De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders

作者：Yuyang Chen, Ruebena Dawes, Hyung Chul Kim, Sarah L. Stenton, Susan Walker, Alicia Ljungdahl, Jenny Lord, Vijay S Ganesh, Jialan Ma, Alexandra C Martin-Geary, Gabrielle Lemire, Elston N. D’Souza, Shan Dong, Jamie M. Ellingford, David R. Adams, Kirsten Allan, Madhura Bakshi, Erin E. Baldwin, Seth Berger, Jonathan A. Bernstein, Natasha J. Brown, Lindsay C. Burrage, Kimberly A. Chapman, Alison G. Compton, Chloe A Cunningham, Precilla D’Souza, Emmanuèle C. Délot, Kerith‐Rae Dias, Ellen Roy Elias, Carey‐Anne Evans, Lisa Ewans, Kimberly Ezell, Jamie L. Fraser, Lyndon Gallacher, Casie A. Genetti, Christina Grant, Tobias B. Haack, Alma Kuechler, Seema R. Lalani, Elsa Leitão, Anna Le Fevre, Richard J. Leventer, Jan Liebelt, Paul J. Lockhart, Alan Ma, Ellen F. Macnamara, Taylor Maurer, Rodrigo Mendez, Stephen B. Montgomery, Marie‐Cécile Nassogne, Serena Neumann, Melanie O’Leary, Elizabeth E. Palmer, John Phillips, Georgia Pitsava, Ryan Pysar, Heidi L. Rehm, Chloe M. Reuter, Nicole Revençu, Angelika Rieß, Rocío Rius, Lance H. Rodan, Tony Roscioli, Jill A. Rosenfeld, Rani Sachdev, Cas Simons, Sanjay M. Sisodiya, Penny Snell, Laura St Clair, Zornitza Stark, Tiong Yang Tan, Natalie B. Tan, Suzanna E.L. Temple, David R. Thorburn, Cynthia J. Tifft, Eloise Uebergang, Grace E. VanNoy, Éric Vilain, David Viskochil, Laura Wedd, Matthew T. Wheeler, Susan M. White, Monica H. Wojcik, Lynne A. Wolfe, Zoe Wolfenson, Changrui Xiao, David Zocche, John L.R. Rubenstein, Eirene Markenscoff-Papadimitriou, Sebastian M. Fica, Diana Baralle, Christel Depienne, Daniel G. MacArthur, Joanna M. M. Howson, Stephan Sanders, Anne O’Donnell‐Luria, Nicola Whiffin · 发表于：medRxiv · 年份：2024 · DOI：10.1101/2024.04.07.24305438 · 被引用次数：10 · 研究领域：RNA Research and Splicing、RNA regulation and disease、RNA modifications and cancer

Abstract Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Increasingly, 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 novel 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 bp 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 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 that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2 ’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.