Integrative Analyses Identify Potential Key Genes and Calcium-Signaling Pathway in Familial Atrioventricular Nodal Reentrant Tachycardia Using Whole-Exome Sequencing
BackgroundAtrioventricular nodal reentrant tachycardia (AVNRT) is a common arrhythmia. Growing evidence suggests that family aggregation and genetic factors are involved in AVNRT. However, in families with a history of AVNRT, disease-causing genes have not been reported.ObjectiveTo investigate the g...
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2022.910826/full |
| _version_ | 1818479205470437376 |
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| author | Jichang Huang Rong Luo Chenqing Zheng Xin Cao Yuncai Zhu Tao He Mingjiang Liu Zhenglin Yang Xiushan Wu Xiushan Wu Xiaoping Li |
| author_facet | Jichang Huang Rong Luo Chenqing Zheng Xin Cao Yuncai Zhu Tao He Mingjiang Liu Zhenglin Yang Xiushan Wu Xiushan Wu Xiaoping Li |
| author_sort | Jichang Huang |
| collection | DOAJ |
| description | BackgroundAtrioventricular nodal reentrant tachycardia (AVNRT) is a common arrhythmia. Growing evidence suggests that family aggregation and genetic factors are involved in AVNRT. However, in families with a history of AVNRT, disease-causing genes have not been reported.ObjectiveTo investigate the genetic contribution of familial AVNRT using a whole-exome sequencing (WES) approach.MethodsBlood samples were collected from 20 patients from nine families with a history of AVNRT and 100 control participants, and we systematically analyzed mutation profiles using WES. Gene-based burden analysis, integration of previous sporadic AVNRT data, pedigree-based co-segregation, protein-protein interaction network analysis, single-cell RNA sequencing, and confirmation of animal phenotype were performed.ResultsAmong 95 related reference genes, seven candidate pathogenic genes have been identified both in sporadic and familial AVNRT, including CASQ2, AGXT, ANK2, SYNE2, ZFHX3, GJD3, and SCN4A. Among the 37 reference genes from sporadic AVNRT, five candidate pathogenic genes were identified in patients with both familial and sporadic AVNRT: LAMC1, ryanodine receptor 2 (RYR2), COL4A3, NOS1, and ATP2C2. To identify the common pathogenic mechanisms in all AVNRT cases, five pathogenic genes were identified in patients with both familial and sporadic AVNRT: LAMC1, RYR2, COL4A3, NOS1, and ATP2C2. Considering the unique internal candidate pathogenic gene within pedigrees, three genes, TRDN, CASQ2, and WNK1, were likely to be the pathogenic genes in familial AVNRT. Notably, the core calcium-signaling pathway may be closely associated with the occurrence of AVNRT, including CASQ2, RYR2, TRDN, NOS1, ANK2, and ATP2C2.ConclusionOur pedigree-based studies demonstrate that RYR2 and related calcium signaling pathway play a critical role in the pathogenesis of familial AVNRT using the WES approach. |
| first_indexed | 2024-12-10T09:57:42Z |
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| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-12-10T09:57:42Z |
| publishDate | 2022-07-01 |
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| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-617026653a1e4cfba7e9c6b87d7618b02022-12-22T01:53:25ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2022-07-01910.3389/fcvm.2022.910826910826Integrative Analyses Identify Potential Key Genes and Calcium-Signaling Pathway in Familial Atrioventricular Nodal Reentrant Tachycardia Using Whole-Exome SequencingJichang Huang0Rong Luo1Chenqing Zheng2Xin Cao3Yuncai Zhu4Tao He5Mingjiang Liu6Zhenglin Yang7Xiushan Wu8Xiushan Wu9Xiaoping Li10Institute of Geriatric Cardiovascular Disease, Chengdu Medical College, Chengdu, ChinaInstitute of Geriatric Cardiovascular Disease, Chengdu Medical College, Chengdu, ChinaState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaSchool of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, ChinaDepartment of Cardiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, ChinaDepartment of Cardiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, ChinaDepartment of Cardiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, ChinaThe Sichuan Provincial Key Laboratory of