De novo mutations in folate-related genes associated with common developmental disorders
Folate deficiency is an environmental risk factor for several developmental disorders. De novo mutations (DNMs) also play important etiological roles in various developmental disorders. However, it remains unclear whether DNMs in folate-related genes (FRGs) contribute to developmental disorders. We...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-01-01
|
| Series: | Computational and Structural Biotechnology Journal |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037021000623 |
| id |
doaj-92cdb209b2234756b381e7dffe3a998f |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Tengfei Luo Kuokuo Li Zhengbao Ling Guihu Zhao Bin Li Zheng Wang Xiaomeng Wang Ying Han Lu Xia Yi Zhang Qiao Zhou Zhenghuan Fang Yijing Wang Qian Chen Xun Zhou Hongxu Pan Yuwen Zhao Yige Wang Lijie Dong Yuanfeng Huang Zhengmao Hu Qian Pan Kun Xia Jinchen Li |
| spellingShingle |
Tengfei Luo Kuokuo Li Zhengbao Ling Guihu Zhao Bin Li Zheng Wang Xiaomeng Wang Ying Han Lu Xia Yi Zhang Qiao Zhou Zhenghuan Fang Yijing Wang Qian Chen Xun Zhou Hongxu Pan Yuwen Zhao Yige Wang Lijie Dong Yuanfeng Huang Zhengmao Hu Qian Pan Kun Xia Jinchen Li De novo mutations in folate-related genes associated with common developmental disorders Computational and Structural Biotechnology Journal Developmental disorders Folate-related gene De novo mutation Candidate disease-associated genes Expression patterns |
| author_facet |
Tengfei Luo Kuokuo Li Zhengbao Ling Guihu Zhao Bin Li Zheng Wang Xiaomeng Wang Ying Han Lu Xia Yi Zhang Qiao Zhou Zhenghuan Fang Yijing Wang Qian Chen Xun Zhou Hongxu Pan Yuwen Zhao Yige Wang Lijie Dong Yuanfeng Huang Zhengmao Hu Qian Pan Kun Xia Jinchen Li |
| author_sort |
Tengfei Luo |
| title |
De novo mutations in folate-related genes associated with common developmental disorders |
| title_short |
De novo mutations in folate-related genes associated with common developmental disorders |
| title_full |
De novo mutations in folate-related genes associated with common developmental disorders |
| title_fullStr |
De novo mutations in folate-related genes associated with common developmental disorders |
| title_full_unstemmed |
De novo mutations in folate-related genes associated with common developmental disorders |
| title_sort |
de novo mutations in folate-related genes associated with common developmental disorders |
| publisher |
Elsevier |
| series |
Computational and Structural Biotechnology Journal |
| issn |
2001-0370 |
| publishDate |
2021-01-01 |
| description |
Folate deficiency is an environmental risk factor for several developmental disorders. De novo mutations (DNMs) also play important etiological roles in various developmental disorders. However, it remains unclear whether DNMs in folate-related genes (FRGs) contribute to developmental disorders. We obtained a list of 1,821 FRGs from folate metabolism pathways and the Comparative Toxicogenomics Database, along with data concerning DNMs in 15,404 cases and 3,391 controls from the Gene4Denovo database. We used a TADA-Denovo model to prioritize candidate disease-associated FRGs, and characterized these genes in terms of genic intolerance, functional networks, and expression patterns. Compared with the controls, FRGs were significantly enriched in likely damaging DNMs (ldDNMs) in patients with developmental disorders (1.54 ≤ odds ratio ≤ 3.39, Padj ≤ 0.0075). Furthermore, FRGs with ldDNMs rather than with likely non-damaging DNMs (lndDNMs) overlapped significantly among the five developmental disorders included in the datasets. The TADA-Denovo model prioritized 96 candidate disease-associated FRGs, which were intolerant to genetic variants. Their functional networks mainly involved pathways associated with chromatin modification, organ development, and signal transduction pathways. DNMT3A, KMT2B, KMT2C, and YY1 emerged as hub FRGs from the protein–protein interaction network. These candidate disease-associated FRGs are preferentially expressed in the excitatory neurones during embryonic development, and in the cortex, cerebellum, striatum, and amygdala during foetal development. Overall, these findings show that DNMs in FRGs are associated with the risk of developmental disorders. Further research on these DNMs may facilitate the discovery of developmental disorder biomarkers and therapeutic targets, enabling detailed, personalized, and precise folate treatment plan. |
| topic |
Developmental disorders Folate-related gene De novo mutation Candidate disease-associated genes Expression patterns |
| url |
http://www.sciencedirect.com/science/article/pii/S2001037021000623 |
| work_keys_str_mv |
