Nature genetics · 2026

Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes.

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Rius Rocio, Blakes Alexander J M, Chen Yuyang, De Jonghe Joachim, Lecoquierre François, Dawes Ruebena, Cogne Benjamin, Kim Hyung Chul, Alvi Javeria R, Amblard Florence, Ansari Morad, Arlt Annabelle, Austin-Tse Christina, Baer Sarah, Balasubramanian Meena, Balton Elsa V, Barcia Giulia, Beleza-Meireles Ana, Bernstein Jonathan A, Beygo Jasmin, Blanc Pierre, Bramswig Nuria C, Braun Frederik, Buchzik Daniel, Calame Daniel G, Campbell Jamie, Coutton Charles, Cunningham Chloe A, Dargie Nitsuh, Depienne Christel, Dipple Katrina M, Dieux Anne, Dixit Abhijit, Dreyer Lauren, Du Haowei, El Chehadeh Salima, Field Michael, Ewans Lisa J, Geiger Vanessa, Gibbs Richard A, Glass Ian, Grunewald Olivier, Gueguen Paul, Haack Tobias B, Hadj Abdallah Hamza, Harbuz Radu, Helbig Ingo, Horvath Judit, Hustinx Alexander, Isidor Bertrand, Jacquemont Marie-Line, Jamie Fraser, Jeanne Médéric, Kessler Riley, Klinkhammer Hannah, Korenke G Christoph, Kotzaeridou Urania, Krawitz Peter, Laurie Steven, Leventer Richard J, Levy Rebecca J, Lupski James R, Marijon Pierre, McGinnis Kaitlin E, Mendez Rodrigo, Messaoud Olfa, Nava Caroline, Nizard Mevyn, O'Donnell-Luria Anne, O'Leary Melanie C, Olivieri Simone, Parida Amitav, Pehlivan Davut, Prentice Anna Jenne, Posey Jennifer E, Reuter Chloe M, Satre Véronique, Schluth-Bolard Caroline, Smol Thomas, Sultan Tipu, Taylor John, Thauvin-Robinet Christel, Thevenon Julien, Uebergang Eloise, Ueberberg Sandra, Vincent-Delorme Catherine, Wassmer Evangeline, Westwood Emma, Wheeler Matthew T, Gulec Elif Yilmaz, Vanderver Adeline, Vossough Arastoo, Sanders Stephan J, Banka Siddharth, Findlay Gregory M, MacArthur Daniel G, Simons Cas, Whiffin Nicola

Аннотация

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.

Предметные рубрики MeSH

Humans Neurodevelopmental Disorders Genes, Recessive White Matter RNA, Small Nuclear Female Alleles Male Phenotype Child RNA, Untranslated Child, Preschool

Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes.

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Аннотация

Предметные рубрики MeSH