De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.
Creators: name: Chen, Yuyang
name: Dawes, Ruebena
name: Kim, Hyung Chul
name: Ljungdahl, Alicia
name: Stenton, Sarah L
name: Walker, Susan
name: Lord, Jenny
name: Lemire, Gabrielle
name: Martin-Geary, Alexandra C
name: Ganesh, Vijay S
name: Ma, Jialan
name: Ellingford, Jamie M
name: Delage, Erwan
name: D'Souza, Elston N
name: Dong, Shan
name: Adams, David R
name: Allan, Kirsten
name: Bakshi, Madhura
name: Baldwin, Erin E
name: Berger, Seth I
name: Bernstein, Jonathan A
name: Bhatnagar, Ishita
name: Blair, Ed
name: Brown, Natasha J
name: Burrage, Lindsay C
name: Chapman, Kimberly
name: Coman, David J
name: Compton, Alison G
name: Cunningham, Chloe A
name: D'Souza, Precilla
name: Danecek, Petr
name: Délot, Emmanuèle C
name: Dias, Kerith-Rae
name: Elias, Ellen R
name: Elmslie, Frances
name: Evans, Care-Anne
name: Ewans, Lisa
name: Ezell, Kimberly
name: Fraser, Jamie L
name: Gallacher, Lyndon
name: Genetti, Casie A
name: Goriely, Anne
name: Grant, Christina L
name: Haack, Tobias
name: Higgs, Jenny E
name: Hinch, Anjali G
name: Hurles, Matthew E
name: Kuechler, Alma
name: Lachlan, Katherine L
name: Lalani, Seema R
name: Lecoquierre, François
name: Leitão, Elsa
name: Le Fevre, Anna
name: Leventer, Richard J
name: Liebelt, Jan E
name: Lindsay, Sarah
name: Lockhart, Paul J
name: S, Alan
name: Macnamara, Ellen F
name: Mansour, Sahar
name: Maurer, Taylor M
name: Mendez, Hector R
name: Metcalfe, Kay
name: Montgomery, Stephen B
name: Moosajee, Mariya
name: Nassogne, Marie-Cécile
name: Neumann, Serena
name: O'Donoghue, Michael
name: O'Leary, Melanie
name: Palmer, Elizabeth E
name: Pattani, Nikhil
name: Phillips, John
name: Pitsava, Georgia
name: Pysar, Ryan
name: Rehm, Heidi L
name: Reuter, Chloe M
name: Revencu, Nicole
name: Riess, Angelika
name: Rius, Rocio
name: Rodan, Lance
name: Roscioli, Tony
name: Rosenfeld, Jill A
name: Sachdev, Rani
name: Shaw-Smith, Charles J
name: Simons, Cas
name: Sisodiya, Sanjay M
name: Snell, Penny
name: St Clair, Laura
name: Stark, Zornitza
name: Stewart, Helen S
name: Tan, Tiong Yang
name: Tan, Natalie B
name: Temple, Suzanna EL
name: Thorburn, David R
name: Tifft, Cynthia J
name: Uebergang, Eloise
name: VanNoy, Grace E
name: Vasudevan, Pradeep
name: Vilain, Eric
name: Viskochil, David H
name: Wedd, Laura
name: Wheeler, Matthew T
name: White, Susan M
name: Wojcik, Monica
name: Wolfe, Lynne A
name: Wolfenson, Zoe
name: Wright, Caroline F
name: Xiao, Changrui
name: Zocche, David
name: Rubenstein, John L
name: Markenscoff-Papadimitriou, Eirene
name: Fica, Sebastian M
name: Baralle, Diana
name: Depienne, Christel
name: MacArthur, Daniel G
name: Howson, Joanna MM
name: Sanders, Stephan J
name: O'Donnell-Luria, Anne
name: Whiffin, Nicola
Publisher: name: The Francis Crick Institute
Year: 2024
Subjects: classificationCode: Stem Cells
subject: Stem Cells
classificationCode: Gene Expression
subject: Gene Expression
classificationCode: Genetics & Genomics
subject: Genetics &amp; Genomics
classificationCode: Developmental Biology
subject: Developmental Biology
classificationCode: Neurosciences
subject: Neurosciences
subject: FOS: Clinical medicine
classificationCode: Human Biology & Physiology
subject: Human Biology &amp; Physiology
classificationCode: Model organisms
subject: Model organisms

description: 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 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 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals where 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 homologs. Using RNA-sequencing, we show how 5' splice site usage 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 bp 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.