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<p>A narrow spectrum of heterozygous variants in <i>RNU4-2</i>, encoding the small nuclear RNA (snRNA) U4, underlies ReNU syndrome, a neurodevelopmental disorder (NDD) characterized by moderate to severe developmental delay (DD), intellectual disability (ID), a distinctive facial gestalt, and multisystem involvement. Pathogenic variants have primarily been reported within an 18-nt critical region contributing to stabilizing the U4/U6 snRNA duplex and proper spliceosome assembly. By combining whole genome sequencing reanalysis and targeted direct sequencing in 190 molecularly unexplained NDD cases, we report on five affected individuals carrying pathogenic/putative pathogenic <i>RNU4-2</i> variants (2.6%). Three individuals harbored the recurrent pathogenic n.64_65insT variant, while two were heterozygous for private/rare maternally inherited variants (n.30 A &gt; T and n.43_44insT) within the 5’ Stem-loop region. Deep clinical phenotyping confirmed a homogeneous constellation of features in all individuals, with global DD, ID, brain malformations, and a recognizable facial gestalt representing core findings. Based on structural homology models and available cryo-EM data, n.30 A &gt; T and n.43_44insT were predicted to disrupt key intra- and inter-molecular interactions critical for spliceosome function. Our findings expand the mutational spectrum of ReNU syndrome, and confirm the 5’ Stem-loop as a second mutational hotspot in <i>RNU4-2</i>. We propose that a more complex genetics likely underlies the inheritance of a subset of disease-causing <i>RNU4-2</i> variants from an apparently unaffected parent. We anticipate a relatively high proportion of pathogenic <i>RNU4-2</i> variants among individuals with unclassified NDD despite extensive genomic testing, and propose a set of facial gestalt core features as a clinical screening tool to prioritize patients for <i>RNU4-2</i> analysis.</p>

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Expanding the mutational spectrum of ReNU syndrome: insights into 5’ Stem-loop variants

  • 期刊论文

  • 发表日期：

    2025年2月26日

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  • Alessandro Bruselles,
  • Cecilia Mancini,
  • Luigi Chiriatti,
  • Mattia Carvetta,
  • Maria Chiara Baroni,
  • Camilla Cappelletti,
  • Stefano Giuseppe Caraffi,
  • Massimiliano Celario,
  • Andrea Ciolfi,
  • Viviana Cordeddu,
  • Alessandro De Falco,
  • Marco Ferilli,
  • Livia Garavelli,
  • Chiara Leoni,
  • Camilla Meossi,
  • Marcello Niceta,
  • Roberta Onesimo,
  • Francesca Peluso,
  • Davide Politano,
  • Manuela Priolo,
  • Francesca Clementina Radio,
  • Filippo Santorelli,
  • Sabrina Signorini,
  • Fabio Sirchia,
  • Enza Maria Valente,
  • Giuseppe Zampino,
  • Marco Tartaglia

摘要

A narrow spectrum of heterozygous variants in RNU4-2, encoding the small nuclear RNA (snRNA) U4, underlies ReNU syndrome, a neurodevelopmental disorder (NDD) characterized by moderate to severe developmental delay (DD), intellectual disability (ID), a distinctive facial gestalt, and multisystem involvement. Pathogenic variants have primarily been reported within an 18-nt critical region contributing to stabilizing the U4/U6 snRNA duplex and proper spliceosome assembly. By combining whole genome sequencing reanalysis and targeted direct sequencing in 190 molecularly unexplained NDD cases, we report on five affected individuals carrying pathogenic/putative pathogenic RNU4-2 variants (2.6%). Three individuals harbored the recurrent pathogenic n.64_65insT variant, while two were heterozygous for private/rare maternally inherited variants (n.30 A > T and n.43_44insT) within the 5’ Stem-loop region. Deep clinical phenotyping confirmed a homogeneous constellation of features in all individuals, with global DD, ID, brain malformations, and a recognizable facial gestalt representing core findings. Based on structural homology models and available cryo-EM data, n.30 A > T and n.43_44insT were predicted to disrupt key intra- and inter-molecular interactions critical for spliceosome function. Our findings expand the mutational spectrum of ReNU syndrome, and confirm the 5’ Stem-loop as a second mutational hotspot in RNU4-2. We propose that a more complex genetics likely underlies the inheritance of a subset of disease-causing RNU4-2 variants from an apparently unaffected parent. We anticipate a relatively high proportion of pathogenic RNU4-2 variants among individuals with unclassified NDD despite extensive genomic testing, and propose a set of facial gestalt core features as a clinical screening tool to prioritize patients for RNU4-2 analysis.