De novovariants in the non-coding spliceosomal snRNA geneRNU4-2are a frequent cause of syndromic neurodevelopmental disorders
Authors: Chen Yuyang , Dawes Ruebena , Kim Hyung Chul , Stenton Sarah L , Walker Susan , Ljungdahl Alicia , Lord Jenny , Ganesh Vijay S , Ma Jialan , Martin-Geary Alexandra C , Lemire Gabrielle , D’Souza Elston N , Dong Shan , Ellingford Jamie M , Adams David R , Allan Kirsten , Bakshi Madhura , Baldwin Erin E , Berger Seth I , Bernstein Jonathan A , Brown Natasha J , Burrage Lindsay C , Chapman Kimberly , Compton Alison G , Cunningham Chloe A , D’Souza Precilla , Délot Emmanuèle C , Dias Kerith-Rae , Elias Ellen R , Evans Carey-Anne , Ewans Lisa , Ezell Kimberly , Fraser Jamie L , Gallacher Lyndon , Genetti Casie A , Grant Christina L , Haack Tobias , Kuechler Alma , Lalani Seema R , Leitão Elsa , Fevre Anna Le , Leventer Richard J , Liebelt Jan E , Lockhart Paul J , Ma Alan S , Macnamara Ellen F , Maurer Taylor M , Mendez Hector R , Montgomery Stephen B , Nassogne Marie-Cécile , Neumann Serena , O’Leary Melanie , Palmer Elizabeth E , 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 , Simons Cas , Sisodiya Sanjay M , Snell Penny , Clair Laura St , Stark Zornitza , Tan Tiong Yang , Tan Natalie B , Temple Suzanna EL , Thorburn David R , Tifft Cynthia J , Uebergang Eloise , VanNoy Grace E , Vilain Eric , Viskochil David H , Wedd Laura , Wheeler Matthew T , White Susan M , Wojcik Monica , Wolfe Lynne A , Wolfenson Zoe , Xiao Changrui , Zocche David , Rubenstein John L , Markenscoff-Papadimitriou Eirene , Fica Sebastian M , Baralle Diana , Depienne Christel , MacArthur Daniel G , Howson Joanna MM , Sanders Stephan J , O’Donnell-Luria Anne , Whiffin Nicola 
Published: April 2024

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.