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; Goriely, A; Hinch, AG; Stewart, HS; Fica, SM; Sanders, SJ; Whiffin, N

Women's Health Collection

Journal article

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 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.

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Chen, Y., Dawes, R., Kim, H. C., Ljungdahl, A., Stenton, S. L., Walker, S., Lord, J., Lemire, G., Martin-Geary, A. C., Ganesh, V. S., Ma, J., Ellingford, J. M., Delage, E., D’Souza, E. N., Dong, S., Adams, D. R., Allan, K., Bakshi, M., Baldwin, E. E., … Whiffin, N. (2024). De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome. Nature, 632(8026), 832–840.

MLA Style

Chen, Y, et al. “De Novo Variants in the RNU4-2 SnRNA Cause a Frequent Neurodevelopmental Syndrome.” Nature, vol. 632, no. 8026, 2024, pp. 832–40.

Chicago Style

Chen, Y, R Dawes, HC Kim, et al. 2024. “De Novo Variants in the RNU4-2 SnRNA Cause a Frequent Neurodevelopmental Syndrome.” Nature 632 (8026): 832–40.
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