AT tengfeiluo denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT kuokuoli denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT zhengbaoling denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT guihuzhao denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT binli denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT zhengwang denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT xiaomengwang denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT yinghan denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT luxia denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT yizhang denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT qiaozhou denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT zhenghuanfang denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT yijingwang denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT qianchen denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT xunzhou denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT hongxupan denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT yuwenzhao denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT yigewang denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT lijiedong denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT yuanfenghuang denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT zhengmaohu denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT qianpan denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT kunxia denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders AT jinchenli denovomutationsinfolaterelatedgenesassociatedwithcommondevelopmentaldisorders |
| _version_ |
1724222187836014592 |
| spelling |
doaj-92cdb209b2234756b381e7dffe3a998f2021-03-13T04:22:27ZengElsevierComputational and Structural Biotechnology Journal2001-03702021-01-011914141422De novo mutations in folate-related genes associated with common developmental disordersTengfei Luo0Kuokuo Li1Zhengbao Ling2Guihu Zhao3Bin Li4Zheng Wang5Xiaomeng Wang6Ying Han7Lu Xia8Yi Zhang9Qiao Zhou10Zhenghuan Fang11Yijing Wang12Qian Chen13Xun Zhou14Hongxu Pan15Yuwen Zhao16Yige Wang17Lijie Dong18Yuanfeng Huang19Zhengmao Hu20Qian Pan21Kun Xia22Jinchen Li23Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, Anhui, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaNational Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, ChinaNational Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, ChinaNational Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaNational Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaNational Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaNational Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaNational Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaNational Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaNational Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaNational Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, ChinaCenter for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China; Corresponding authors at: National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China (J. Li); Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China (Q. Pan and K. Xia).Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China; School of Basic Medical Science, Central South University, Changsha, Hunan, China; Corresponding authors at: National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China (J. Li); Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China (Q. Pan and K. Xia).National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Corresponding authors at: National Clinical Research Center for Geriatric Disorders, Department of Geriatrics, Xiangya Hospital, Central South University, Changsha, Hunan, China (J. Li); Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China (Q. Pan and K. Xia).Folate deficiency is an environmental risk factor for several developmental disorders. De novo mutations (DNMs) also play important etiological roles in various developmental disorders. However, it remains unclear whether DNMs in folate-related genes (FRGs) contribute to developmental disorders. We obtained a list of 1,821 FRGs from folate metabolism pathways and the Comparative Toxicogenomics Database, along with data concerning DNMs in 15,404 cases and 3,391 controls from the Gene4Denovo database. We used a TADA-Denovo model to prioritize candidate disease-associated FRGs, and characterized these genes in terms of genic intolerance, functional networks, and expression patterns. Compared with the controls, FRGs were significantly enriched in likely damaging DNMs (ldDNMs) in patients with developmental disorders (1.54 ≤ odds ratio ≤ 3.39, Padj ≤ 0.0075). Furthermore, FRGs with ldDNMs rather than with likely non-damaging DNMs (lndDNMs) overlapped significantly among the five developmental disorders included in the datasets. The TADA-Denovo model prioritized 96 candidate disease-associated FRGs, which were intolerant to genetic variants. Their functional networks mainly involved pathways associated with chromatin modification, organ development, and signal transduction pathways. DNMT3A, KMT2B, KMT2C, and YY1 emerged as hub FRGs from the protein–protein interaction network. These candidate disease-associated FRGs are preferentially expressed in the excitatory neurones during embryonic development, and in the cortex, cerebellum, striatum, and amygdala during foetal development. Overall, these findings show that DNMs in FRGs are associated with the risk of developmental disorders. Further research on these DNMs may facilitate the discovery of developmental disorder biomarkers and therapeutic targets, enabling detailed, personalized, and precise folate treatment plan.http://www.sciencedirect.com/science/article/pii/S2001037021000623Developmental disordersFolate-related geneDe novo mutationCandidate disease-associated genesExpression patterns |