Journal Article

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

Rehm, Heidi L., O’Donnell-Luria, Anne, Hinch, Anjali G., Lockhart, Paul J., Kim, Hyung Chul, St Clair, Laura, Fevre, Anna Le, Viskochil, David H., Chapman, Kimberly, Ewans, Lisa, Wheeler, Matthew T., Goriely, Anne, Allan, Kirsten, Baldwin, Erin E., Stewart, Helen S., Sanders, Stephan J., Martin-Geary, Alexandra C., Ma, Jialan, Moosajee, Mariya, D’Souza, Elston N., Wright, Caroline F., Ezell, Kimberly, O’Donoghue, Michael, Rius, Rocio, Coman, David J., Simons, Cas, Fica, Sebastian M., Stenton, Sarah L., Xiao, Changrui, Ganesh, Vijay S., Leventer, Richard J., Brown, Natasha J., Pitsava, Georgia, Stark, Zornitza, Kuechler, Alma, Zocche, David, Shaw-Smith, Charles J., Fraser, Jamie L., Lord, Jenny, Howson, Joanna M. M., Whiffin, Nicola, White, Susan M., Revencu, Nicole, Walker, Susan, Mansour, Sahar, Lalani, Seema R., D’Souza, Precilla, Danecek, Petr, Lecoquierre, François, Vasudevan, Pradeep, Bakshi, Madhura, O’Leary, Melanie, Liebelt, Jan E., Adams, David R., Berger, Seth I., Ellingford, Jamie M., Lindsay, Sarah, Tifft, Cynthia J., Roscioli, Tony, MacArthur, Daniel G., Tan, Tiong Yang, Temple, Suzanna E. L.

2024

Overview

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . 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 2 . 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. The non-coding RNA RNU4-2 , which is highly expressed in the developing human brain, is identified as a syndromic neurodevelopmental disorder gene, and, using RNA sequencing, 5′ splice-site use is shown to be systematically disrupted in individuals with RNU4-2 variants.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/23 / 38/39 / 38/91 / 631/114/2785 / 631/208/2489/144 / 631/337/384 / 631/378/2583 / 692/699/375/366 / Adolescent / Alleles / Brain - growth & development / Brain - metabolism / Child / Child, Preschool / Critical components / Disorders / Female / Gene Expression Regulation, Developmental / Gene sequencing / Genes / Genetic screening / Genomes / Genomics / Genotype & phenotype / Heterozygote / Humanities and Social Sciences / Humans / Infant / Male / Microcephaly / multidisciplinary / Mutation / Neurodevelopmental disorders / Neurodevelopmental Disorders - genetics / Non-coding RNA / Population genetics / Rare Diseases - genetics / Ribonucleic acid / Ribonucleoproteins (small nuclear) / RNA / RNA Splice Sites - genetics / RNA, Small Nuclear - genetics / Science / Science (multidisciplinary) / snRNA / Spliceosomes - genetics / Structural members / Syndrome / Young Adult