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Clinical features of CNOT3-associated neurodevelopmental disorder in three Chinese patients

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Abstract

CNOT3 is the central component of the CCR4-NOT protein complex, which is a global regulator of RNA polymerase II transcription. Loss of function mutations in CNOT3 lead to intellectual developmental disorder with speech delay, autism, and dysmorphic facies (IDDSADF), which is very rare. Herein, we reported two novel heterozygous frameshift mutations (c.1058_1059insT and c.724delT) and one novel splice site variant (c.387 + 2 T > C) in CNOT3 (NM_014516.3) gene in three Chinese patients with dysmorphic features, developmental delay, and behavior anomalies. The functional study showed that the CNOT3 mRNA levels were significantly decreased in the peripheral blood of two patients with c.1058_1059insT and c.387 + 2 T > C variants, respectively, and minigene assay demonstrated that the splice variant (c.387 + 2 T > C) resulted in exon skipping. We also found that CNOT3 deficiency was linked to alterations of expression levels of other CCR4-NOT complex subunits in mRNA level in the peripheral blood. By analyzing the clinical manifestations of all these patients with CNOT3 variants, including our three cases and 22 patients previously reported, we did not observe a correlation between genotypes and phenotypes. In summary, this is the first time to report cases with IDDSADF in the Chinese population, and three novel CNOT3 variants in these patients expand its mutational spectrum.

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Acknowledgements

We appreciate the patients participating in this study.

Funding

This work was supported by the grants of the Wuhan Municipal Health Commission (no. WX19C19 and WX16C13), the Construction Project of Clinical Medical Research Center for Neurodevelopment Disorders in Children in Hubei Province (no. HST2020-19), the Wuhan Children’s Imaging Clinical Medical Research Center (no. WK2022-38), the Wuhan Children’s Neurological Disease Clinical Medical Research Center (no. WK2014-160), and the Construction Project of Clinical Medical Research Center for Neurodevelopmental Disorders in Children in Hubei Province (no. HST2020-19).

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  1. Peiwei Zhao, Qingjie Meng, Chunhui Wan, and Tao Lei contributed equally to this work.

Authors and Affiliations

  1. Precision Medical Center, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Center), Tongji Medical College, Huazhong University of Science & Technology, No. 100, Hongkong Rd, Wuhan, 430016, Jiangan, China

    Peiwei Zhao, Chunhui Wan, Lei Zhang, Xiankai Zhang, Li Tan & Xuelian He

  2. Department of Clinical Laboratory, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Center), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China

    Qingjie Meng

  3. Rehabilitation Department, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Center), Tongji Medical College, Huazhong University of Science & Technology, No. 100, Hongkong Rd, Wuhan, 430016, Jiangan, China

    Tao Lei & Hongmin Zhu

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  1. Peiwei Zhao
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Contributions

Study concepts: Xuelian He, Peiwei Zhao, and Hongmin Zhu.

Study design: Peiwei Zhao, Qingjie Meng, and Tao Lei.

Literature research: Lei Zhang, Qingjie Meng, and Li Tan.

Clinical information collection: Xiankai Zhang, Li Tan, Lei Zhang, and Tao Lei.

Data analysis/interpretation: Peiwei Zhao, Qingjie Meng, and Xiankai Zhang.

Manuscript preparation: Xuelian He and Peiwei Zhao.

Manuscript editing: Xuelian He and Hongmin Zhu.

Manuscript revision/review: Xuelian He and Peiwei Zhao.

Corresponding authors

Correspondence to Hongmin Zhu or Xuelian He.

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Zhao, P., Meng, Q., Wan, C. et al. Clinical features of CNOT3-associated neurodevelopmental disorder in three Chinese patients. Neurogenetics 24, 129–136 (2023). https://doi.org/10.1007/s10048-023-00713-z

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