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.
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Data availability
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. Pathogenic and probably pathogenic variants in our cohort that had not previously been reported were submitted to ClinVar (Supplementary Data S3).
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Funding
Research reported in this publication was supported by Jordan’s Guardian Angels, the Sunderland Foundation and the Brotman Baty Institute (to G.M.M.). E.W. : The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003]. This study makes use of DECIPHER (http://www.deciphergenomics.org), which is funded by Wellcome [grant number WT223718/Z/21/Z]. See Nature PMID: 25533962 or www.ddduk.org/access.html for full acknowledgement. P.Z.’s work is being supported by Stiftung Michael through the generous assistance of the Canger-Janz-Fellowship. L.N. was supported by the project National Institute for Neurological Research (Programme EXCELES, ID Project No. LX22NPO5107) - Funded by the E’uropean Union – Next Generation EU. L.N. and S.K. were supported by grant NU23-07-00281 from the Ministry of Health of the Czech Republic, by the institutional program UNCE/24/MED/022 of Charles University in Prague and they thank to the National Center for Medical Genomics (LM2023067) for WES analyses. This work was partially funded by the Italian Ministry of Health RC2025/2026.
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CE, MR, JA collected clinical and molecular data. CE, JP analyzed and interpreted data and wrote the manuscript. JP designed the study. EA, FA, ALAD, EKB, PB, LPB, BC, VC, MC, BC, SC, CC, BD, ED, ADD, ASDP, BD, LD, JF, DG, TG, MMH, DH, IH, MI, BI, BK, SK, DAK, AK, JL, CL, JL, CL, SM, SM, CM, GM, IN, SN, LN, EP, AP, JP, JP, FP, AR, AR, MR, AR, LR, MS, JS, EHS, AS, RS, TS, JS, PS, MS, HS, FTMT, AMT, JVG, GV, JJAV, CV, CVD, EV, EW, PZ, FZ, PK, JP characterized the clinical and molecular features of the disease. All the authors edited or commented the manuscript.
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Individuals were referred by clinical geneticists for genetic testing as part of routine clinical care. All patients enrolled and/or their legal representative have signed informed consent for use of data and/or photographs.
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Engel, C., Rendek, M., Assoumani, J. et al. Comprehensive analysis of CNOT3-related neurodevelopmental disorders: phenotypic and genotypic characterization. Eur J Hum Genet 33, 989–996 (2025). https://doi.org/10.1038/s41431-025-01884-z
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DOI: https://doi.org/10.1038/s41431-025-01884-z
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