Human Disease Study, Institute of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, ChinaThe Center for Heart Development, Hunan Normal University, Changsha, ChinaGuangdong Provincial Key Laboratory of Pathogenesis, Targeted Prevention and Treatment of Heart Disease, Guangzhou, ChinaDepartment of Cardiology, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, ChinaBackgroundAtrioventricular nodal reentrant tachycardia (AVNRT) is a common arrhythmia. Growing evidence suggests that family aggregation and genetic factors are involved in AVNRT. However, in families with a history of AVNRT, disease-causing genes have not been reported.ObjectiveTo investigate the genetic contribution of familial AVNRT using a whole-exome sequencing (WES) approach.MethodsBlood samples were collected from 20 patients from nine families with a history of AVNRT and 100 control participants, and we systematically analyzed mutation profiles using WES. Gene-based burden analysis, integration of previous sporadic AVNRT data, pedigree-based co-segregation, protein-protein interaction network analysis, single-cell RNA sequencing, and confirmation of animal phenotype were performed.ResultsAmong 95 related reference genes, seven candidate pathogenic genes have been identified both in sporadic and familial AVNRT, including CASQ2, AGXT, ANK2, SYNE2, ZFHX3, GJD3, and SCN4A. Among the 37 reference genes from sporadic AVNRT, five candidate pathogenic genes were identified in patients with both familial and sporadic AVNRT: LAMC1, ryanodine receptor 2 (RYR2), COL4A3, NOS1, and ATP2C2. To identify the common pathogenic mechanisms in all AVNRT cases, five pathogenic genes were identified in patients with both familial and sporadic AVNRT: LAMC1, RYR2, COL4A3, NOS1, and ATP2C2. Considering the unique internal candidate pathogenic gene within pedigrees, three genes, TRDN, CASQ2, and WNK1, were likely to be the pathogenic genes in familial AVNRT. Notably, the core calcium-signaling pathway may be closely associated with the occurrence of AVNRT, including CASQ2, RYR2, TRDN, NOS1, ANK2, and ATP2C2.ConclusionOur pedigree-based studies demonstrate that RYR2 and related calcium signaling pathway play a critical role in the pathogenesis of familial AVNRT using the WES approach.https://www.frontiersin.org/articles/10.3389/fcvm.2022.910826/fullfamilial AVNRTarrhythmiawhole-exome sequencingpathogenic genescalcium-signaling pathway |
| spellingShingle | Jichang Huang Rong Luo Chenqing Zheng Xin Cao Yuncai Zhu Tao He Mingjiang Liu Zhenglin Yang Xiushan Wu Xiushan Wu Xiaoping Li Integrative Analyses Identify Potential Key Genes and Calcium-Signaling Pathway in Familial Atrioventricular Nodal Reentrant Tachycardia Using Whole-Exome Sequencing Frontiers in Cardiovascular Medicine familial AVNRT arrhythmia whole-exome sequencing pathogenic genes calcium-signaling pathway |
| title | Integrative Analyses Identify Potential Key Genes and Calcium-Signaling Pathway in Familial Atrioventricular Nodal Reentrant Tachycardia Using Whole-Exome Sequencing |
| title_full | Integrative Analyses Identify Potential Key Genes and Calcium-Signaling Pathway in Familial Atrioventricular Nodal Reentrant Tachycardia Using Whole-Exome Sequencing |
| title_fullStr | Integrative Analyses Identify Potential Key Genes and Calcium-Signaling Pathway in Familial Atrioventricular Nodal Reentrant Tachycardia Using Whole-Exome Sequencing |
| title_full_unstemmed | Integrative Analyses Identify Potential Key Genes and Calcium-Signaling Pathway in Familial Atrioventricular Nodal Reentrant Tachycardia Using Whole-Exome Sequencing |
| title_short | Integrative Analyses Identify Potential Key Genes and Calcium-Signaling Pathway in Familial Atrioventricular Nodal Reentrant Tachycardia Using Whole-Exome Sequencing |
| title_sort | integrative analyses identify potential key genes and calcium signaling pathway in familial atrioventricular nodal reentrant tachycardia using whole exome sequencing |
| topic | familial AVNRT arrhythmia whole-exome sequencing pathogenic genes calcium-signaling pathway |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2022.910826/full |
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