Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes More about Open Access at the Crick
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Rocio Rius Alexander JM Blakes Yuyang Chen Joachim De Jonghe François Lecoquierre Ruebena Dawes Benjamin Cogne Hyung Chul Kim Javeria R Alvi Florence Amblard Morad Ansari Annabelle Arlt Christina Austin-Tse Sarah Baer Meena Balasubramanian Elsa V 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 Glass Olivier Grunewald Paul Gueguen Tobias B Haack Hamza Hadj Abdallah Radu Harbuz Ingo Helbig Judit 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 E McGinnis Rodrigo Mendez Olfa Messaoud Caroline Nava Mevyn Nizard Anne O'Donnell-Luria Melanie C 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-Robinetvin Julien Thevenon Eloise Uebergang Sandra Ueberberg Catherine Vincent-Delorme Evangeline Wassmer Emma Westwood Matthew T Wheeler Elif Yilmaz Gulec Adeline Vanderver Arastoo Vossough Stephan J Sanders Siddharth Banka Greg Findlay Daniel G MacArthur Cas Simons Nicola Whiffin
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Abstract
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.
Journal details
Journal
Nature Genetics
Volume
58
Issue number
4
Pages
761-773
Available online
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10.1038/s41588-026-02554-6
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Europe PubMed Central
41951959
Pubmed
41951959
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