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<p>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 <i>CNOT3</i> variants, aiming to expand the understanding of <i>CNOT3</i>-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 <i>CNOT3</i>-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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年6月25日

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  • Camille Engel,
  • Michaela Rendek,
  • Jessica Assoumani,
  • Emanuela Argilli,
  • Francesca Ariani,
  • Anne-Laude Avice-Denizet,
  • Emilia K. Bijlsma,
  • 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,
  • Alessandra Renieri,
  • Marlène Rio,
  • Alyssa Rippert,
  • Lukáš Ryba,
  • Marcello Scala,
  • Jolanda H. Schieving,
  • Elliott H. Sherr,
  • Andrew Shuen,
  • Richard Sidlow,
  • Thomas Smol,
  • Julie Soblet,
  • Pasquale Striano,
  • Mohnish Suri,
  • Hannes Syryn,
  • Frédéric Tran Mau-Them,
  • Andre M. Travessa,
  • Julien Van Gils,
  • Georgia Vasileiou,
  • Jolijn J. A. Verseput,
  • Catheline Vilain,
  • Catherine Vincent-Delorme,
  • Emílie Vyhnálková,
  • Emma L. Wakeling,
  • Pia Zacher,
  • Federico Zara,
  • Paul Kuentz,
  • Juliette Piard

摘要

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.