De novovariants in the non-coding spliceosomal snRNA geneRNU4-2are a frequent cause of syndromic neurodevelopmental disorders
Author:
Chen Yuyang, Dawes Ruebena, Kim Hyung Chul, Stenton Sarah L, Walker Susan, Ljungdahl Alicia, Lord Jenny, Ganesh Vijay SORCID, Ma Jialan, Martin-Geary Alexandra C, Lemire Gabrielle, D’Souza Elston N, Dong Shan, Ellingford Jamie M, Adams David RORCID, Allan Kirsten, Bakshi Madhura, Baldwin Erin E, Berger Seth IORCID, Bernstein Jonathan AORCID, Brown Natasha J, Burrage Lindsay CORCID, Chapman Kimberly, Compton Alison GORCID, Cunningham Chloe AORCID, D’Souza PrecillaORCID, Délot Emmanuèle C, Dias Kerith-RaeORCID, Elias Ellen R, Evans Carey-Anne, Ewans Lisa, Ezell KimberlyORCID, Fraser Jamie LORCID, Gallacher LyndonORCID, Genetti Casie A, Grant Christina LORCID, Haack Tobias, Kuechler Alma, Lalani Seema RORCID, Leitão ElsaORCID, Fevre Anna LeORCID, Leventer Richard JORCID, Liebelt Jan E, Lockhart Paul JORCID, Ma Alan SORCID, Macnamara Ellen FORCID, Maurer Taylor MORCID, Mendez Hector RORCID, Montgomery Stephen BORCID, Nassogne Marie-Cécile, Neumann Serena, O’Leary Melanie, Palmer Elizabeth EORCID, Phillips John, Pitsava Georgia, Pysar Ryan, Rehm Heidi LORCID, Reuter Chloe MORCID, Revencu Nicole, Riess Angelika, Rius RocioORCID, Rodan Lance, Roscioli Tony, Rosenfeld Jill AORCID, Sachdev Rani, Simons CasORCID, Sisodiya Sanjay M, Snell Penny, Clair Laura St, Stark ZornitzaORCID, Tan Tiong YangORCID, Tan Natalie BORCID, Temple Suzanna EL, Thorburn David RORCID, Tifft Cynthia JORCID, Uebergang EloiseORCID, VanNoy Grace EORCID, Vilain EricORCID, Viskochil David H, Wedd Laura, Wheeler Matthew TORCID, White Susan MORCID, Wojcik MonicaORCID, Wolfe Lynne A, Wolfenson Zoe, Xiao ChangruiORCID, Zocche DavidORCID, Rubenstein John L, Markenscoff-Papadimitriou Eirene, Fica Sebastian M, Baralle Diana, Depienne ChristelORCID, MacArthur Daniel G, Howson Joanna MMORCID, Sanders Stephan JORCID, O’Donnell-Luria AnneORCID, Whiffin NicolaORCID
Abstract
AbstractAround 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 RNARNU4-2as a novel syndromic NDD gene.RNU4-2encodes 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 ofRNU4-2mapping 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 thatRNU4-2is highly expressed in the developing human brain, in contrast to its contiguous counterpartRNU4-1and other U4 homologs, supportingRNU4-2’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.
Publisher
Cold Spring Harbor Laboratory
Cited by
4 articles.
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