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

Abstract

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.

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Item Type:	Article
Authors/Creators:	Chen, Y. https://orcid.org/0000-0001-5593-6920 Dawes, R. https://orcid.org/0000-0003-2135-0117 Kim, H.C. https://orcid.org/0000-0001-5877-5456 Ljungdahl, A. Stenton, S.L. https://orcid.org/0000-0003-4071-449X Walker, S. https://orcid.org/0000-0002-5016-6426 Lord, J. https://orcid.org/0000-0002-0539-9343 Lemire, G. Martin-Geary, A.C. https://orcid.org/0000-0002-5818-1962 Ganesh, V.S. Ma, J. Ellingford, J.M. Delage, E. https://orcid.org/0000-0002-7653-5111 D’Souza, E.N. https://orcid.org/0000-0002-5394-7260 Dong, S. Adams, D.R. Allan, K. Bakshi, M. Baldwin, E.E. Berger, S.I. https://orcid.org/0000-0001-7517-4302 Bernstein, J.A. https://orcid.org/0000-0001-5369-346X Bhatnagar, I. Blair, E. Brown, N.J. Burrage, L.C. Chapman, K. Coman, D.J. https://orcid.org/0000-0001-6303-6471 Compton, A.G. https://orcid.org/0000-0002-2725-7055 Cunningham, C.A. D’Souza, P. Danecek, P. Délot, E.C. Dias, K.-R. https://orcid.org/0000-0002-4707-8089 Elias, E.R. Elmslie, F. https://orcid.org/0000-0002-2508-9107 Evans, C.-A. Ewans, L. Ezell, K. Fraser, J.L. https://orcid.org/0000-0002-7794-8903 Gallacher, L. https://orcid.org/0000-0003-2245-9034 Genetti, C.A. Goriely, A. https://orcid.org/0000-0001-9229-7216 Grant, C.L. https://orcid.org/0000-0002-0627-4614 Haack, T. https://orcid.org/0000-0001-6033-4836 Higgs, J.E. Hinch, A.G. https://orcid.org/0000-0002-0836-3418 Hurles, M.E. https://orcid.org/0000-0002-2333-7015 Kuechler, A. Lachlan, K.L. Lalani, S.R. Lecoquierre, F. Leitão, E. https://orcid.org/0000-0001-5051-9714 Fevre, A.L. https://orcid.org/0000-0001-5843-9516 Leventer, R.J. Liebelt, J.E. Lindsay, S. https://orcid.org/0000-0002-0965-3070 Lockhart, P.J. https://orcid.org/0000-0003-2531-8413 Ma, A.S. Macnamara, E.F. Mansour, S. Maurer, T.M. https://orcid.org/0009-0002-2330-7980 Mendez, H.R. https://orcid.org/0000-0001-6465-452X Metcalfe, K. Montgomery, S.B. https://orcid.org/0000-0002-5200-3903 Moosajee, M. Nassogne, M.-C. Neumann, S. https://orcid.org/0009-0001-0957-7338 O’Donoghue, M. O’Leary, M. https://orcid.org/0000-0002-8718-4759 Palmer, E.E. Pattani, N. https://orcid.org/0000-0002-7233-3635 Phillips, J. Pitsava, G. Pysar, R. Rehm, H.L. Reuter, C.M. Revencu, N. https://orcid.org/0000-0002-7120-4903 Riess, A. Rius, R. https://orcid.org/0000-0002-9871-3126 Rodan, L. Roscioli, T. Rosenfeld, J.A. https://orcid.org/0000-0001-5664-7987 Sachdev, R. Shaw-Smith, C.J. Simons, C. https://orcid.org/0000-0003-3147-8042 Sisodiya, S.M. Snell, P. https://orcid.org/0000-0002-9821-5282 St Clair, L. Stark, Z. Stewart, H.S. Tan, T.Y. Tan, N.B. Temple, S.E.L. Thorburn, D.R. https://orcid.org/0000-0002-7725-9470 Tifft, C.J. Uebergang, E. https://orcid.org/0000-0003-0305-7822 VanNoy, G.E. Vasudevan, P. https://orcid.org/0009-0002-6095-2030 Vilain, E. Viskochil, D.H. Wedd, L. Wheeler, M.T. https://orcid.org/0000-0001-8721-3022 White, S.M. Wojcik, M. Wolfe, L.A. Wolfenson, Z. https://orcid.org/0009-0008-2207-5755 Wright, C.F. https://orcid.org/0000-0003-2958-5076 Xiao, C. Zocche, D. Rubenstein, J.L. Markenscoff-Papadimitriou, E. Fica, S.M. https://orcid.org/0000-0001-9186-0361 Baralle, D. Depienne, C. https://orcid.org/0000-0002-7212-9554 MacArthur, D.G. Howson, J.M.M. https://orcid.org/0000-0001-7618-0050 Sanders, S.J. https://orcid.org/0000-0001-9112-5148 O’Donnell-Luria, A. https://orcid.org/0000-0001-6418-9592 Whiffin, N. https://orcid.org/0000-0003-1554-6594
Copyright, Publisher and Additional Information:	© The author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Disease genetics; Genetics of the nervous system; Genome informatics; Neurodevelopmental disorders; Non-coding RNAs
Dates:	Published: 22 August 2024 Published (online): 11 July 2024 Accepted: 2 July 2024 Submitted: 7 April 2024
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Depositing User:	Symplectic Sheffield
Date Deposited:	12 Jul 2024 08:27
Last Modified:	27 Aug 2024 08:51
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41586-024-07773-7
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:214723

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

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