De novo variants in CNOT9 cause a neurodevelopmental disorder with or without epilepsy

Lydia von Wintzingerode*, Bruria Ben-Zeev, Claudia Cesario, Katie M. Chan, Christel Depienne, Orly Elpeleg, Maria Iascone, Whitley V. Kelley, Marie Cécile Nassogne, Marcello Niceta, Lidia Pezzani, Nils Rahner, Nicole Revencu, Mir Reza Bekheirnia, Teresa Santiago-Sim, Marco Tartaglia, Michelle L. Thompson, Marina Trivisano, Julia Hentschel, Heinrich StichtRami Abou Jamra, Henry Oppermann*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Purpose: The study aimed to clinically and molecularly characterize the neurodevelopmental disorder associated with heterozygous de novo variants in CNOT9. Methods: Individuals were clinically examined. Variants were identified using exome or genome sequencing. These variants were evaluated using in silico predictions, and their functional relevance was further assessed by molecular models and research in the literature. The variants have been classified according to the criteria of the American College of Medical Genetics. Results: We report on 7 individuals carrying de novo missense variants in CNOT9, p.(Arg46Gly), p.(Pro131Leu), and p.(Arg227His), and, recurrent in 4 unrelated individuals, p.(Arg292Trp). All affected persons have developmental delay/intellectual disability, with 5 of them showing seizures. Other symptoms include muscular hypotonia, facial dysmorphism, and behavioral abnormalities. Molecular modeling predicted that the variants are damaging and would lead to reduced protein stability or impaired recognition of interaction partners. Functional analyses in previous studies showed a pathogenic effect of p.(Pro131Leu) and p.(Arg227His). Conclusion: We propose CNOT9 as a novel gene for neurodevelopmental disorder and epilepsy.

Original languageEnglish
Article number100859
JournalGenetics in Medicine
Issue number7
StatePublished - Jul 2023
Externally publishedYes


  • CCR4-NOT
  • CNOT9
  • Epilepsy
  • Neurodevelopmental delay
  • RQCD1


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