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Publications

Journal Article Ppublish 3 citations

PubMed: 40562808 DOI: 10.1038/s41431-025-01884-z

Comprehensive analysis of CNOT3-related neurodevelopmental disorders: phenotypic and genotypic characterization.

Eur J Hum Genet 33(8):989-996

Authors: Camille Engel, Michaela Rendek, Jessica Assoumani, Emanuela Argilli, Francesca Ariani, Anne-Laude Avice-Denizet, Emilia K Bijlsmaa, Pierre Blanc, Lucia Pia Bruno, Bert Callewaert, Valeria Capra, Michele Carullo, Bertrand Chesneau, Sandra Coppens, Cynthia Curry, Breanne Dale, Eric Dahlen, Andrée Delahaye-Duriez, Anne-Sophie Denommé-Pichon, Bénédicte Demeer, Lenka Dvořáková, Jan Fischer, David Geneviève, Thea Giacomini, Mette M Handrup, Delphine Heron, Irina Hüning, Michelle Iacomino, Bertrand Isidor, Boris Keren, Stanislav Kmoch, David A Koolen, Andrea Kübler, Jana Laštůvková, Carolyn Le, Jonathan Levy, Caterina Lo Rizzo, Silvia Maitz, Sandrine Marlin, Cyril Mignot, Ghayda Mirzaa, Inga Nagel, Sebastian Neuens, Lenka Nosková, Emily Pao, Anna Pecková, Julie Plaisancie, Joseph Porrmann, Flavia Privitera, André Reis … and 27 other authors

Affiliations

  • Université de Franche-Comté, Centre de Génétique Humaine, CHU Besançon, Besançon, France.
  • Université de Bourgogne, INSERM UMR1231 GAD "Génétique des Anomalies du Développement", Dijon, France.
  • Université de Franche-Comté, Centre de Génétique Humaine, CHU Besançon, Besançon, France.
  • Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
  • Medical Genetics, University of Siena, Siena, Italy.
  • Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy.
  • Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
  • Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
  • Laboratoire Seqoia, Paris, France.
  • Department of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy.
  • Reference centre for Mendelian connective tissue disorders - UZ Gent, Ghent University Hospital-UZ Gent, Gent, Belgium.
  • Genomics and Clinical Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  • Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy.
  • Service de Génétique Médicale, Hôpital Purpan, CHU de Toulouse, Toulouse, France.
  • Center for Medical Genetics, Hôpital Erasme, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.
  • Genetic Medicine, University of California, San Francisco/Fresno, Fresno, CA, USA.
  • Genetics and Metabolics Clinic, McMaster Children's Hospital, Hamilton, ON, Canada.
  • Université de Franche-Comté, CHU Besançon, Oncobiologie Génétique Bioinformatique, FHU-TRANSLAD et Institut GIMI, Besançon, France.
  • UF médecine génomique et génétique clinique, Hôpital Jean Verdier, Hôpitaux Universitaires de Paris Seine Saint Denis, AP-HP, Bondy, France.
  • UFR de Santé Médecine et Biologie humaine, Université Sorbonne Paris Nord, Bobigny, France.
  • NeuroDiderot UMR 1141, Inserm, FHU I2-D2, Université de Paris, Paris, France.
  • Université de Bourgogne, INSERM UMR1231 GAD "Génétique des Anomalies du Développement", Dijon, France.
  • Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
  • Service de Génétique Clinique et Oncogénétique, CHU Amiens-Picardie, Amiens, France.
  • Department of Biology and Medical Genetics, Charles University-2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic.
  • Institute for Clinical Genetics, University Hospital Carl Gustav Carus at TUD Dresden University of Technology, Dresden, Germany.
  • Université Montpellier, Centre de référence anomalies du développement et syndromes malformatifs, Génétique Clinique, CHU Montpellier, Montpellier, France.
  • Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
  • Child Neuropsychiatry Unit, IRCCS G. Gaslini Institute, Genoa, Italy.
  • Center for Rare Diseases, Pediatric and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Département de génétique médicale, Hôpital Pitié-Salpêtrière, AP-HP.Sorbonne Université, Paris, France.
  • Institute of Human Genetics, University Hospital Schleswig-Holstein, Lübeck, Germany.
  • Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
  • Service de génétique médicale, Unité de génétique clinique, CHU Hôtel Dieu, 1, place Alexis Ricordeau, Nantes, France.
  • Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
  • Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Department of Medical Genetics, Masaryk Hospital in Ústí nad Labem, Regional Health Corporation, Ústí nad Labem, Czech Republic.
  • Genetics Department, AP-HP, Robert-Debré University Hospital, Paris, France.
  • Service of Medical Genetics, Oncologic Institute of Southern Switzerland, EOC, Switzerland, Switzerland.
  • Centre de référence « Surdités Génétiques », Service de Médecine génomique des Maladies rares, Hôpital Necker, Assistance Publique - Hôpitaux de Paris, Paris, France.
  • Institut Imagine, Paris, France.
  • Department of Pediatrics, University of Washington, Seattle, WA, USA.
  • Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
  • Brotman Baty Institute for Precision Medicine, Seattle, WA, USA.
  • Institute of Human Genetics, University Hospital Schleswig-Holstein, Kiel, Germany.
  • Department of Genetics, Hôpital Universitaire des Enfants Reine Fabiola, Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium.
  • Department of Neurobiology and Molecular Medicine, IRCCS Fondazione Stella Maris, Pisa, Italy.
  • Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
  • Centre for Rare Diseases Erlangen (ZSEER), Erlangen, Germany.

Abstract

The CCR4-NOT complex, crucial in gene expression regulation, includes CNOT3, a subunit linked to neurodevelopmental disorders when mutated. This study investigates 51 patients from 42 families with heterozygous CNOT3 variants, aiming to expand the understanding of CNOT3-related neurodevelopmental disorders and explore genotype-phenotype correlations. Patients originated from various countries, reflecting the disorder's global significance. All patients exhibited developmental delays, particularly in the language area. Intellectual disability was found in 87% of patients and was typically mild to moderate. Behavioral issues, including autism spectrum disorders and attention deficits, were common, affecting over half of the patients. Dysmorphic features were highlighted and may help establishing the diagnosis. Epilepsy was uncommon (10%). Twenty-eight novel variants were identified, including missense, nonsense, frameshift, intronic variations and a deletion of 12 exons. Missense variants clustered at the N- and C-terminal regions of the protein, indicating critical functional roles. No clear genotype-phenotype correlation was observed, suggesting that all identified variants resulted in a loss-of-function effect. Finally, this work delineates the clinical and molecular spectrum of CNOT3-related disorders thanks to an in-depth characterization of a large cohort. Further research will be necessary to understand the functional consequences of the variants and enhance patient long-term outcomes.

MeSH

Phenotype, Neurodevelopmental Disorders, Genotype, Genetics, Medical, Neurodevelopment