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<p>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 <i>RNU2-2</i> are enriched and over-transmitted in individuals with unresolved NDDs. We define a recessive <i>RNU2-2</i> 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 <i>RNU2-2</i> syndrome is genetically, clinically and mechanistically distinct from the dominant <i>RNU2-2</i> disorder. Within our cohort, the recessive <i>RNU2-2</i> syndrome emerges as by far the most frequent recessive NDD, greatly disproportionate to the small genomic footprint of this non-protein-coding gene.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月30日

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

摘要

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.