(University of Sheffield), Gabrielle Lemire(Broad Institute), Alexandra C Martin-Geary(Centre for Human Genetics), Vijay S Ganesh(Broad Institute), Jialan Ma(Broad Institute), Jamie M. Ellingford(University of Manchester), Erwan Delage(Wellcome Sanger Institute), Elston N. D’Souza(Centre for Human Genetics), Shan Dong(University of California, San Francisco), David R. Adams(National Human Genome Research Institute), Kirsten Allan(Victorian Clinical Genetics Services), Madhura Bakshi(Liverpool Hospital), Erin E. Baldwin(University of Utah), Seth Berger(Children's National), Jonathan A. Bernstein(Stanford Medicine), Ishita Bhatnagar(Oxford University Hospitals NHS Trust), Ed Blair(Oxford University Hospitals NHS Trust), Natasha J. Brown(The University of Melbourne), Lindsay C. Burrage(Baylor College of Medicine), Kimberly A. Chapman(Children's National), David Coman(Griffith University), Alison G. Compton(The University of Melbourne), Chloe A Cunningham(The University of Melbourne), Precilla D’Souza(National Human Genome Research Institute), Petr Danecek(Wellcome Sanger Institute), Emmanuèle C. Délot(Children's National), Kerith‐Rae Dias(UNSW Sydney), Ellen Roy Elias(Children's Hospital Colorado), Frances Elmslie(St George’s University Hospitals NHS Foundation Trust), Care-Anne Evans(Prince of Wales Hospital), Lisa Ewans(Garvan Institute of Medical Research), Kimberly Ezell(Vanderbilt University Medical Center), Jamie L. Fraser(Children's National), Lyndon Gallacher(The University of Melbourne), Casie A. Genetti(Boston Children's Hospital), Anne Goriely(University of Oxford), Christina Grant(Children's National), Tobias B. Haack(University of Tübingen), Jenny Higgs(University of Liverpool), Anjali Gupta Hinch(Centre for Human Genetics), Matthew E. Hurles(Wellcome Sanger Institute), Alma Kuechler(University of Duisburg-Essen), Katherine Lachlan(University Hospital Southampton NHS Foundation Trust), Seema R. Lalani(Baylor College of Medicine), François Lecoquierre(Inserm), Elsa Leitão(University of Duisburg-Essen), Anna Le Fevre(Victorian Clinical Genetics Services), Richard J. Leventer(Royal Children's Hospital), Jan Liebelt(Women's and Children's Hospital), Sarah Lindsay(Wellcome Sanger Institute), Paul J. Lockhart(The University of Melbourne), Alan Ma(The University of Sydney), Ellen F. Macnamara(National Human Genome Research Institute), Sahar Mansour(St George’s University Hospitals NHS Foundation Trust), Taylor Maurer(Stanford Medicine), Rodrigo Mendez(Stanford Medicine), Kay Metcalfe(Manchester University NHS Foundation Trust), Stephen B. Montgomery(Stanford Medicine), Mariya Moosajee(Moorfields Eye Hospital NHS Foundation Trust), Marie‐Cécile Nassogne(Cliniques Universitaires Saint-Luc), Serena Neumann(Vanderbilt University Medical Center), Michael O’Donoghue(Nottingham University Hospitals NHS Trust), Melanie O’Leary(Broad Institute), Elizabeth E. Palmer(UNSW Sydney), Nikhil Pattani(St George’s University Hospitals NHS Foundation Trust), John Phillips(Vanderbilt University Medical Center), Georgia Pitsava(University of California, Irvine), Ryan Pysar(Children's Hospital at Westmead), Heidi L. Rehm(Broad Institute), Chloe M. Reuter(Stanford Medicine), Nicole Revençu(Cliniques Universitaires Saint-Luc), Angelika Rieß(University of Tübingen), Rocío Rius(Garvan Institute of Medical Research), Lance H. Rodan(Boston Children's Hospital), Tony Roscioli(UNSW Sydney), Jill A. Rosenfeld(Baylor College of Medicine), Rani Sachdev(UNSW Sydney), Charles Shaw‐Smith(Peninsula College of Medicine and Dentistry), Cas Simons(Garvan Institute of Medical Research), Sanjay M. Sisodiya(National Hospital for Neurology and Neurosurgery), Penny Snell(Murdoch Children's Research Institute), Laura St Clair(Sydney Children’s Hospitals Network), Zornitza Stark(The University of Melbourne), Helen Stewart(Oxford University Hospitals NHS Trust), Tiong Yang Tan(The University of Melbourne), Natalie B. Tan(Victorian Clinical Genetics Services), Suzanna E.L. Temple(Liverpool Hospital), David R. Thorburn(The University of Melbourne), Cynthia J. Tifft(National Human Genome Research Institute), Eloise Uebergang(Murdoch Children's Research Institute), Grace E. VanNoy(Broad Institute), Pradeep Vasudevan(Leicester Royal Infirmary), Éric Vilain(University of California, Irvine), David Viskochil(University of Utah), Laura Wedd(Garvan Institute of Medical Research), Matthew T. Wheeler(Stanford Medicine), Susan M. White(The University of Melbourne), Monica H. Wojcik(Boston Children's Hospital), 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(St Mark's Hospital), John L.R. Rubenstein(University of California, San Francisco), Eirene Markenscoff-Papadimitriou(Langley Porter Psychiatric Hospital and Clinics), Sebastian M. Fica(University of Oxford), Diana Baralle(University Hospital Southampton NHS Foundation Trust), Christel Depienne(University of Duisburg-Essen), Daniel G. MacArthur(Garvan Institute of Medical Research), Joanna M. M. Howson(Novo Nordisk (United Kingdom)), Stephan Sanders(University of California, San Francisco), Anne O’Donnell‐Luria(Broad Institute), Nicola Whiffin(Broad Institute)
Nature
July 11, 2024
10.1038/s41586-024-07773-7
Cited by 112Open Access
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Abstract

Abstract Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . 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 spliceosome 2 . 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.

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