Rocío Rius, Alexander J. M. Blakes, Yuyang Chen, Joachim De Jonghe, François Lecoquierre, Ruebena Dawes, Benjamin Cogné, Hyung Chul Kim, Javeria R. Alvi, Florence Amblard, Morad Ansari, Annabelle Arlt, Christina Austin-Tse, Sarah Baer, Meena Balasubramanian, Elsa Balton, Giulia Barcia, Ana Beleza-Meireles, Jonathan A. Bernstein, Jasmin Beygo, Pierre Blanc, Nuria C. Bramswig, Frederik Braun, Daniel Buchzik, Daniel G. Calame, Jamie Campbell, Charles Coutton, Chloe A Cunningham, Nitsuh Dargie, Christel Depienne, Katrina M. Dipple, Anne Dieux, Abhijit Dixit, Lauren Dreyer, Haowei Du, Salima El Chehadeh, Michael Field, Lisa J. Ewans, Vanessa Geiger, Richard A. Gibbs, Ian A. Glass, Olivier Grunewald, Paul Gueguen, Tobias B. Haack, Hamza Hadj Abdallah, Radu Harbuz, Ingo Helbig, Jane Horvath, Alexander Hustinx, Bertrand Isidor, Marie‐Line Jacquemont, Fraser Jamie, Médéric Jeanne, Riley Kessler, Hannah Klinkhammer, G. Christoph Korenke, Urania Kotzaeridou, Peter Krawitz, Steven Laurie, Richard J. Leventer, Rebecca J. Levy, James R. Lupski, Pierre Marijon, Kaitlin McGINNIS, Rodrigo Mendez, Olfa Messaoud, Caroline Nava, Mevyn Nizard, Anne O’Donnell-Luria, Melanie O’Leary, Simone Olivieri, Amitav Parida, Davut Pehlivan, Anna Jenne Prentice, Jennifer E. Posey, Chloe M. Reuter, Véronique Satre, Caroline Schluth-Bolard, Thomas Smol, Tipu Sultan, John Taylor, Christel Thauvin‐Robinet, Julien Thevenon, Eloise Uebergang, Sandra Ueberberg, C Vincent-Delorme, Evangeline Wassmer, Emma Westwood, Matthew T. Wheeler, Elif Yilmaz Gulec, Adeline Vanderver, Arastoo Vossough, Stephan Sanders, Siddharth Banka, Gregory M. Findlay, Daniel G. MacArthur, Cas Simons, Nicola Whiffin
Genetic variants in RNU4-2, which is transcribed into the U4 small nuclear RNA component of the major spliceosome, were recently shown to cause ReNU syndrome, a prevalent dominant neurodevelopmental disorder (NDD). These variants almost exclusively arise de novo and cluster within 18 nucleotides of RNU4-2. Here we describe a new recessive NDD associated with homozygous and compound heterozygous variants in RNU4-2. We identify 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site. We characterize the clinical phenotype in 31 individuals, demonstrating that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces. Finally, we find reduced RNU4-2 transcript levels in individuals with the recessive disorder, suggesting a loss-of-function disease mechanism that is distinct from the mechanism underlying ReNU syndrome. Together, these findings expand the genotypic and phenotypic spectrum of RNU4-2-associated NDDs.