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

• 成果类型: Article
• 署名作者: 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; Delot, Emmanuele 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.; Lecoquierre, Francois; Leitao, Elsa; Le Fevre, Anna; Leventer, Richard J.; Liebelt, Jan E.; Lindsay, Sarah; Lockhart, Paul J.; Ma, Alan S.; Macnamara, Ellen F.; Mansour, Sahar; Maurer, Taylor M.; Mendez, Hector R.; Metcalfe, Kay; Montgomery, Stephen B.; Moosajee, Mariya; Nassogne, Marie-Cecile; Neumann, Serena; O'Donoghue, Michael; O'Leary, Melanie; Palmer, Elizabeth E.; Pattani, Nikhil; Phillips, John; Pitsava, Georgia; Pysar, Ryan; Rehm, Heidi L.; Reuter, Chloe M.; Revencu, Nicole; Riess, Angelika; Rius, Rocio; Rodan, Lance; Roscioli, Tony; Rosenfeld, Jill A.; Sachdev, Rani; Shaw-Smith, Charles J.; Simons, Cas; Sisodiya, Sanjay M.; Snell, Penny; St Clair, Laura; Stark, Zornitza; Stewart, Helen S.; Tan, Tiong Yang; Tan, Natalie B.; Temple, Suzanna E. L.; Thorburn, David R.; Tifft, Cynthia J.; Uebergang, Eloise; VanNoy, Grace E.; Vasudevan, Pradeep; Vilain, Eric; Viskochil, David H.; Wedd, Laura; Wheeler, Matthew T.; White, Susan M.; Wojcik, Monica; Wolfe, Lynne A.; Wolfenson, Zoe; Wright, Caroline F.; Xiao, Changrui; Zocche, David; Rubenstein, John L.; Markenscoff-Papadimitriou, Eirene; Fica, Sebastian M.; Baralle, Diana; Depienne, Christel; MacArthur, Daniel G.; Howson, Joanna M. M.; Sanders, Stephan J.; O'Donnell-Luria, Anne; Whiffin, Nicola
• 署名单位: University of Oxford; University of Oxford; Wellcome Centre for Human Genetics; University of Oxford; University of California System; University of California San Francisco; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; University of Sheffield; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; Manchester University NHS Foundation Trust; University of Manchester; Wellcome Trust Sanger Institute; National Institutes of Health (NIH) - USA; NIH National Human Genome Research Institute (NHGRI); Murdoch Children's Research Institute; Victorian Clinical Genetics Services; Liverpool Hospital; Utah System of Higher Education; University of Utah; Children's National Health System; Children's National Health System; Stanford University; Stanford University; Stanford University; Oxford University Hospitals NHS Foundation Trust; University of Melbourne; Baylor College of Medicine; Childrens Health Queensland Hospital & Health Service; Queensland Childrens Hospital; University of Queensland; Griffith University; Griffith University - Gold Coast Campus; Murdoch Children's Research Institute; Neuroscience Research Australia; University of New South Wales Sydney; Children's Hospital Colorado; University of Colorado System; University of Colorado Anschutz Medical Campus; University of New South Wales Sydney; Prince of Wales Hospital (POWH); University of New South Wales Sydney; NSW Health; Sydney Childrens Hospitals Network; Garvan Institute of Medical Research; Vanderbilt University; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; University of Oxford; University of Oxford; Eberhard Karls University of Tubingen; Eberhard Karls University of Tubingen; University of Liverpool; University of Duisburg Essen; University of Southampton; Universite de Rouen Normandie; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite de Rouen Normandie; CHU de Rouen; Royal Children's Hospital Melbourne; Murdoch Children's Research Institute; NSW Health; Sydney Childrens Hospitals Network; University of Sydney; Stanford University; Stanford University; University of Manchester; Manchester University NHS Foundation Trust; Stanford University; University of London; University College London; Francis Crick Institute; University of London; University College London; Moorfields Eye Hospital NHS Foundation Trust; Universite Catholique Louvain; Cliniques Universitaires Saint-Luc; Universite Catholique Louvain; Cliniques Universitaires Saint-Luc; Nottingham University Hospital NHS Trust; University of California System; University of California Irvine; University of Sydney; NSW Health; Sydney Childrens Hospitals Network; The Children's Hospital at Westmead; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Universite Catholique Louvain; Cliniques Universitaires Saint-Luc; Garvan Institute of Medical Research; University of New South Wales Sydney; Murdoch Children's Research Institute; University of London; University College London; University of New South Wales Sydney; University of Leicester; University of California System; University of California Irvine; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; University of Exeter; University of California System; University of California Irvine; Imperial College London; Imperial College London; University of California System; University of California San Francisco; University of Oxford; University of Southampton; University of Southampton; University Hospital Southampton NHS Foundation Trust
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5565
• DOI: 10.1038/s41586-024-07773-7
• 发表日期: 2024-08-22
• 页码: 832-+
• 关键词: resource

摘要

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.