Clinical characteristics and identification of novel CNOT1 variants in three unrelated Chinese families with Vissers-Bodmer Syndrome
Vissers-Bodmer Syndrome, an autosomal dominant disease, is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, hypotonia and autistic features with a highly variable phenotype. It is caused by variants in the CCR4-NOT transcription complex, subunit 1 g...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-02-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844024027749 |
| _version_ | 1827322149992398848 |
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| author | Xiaojun Tang Xiaoping Lan Xiaozhen Song Wuhen Xu Yuanfeng Zhang Simei Wang Man Xiao Yongchen Yang Hong Zhang Shengnan Wu |
| author_facet | Xiaojun Tang Xiaoping Lan Xiaozhen Song Wuhen Xu Yuanfeng Zhang Simei Wang Man Xiao Yongchen Yang Hong Zhang Shengnan Wu |
| author_sort | Xiaojun Tang |
| collection | DOAJ |
| description | Vissers-Bodmer Syndrome, an autosomal dominant disease, is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, hypotonia and autistic features with a highly variable phenotype. It is caused by variants in the CCR4-NOT transcription complex, subunit 1 gene (CNOT1). However, the pathophysiologic mechanism of the Vissers-Bodmer Syndrome remains unclear. Notably, this syndrome has not been previously reported in the Chinese. In this study, we utilized whole exome sequencing to identify three novel variants in the CNOT1 gene, encompassing one frameshift variant and two missense variants, in three Chinese patients mainly presenting with developmental delay, intellectual disability and/or autism. Interestingly, three patients exhibited novel manifestations including spina bifida occulta, horse-shoe kidney and café-au-lait spot. The frameshift variant, p.Gly172Alafs*5, occurring de novo, leading to a premature stop codon in the protein, was classified into pathogenic. Two missense variants c.3451A > G (p.Asn1151Asp) and c.557C > T (p.Ser186Phe) were predicted to be deleterious by multiple prediction algorithms with high conservation among a variety of species. Additionally, three-dimensional structure modeling and predicting indicated the substitution of the mutated amino acids would decrease the stability of CNOT1 protein. Given that CNOT1 is a relatively novel disease gene, we evaluated the gene-disease validity following ClinGen Standard Operating Procedure. The existing evidence substantiates a “Definitive” level of gene-disease relationship. The genetic findings provide a reliable basis for the genetic counseling of the family reproduction. Moreover, our results expand the genetic and phenotypic spectrum of CNOT1-related Vissers-Bodmer Syndrome. |
| first_indexed | 2024-03-07T21:59:58Z |
| format | Article |
| id | doaj.art-4f9b7bec3246402fa31bcd953e0ae070 |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-04-25T01:19:07Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
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| series | Heliyon |
| spelling | doaj.art-4f9b7bec3246402fa31bcd953e0ae0702024-03-09T09:28:54ZengElsevierHeliyon2405-84402024-02-01104e26743Clinical characteristics and identification of novel CNOT1 variants in three unrelated Chinese families with Vissers-Bodmer SyndromeXiaojun Tang0Xiaoping Lan1Xiaozhen Song2Wuhen Xu3Yuanfeng Zhang4Simei Wang5Man Xiao6Yongchen Yang7Hong Zhang8Shengnan Wu9Molecular Diagnostic Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaMolecular Diagnostic Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaMolecular Diagnostic Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaMolecular Diagnostic Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Neurology, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaDepartment of Neurology, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaMolecular Diagnostic Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaMolecular Diagnostic Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaMolecular Diagnostic Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Corresponding author.Molecular Diagnostic Laboratory, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Corresponding author.Vissers-Bodmer Syndrome, an autosomal dominant disease, is a neurodevelopmental disorder characterized by global developmental delay, intellectual disability, hypotonia and autistic features with a highly variable phenotype. It is caused by variants in the CCR4-NOT transcription complex, subunit 1 gene (CNOT1). However, the pathophysiologic mechanism of the Vissers-Bodmer Syndrome remains unclear. Notably, this syndrome has not been previously reported in the Chinese. In this study, we utilized whole exome sequencing to identify three novel variants in the CNOT1 gene, encompassing one frameshift variant and two missense variants, in three Chinese patients mainly presenting with developmental delay, intellectual disability and/or autism. Interestingly, three patients exhibited novel manifestations including spina bifida occulta, horse-shoe kidney and café-au-lait spot. The frameshift variant, p.Gly172Alafs*5, occurring de novo, leading to a premature stop codon in the protein, was classified into pathogenic. Two missense variants c.3451A > G (p.Asn1151Asp) and c.557C > T (p.Ser186Phe) were predicted to be deleterious by multiple prediction algorithms with high conservation among a variety of species. Additionally, three-dimensional structure modeling and predicting indicated the substitution of the mutated amino acids would decrease the stability of CNOT1 protein. Given that CNOT1 is a relatively novel disease gene, we evaluated the gene-disease validity following ClinGen Standard Operating Procedure. The existing evidence substantiates a “Definitive” level of gene-disease relationship. The genetic findings provide a reliable basis for the genetic counseling of the family reproduction. Moreover, our results expand the genetic and phenotypic spectrum of CNOT1-related Vissers-Bodmer Syndrome.http://www.sciencedirect.com/science/article/pii/S2405844024027749CNOT1Vissers-Bodmer syndromeWhole-exome sequencingFrameshiftMissense variant |
| spellingShingle | Xiaojun Tang Xiaoping Lan Xiaozhen Song Wuhen Xu Yuanfeng Zhang Simei Wang Man Xiao Yongchen Yang Hong Zhang Shengnan Wu Clinical characteristics and identification of novel CNOT1 variants in three unrelated Chinese families with Vissers-Bodmer Syndrome Heliyon CNOT1 Vissers-Bodmer syndrome Whole-exome sequencing Frameshift Missense variant |
| title | Clinical characteristics and identification of novel CNOT1 variants in three unrelated Chinese families with Vissers-Bodmer Syndrome |
| title_full | Clinical characteristics and identification of novel CNOT1 variants in three unrelated Chinese families with Vissers-Bodmer Syndrome |
| title_fullStr | Clinical characteristics and identification of novel CNOT1 variants in three unrelated Chinese families with Vissers-Bodmer Syndrome |
| title_full_unstemmed | Clinical characteristics and identification of novel CNOT1 variants in three unrelated Chinese families with Vissers-Bodmer Syndrome |
| title_short | Clinical characteristics and identification of novel CNOT1 variants in three unrelated Chinese families with Vissers-Bodmer Syndrome |
| title_sort | clinical characteristics and identification of novel cnot1 variants in three unrelated chinese families with vissers bodmer syndrome |
| topic | CNOT1 Vissers-Bodmer syndrome Whole-exome sequencing Frameshift Missense variant |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024027749 |
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