De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.
Chen Y., Dawes R., Kim HC., Ljungdahl A., Stenton SL., Walker S., Lord J., Lemire G., Martin-Geary AC., Ganesh VS., Ma J., Ellingford JM., Delage E., D'Souza EN., Dong S., Adams DR., Allan K., Bakshi M., Baldwin EE., Berger SI., Bernstein JA., Bhatnagar I., Blair E., Brown NJ., Burrage LC., Chapman K., Coman DJ., Compton AG., Cunningham CA., D'Souza P., Danecek P., Délot EC., Dias K-R., Elias ER., Elmslie F., Evans C-A., Ewans L., Ezell K., Fraser JL., Gallacher L., Genetti CA., Goriely A., Grant CL., Haack T., Higgs JE., Hinch AG., Hurles ME., Kuechler A., Lachlan KL., Lalani SR., Lecoquierre F., Leitão E., Fevre AL., Leventer RJ., Liebelt JE., Lindsay S., Lockhart PJ., Ma AS., Macnamara EF., Mansour S., Maurer TM., Mendez HR., Metcalfe K., Montgomery SB., Moosajee M., Nassogne M-C., Neumann S., O'Donoghue M., O'Leary M., Palmer EE., Pattani N., Phillips J., Pitsava G., Pysar R., Rehm HL., Reuter CM., Revencu N., Riess A., Rius R., Rodan L., Roscioli T., Rosenfeld JA., Sachdev R., Shaw-Smith CJ., Simons C., Sisodiya SM., Snell P., St Clair L., Stark Z., Stewart HS., Tan TY., Tan NB., Temple SEL., Thorburn DR., Tifft CJ., Uebergang E., VanNoy GE., Vasudevan P., Vilain E., Viskochil DH., Wedd L., Wheeler MT., White SM., Wojcik M., Wolfe LA., Wolfenson Z., Wright CF., Xiao C., Zocche D., Rubenstein JL., Markenscoff-Papadimitriou E., Fica SM., Baralle D., Depienne C., MacArthur DG., Howson JMM., Sanders SJ., O'Donnell-Luria A., Whiffin N.
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.