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DOI 10.1038/s41588-026-02551-9

Медицинская библиотека · Nature genetics · 2026

Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy.

Jackson Adam, Blakes Alexander J M, Alhaddad Bader, Henry Olivia J, Delgado-Vega Angelica M, Wall Elizabeth, Abdelhadi Ola, Agrawal Shakti, Bakur Khadijah, Blair Edward, Brady Angela F, Brittain Helen, Chandler Kate E, Clarke Natasha, Danelli Miriana, Drinkall Nicholas, Duba Irene, Elmslie Frances, Ellingford Jamie, Ewans Lisa J, Fennell Andrew P, Gazdagh Gabriella, Heller Simon P, Hammarsjö Anna, Karrman Kristina, Kini Usha, Lesko Nicole, Lindstrand Anna, Macintosh Rebecca, Mansour Sahar, Menzies Lara, Metcalfe Kay, Milhench Alison, Nashef Lina, O'Keefe Raymond T, Pacheco Nadja Pekkola, Palmer Elizabeth E, Parida Amitav, Prescott Katrina, Redman Melody, Renieri Alessandra, Fallerini Chiara, Rizzo Caterina Lo, Sachdev Rani, Simons Cas, Sisodiya Sanjay M, Stewart Helen, Stödberg Tommy, Banos-Pinero Benito, Taylan Fulya, Thomas Huw B, Tinella Flavia, Wiafe Samuel, Wedell Anna, Whiffin Nicola, Walker Susan, Rius Rocio, Chae Jong Hee, Nordgren Ann, Alkuraya Fowzan, Lord Jenny, Banka Siddharth

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Аннотация

Neurodevelopmental disorders (NDDs) affect 2-4% of the population, are predominantly genetic and remain unsolved in ~50% of individuals. We show that rare biallelic variants in RNU2-2 are enriched and over-transmitted in individuals with unresolved NDDs. We define a recessive RNU2-2 syndrome, delineate its unique genetic architecture and show that it manifests clinically as a severe developmental and epileptic encephalopathy. We find that candidate biallelic variants are significantly correlated with reduced U2-2 abundance, implicating compromised transcript stability as a probable pathomechanism. We identify a decreased ratio of U2-2 to its paralog U2-1 as a potential diagnostic biomarker for this condition. We show that the recessive RNU2-2 syndrome is genetically, clinically and mechanistically distinct from the dominant RNU2-2 disorder. Within our cohort, the recessive RNU2-2 syndrome emerges as by far the most frequent recessive NDD, greatly disproportionate to the small genomic footprint of this non-protein-coding gene.

Для цитирования: Jackson Adam, Blakes Alexander J M, Alhaddad Bader, Henry Olivia J, Delgado-Vega Angelica M, Wall Elizabeth, Abdelhadi Ola, Agrawal Shakti, Bakur Khadijah, Blair Edward, Brady Angela F, Brittain Helen, Chandler Kate E, Clarke Natasha, Danelli Miriana, Drinkall Nicholas, Duba Irene, Elmslie Frances, Ellingford Jamie, Ewans Lisa J, Fennell Andrew P, Gazdagh Gabriella, Heller Simon P, Hammarsjö Anna, Karrman Kristina, Kini Usha, Lesko Nicole, Lindstrand Anna, Macintosh Rebecca, Mansour Sahar, Menzies Lara, Metcalfe Kay, Milhench Alison, Nashef Lina, O'Keefe Raymond T, Pacheco Nadja Pekkola, Palmer Elizabeth E, Parida Amitav, Prescott Katrina, Redman Melody, Renieri Alessandra, Fallerini Chiara, Rizzo Caterina Lo, Sachdev Rani, Simons Cas, Sisodiya Sanjay M, Stewart Helen, Stödberg Tommy, Banos-Pinero Benito, Taylan Fulya, Thomas Huw B, Tinella Flavia, Wiafe Samuel, Wedell Anna, Whiffin Nicola, Walker Susan, Rius Rocio, Chae Jong Hee, Nordgren Ann, Alkuraya Fowzan, Lord Jenny, Banka Siddharth. Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy.. Nature genetics. 2026. DOI: 10.1038/s41588-026-02551-9.

Предметные рубрики MeSH

HumansAllelesGenes, RecessiveEpilepsyNeurodevelopmental DisordersRNA, Small NuclearFemale
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