De Novo Variants in CNOT9 Cause a Neurodevelopmental Disorder With or Without Epilepsy

Authors

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 Sticht
Rami Abou Jamra
Henry Oppermann

Language

English

Publication Date

7-1-2023

Journal

Genetics in Medicine

DOI

10.1016/j.gim.2023.100859

PMID

37092538

Abstract

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.

Keywords

Humans, Epilepsy, Intellectual Disability, Mutation, Missense, Neurodevelopmental Disorders, Phenotype, Seizures, CCR4-NOT. CNOT9. Epilepsy. Neurodevelopmental delay. RQCD1

Published Open-Access

yes

Recommended Citation

von Wintzingerode, Lydia; Ben-Zeev, Bruria; Cesario, Claudia; et al., "De Novo Variants in CNOT9 Cause a Neurodevelopmental Disorder With or Without Epilepsy" (2023). Faculty and Staff Publications. 5154.
https://digitalcommons.library.tmc.edu/baylor_docs/5154