Fiche publication
Date publication
juin 2025
Journal
European journal of human genetics : EJHG
Auteurs
Membres identifiés du Cancéropôle Est :
Pr KUENTZ Paul
Tous les auteurs :
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 JJA, Vilain C, Vincent-Delorme C, Vyhnálková E, Wakeling EL, Zacher P, Zara F, Kuentz P, Piard J
Lien Pubmed
Résumé
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.
Référence
Eur J Hum Genet. 2025 06 25;:
