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

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 Délot, Emmanuèle 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, François Leitão, Elsa Fevre, Anna Le 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-Cécile 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 [UCL] 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 et al.[show all]

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