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<p>We recently showed that mutations in the snRNA genes <i>RNU4-2</i> and <i>RNU2-2</i> are prevalent causes of dominant neurodevelopmental disorders (NDDs). Here, by genetic association, we demonstrate the existence of a recessive form of <i>RNU2-2</i> syndrome. We inferred a log Bayes factor for a recessive model of association of 18.2. Conditional on that model, 17 rare variants had a posterior probability of pathogenicity &gt;0.8. This conservative threshold identified 18 probands and 5 affected siblings, each carrying two alleles in <i>trans</i> at these variants. A relaxed threshold of &gt;0.6 identified a further 13 candidate probands. We identified nine further cases in replication collections. Affected individuals have intellectual disability, global developmental delay and seizures. Recessive <i>RNU2-2</i> syndrome accounts for ~10% of families with a recessive NDD presently diagnosable by sequencing and affects ~60% as many families as the dominant <i>RNU4-2</i>-related NDD ReNU syndrome. The variants are predicted to destabilize stem loops and binding domains of U2-2 snRNA. Whole-blood RNA sequencing data showed a &gt;90% reduction in the expression of pathogenic U2-2 alleles in biallelic cases and monoallelic carriers, albeit with wild-type compensation in carriers, pointing to a loss-of-expression mechanism.</p>

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Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder

  • 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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  • Daniel Greene,
  • Rodrigo Mendez,
  • Jon Lees,
  • Mafalda Barbosa,
  • Alessandro Bruselles,
  • Luigi Chiriatti,
  • Federico Ferraro,
  • Cecilia Mancini,
  • Rachel Schot,
  • Frank Sleutels,
  • Enrico Bertini,
  • Devon E. Bonner,
  • Arjan Bouman,
  • Alice S. Brooks,
  • Thomas A. Cassini,
  • Kimberly M. Ezell,
  • Natalia Gomez-Ospina,
  • Tjitske Kleefstra,
  • Michael O’Donoghue,
  • Lynette Rives,
  • Vandana Shashi,
  • Rebecca C. Spillmann,
  • Mohamed Wafik,
  • Kathleen Freson,
  • Tahsin Stefan Barakat,
  • Marco Tartaglia,
  • Jonathan A. Bernstein,
  • Andrew D. Mumford,
  • Matthew T. Wheeler,
  • Ernest Turro

摘要

We recently showed that mutations in the snRNA genes RNU4-2 and RNU2-2 are prevalent causes of dominant neurodevelopmental disorders (NDDs). Here, by genetic association, we demonstrate the existence of a recessive form of RNU2-2 syndrome. We inferred a log Bayes factor for a recessive model of association of 18.2. Conditional on that model, 17 rare variants had a posterior probability of pathogenicity >0.8. This conservative threshold identified 18 probands and 5 affected siblings, each carrying two alleles in trans at these variants. A relaxed threshold of >0.6 identified a further 13 candidate probands. We identified nine further cases in replication collections. Affected individuals have intellectual disability, global developmental delay and seizures. Recessive RNU2-2 syndrome accounts for ~10% of families with a recessive NDD presently diagnosable by sequencing and affects ~60% as many families as the dominant RNU4-2-related NDD ReNU syndrome. The variants are predicted to destabilize stem loops and binding domains of U2-2 snRNA. Whole-blood RNA sequencing data showed a >90% reduction in the expression of pathogenic U2-2 alleles in biallelic cases and monoallelic carriers, albeit with wild-type compensation in carriers, pointing to a loss-of-expression mechanism.