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

• Published in: Neurogenetics 2023-04, Vol.24 (2), p.129-136
• Main Authors: Zhao, Peiwei, Meng, Qingjie, Wan, Chunhui, Lei, Tao, Zhang, Lei, Zhang, Xiankai, Tan, Li, Zhu, Hongmin, He, Xuelian
• Format: Article
• Language: English
• Subjects: Alternative splicing; Autism; DNA-directed RNA polymerase; East Asian People; Exon skipping; Frameshift mutation; Genotypes; Human Genetics; Humans; Medicine; Medicine & Public Health; Molecular Medicine; Mutation; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Neurology; Neurosciences; Original Article; Peripheral blood; Phenotype; Phenotypes; RNA polymerase; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transcription Factors - genetics
• ISSN: 1364-6753; 1364-6745; 1364-6753
• DOI: 10.1007/s10048-023-00713-z

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.