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

Engel C, Rendek M, Assoumani J, Argilli E, Ariani F, Avice-Denizet AL, Bijlsmaa EK, Blanc P, Bruno LP, Callewaert B, Capra V, Carullo M, Chesneau B, Coppens S, Curry C, Dale B, Dahlen E, Delahaye-Duriez A, Denommé-Pichon AS, Demeer B, Dvořáková L, Fischer J, Geneviève D, Giacomini T, Handrup MM, Heron D, Hüning I, Iacomino M, Isidor B, Keren B, Kmoch S, Koolen DA, Kübler A, Laštůvková J, Le C, Levy J, Rizzo CL, Maitz S, Marlin S, Mignot C, Mirzaa G, Nagel I, Neuens S, Nosková L, Pao E, Pecková A, Plaisancie J, Porrmann J, Privitera F, Reis A, Renieri A, Rio M, Rippert A, Ryba L, Scala M, Schieving JH, Sherr EH, Shuen A, Sidlow R, Smol T, Soblet J, Striano P, Suri M, Syryn H, Tran Mau-Them F, Travessa AM, Van Gils J, Vasileiou G, Verseput JJ, Vilain C, Vincent-Delorme C, Vyhnálková E, Wakeling EL, Zacher P, Zara F, Kuentz P, Piard J (2025)

Publication Type: Journal article

Publication year: 2025

Journal

DOI: 10.1038/s41431-025-01884-z

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.

Authors with CRIS profile

Involved external institutions

Università degli Studi di Siena (UNISI) / University of Siena Italy (IT) University Hospital Ghent Belgium (BE) Istituto Giannina Gaslini Italy (IT) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Nantes University Hospital / Centre hospitalier universitaire de Nantes (CHU) France (FR) Univerzita Karlova v Praze / Charles University in Prague Czech Republic (CZ) Center for Integrative Brain Research United States (USA) (US) Nottingham University Hospitals United Kingdom (GB) Université Bourgogne Europe France (FR) Centre Hospitalier Universitaire de Bordeaux / CHU Bordeaux France (FR) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) Queen Fabiola Childrens Hospital / L'Hôpital universitaire des enfants Reine Fabiola Belgium (BE) Centre Hospitalier Régional Universitaire de Lille (CHRU de Lille) France (FR) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) University of California San Francisco (UCSF) United States (USA) (US) Hôpital Universitaire Robert-Debré France (FR) Motol University Hospital / Fakultní nemocnice v Motole Czech Republic (CZ) Great Ormond Street Hospital (GOSH) United Kingdom (GB) Kleinwachau - Sächsisches Epilepsiezentrum Radeberg gGmbH Germany (DE) Azienda ospedaliero-universitaria Senese Italy (IT) University of Genova / Università degli Studi di Genova Italy (IT) Ente Ospedaliero Cantonale Switzerland (CH) Hôpital Necker-Enfants malades France (FR) Assistance Publique-Hôpitaux de Paris (AP-HP) France (FR) University of Washington United States (USA) (US) Université Marie et Louis Pasteur (prev. Université de Franche-Comté) France (FR) Centre Hospitalier Universitaire (CHU) de Toulouse France (FR) Université Sorbonne Paris Cité France (FR) Leiden University Medical Center Netherlands (NL) GCS SeqOIA France (FR) Fondazione Policlinico Universitario Agostino Gemelli IRCCS Italy (IT) Hôpital Erasme Belgium (BE) Children's Hospital of Philadelphia United States (USA) (US) The Hospital for Sick Children (SickKids) Canada (CA) Valley Children's Hospital (VCH) / Children's Hospital Central California United States (USA) (US) IRCCS Fondazione Stella Maris Italy (IT) Hamilton Health Sciences (HHS) Canada (CA) Hôpital Jean-Verdier France (FR) Centre Hospitalier Universitaire Amiens-Picardie (CHU Amiens-Picardie) France (FR) University of Montpellier / Université Montpellier France (FR) Aarhus University Hospital / Aarhus Universitetshospital Denmark (DK)

How to cite

APA:

Engel, C., Rendek, M., Assoumani, J., Argilli, E., Ariani, F., Avice-Denizet, A.L.,... Piard, J. (2025). Comprehensive analysis of CNOT3-related neurodevelopmental disorders: phenotypic and genotypic characterization. European Journal of Human Genetics. https://doi.org/10.1038/s41431-025-01884-z

MLA:

Engel, Camille, et al. "Comprehensive analysis of CNOT3-related neurodevelopmental disorders: phenotypic and genotypic characterization." European Journal of Human Genetics (2025).

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