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Publications

Journal Article Ppublish 8 citations

PubMed: 40011755 DOI: 10.1038/s41431-025-01820-1

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

Eur J Hum Genet 33(4):432-440

Authors: 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

Affiliations

  • Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161, Rome, Italy.
  • Molecular Genetics and Functional Genomics, Bambino Gesù Children's Hospital, IRCCS, 00146, Rome, Italy.
  • Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University, 00185, Rome, Italy.
  • Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia, 42123, Reggio Emilia, Italy.
  • Department of Medical and Surgical Science, University of Bologna, 40126, Bologna, Italy.
  • Department of Biomedicine and Prevention, University "Tor Vergata", 00173, Rome, Italy.
  • Department of Brain and Behavioural Sciences, University of Pavia, 27100, Pavia, Italy.
  • Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, 27100, Pavia, Italy.
  • Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris, 56128, Calambrone, Pisa, Italy.
  • Department of Computer, Control and Management Engineering, Sapienza University, 00185, Rome, Italy.
  • Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168, Rome, Italy.
  • Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 00168, Rome, Italy.
  • Operative Unit of Medical Genetics and Laboratory of Genetics, AORN A Cardarelli, 80131, Naples, Italy.
  • Department of Molecular Medicine, University of Pavia, 27100, Pavia, Italy.
  • Medical Genetics Unit, IRCCS San Matteo Foundation, Pavia, 27100, Pavia, Italy.
  • Neurogenetics Research Center, IRCCS Mondino Foundation, 27100, Pavia, Italy.
  • Molecular Genetics and Functional Genomics, Bambino Gesù Children's Hospital, IRCCS, 00146, Rome, Italy.

Abstract

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.

MeSH

Microscopy, Electron, Scanning Transmission, Maternal Inheritance, Spliceosomes, Genetics, Medical, Rna, Small Nuclear

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