A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve
Abstract TBX5 has been linked to Holt-Oram syndrome, with congenital heart defect (CHD) and atrial fibrillation (AF) being two major cardiac phenotypes. However, the prevalence of a TBX5 variation in patients with CHD and AF remains obscure. In this research, by sequencing analysis of TBX5 in 178 in...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Sociedade Brasileira de Genética
2020-11-01
|
| Series: | Genetics and Molecular Biology |
| Subjects: | |
| Online Access: | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572020000600104&tlng=en |
| _version_ | 1818719987581321216 |
|---|---|
| author | Wei-Feng Jiang Ying-Jia Xu Cui-Mei Zhao Xin-Hua Wang Xing-Biao Qiu Xu Liu Shao-Hui Wu Yi-Qing Yang |
| author_facet | Wei-Feng Jiang Ying-Jia Xu Cui-Mei Zhao Xin-Hua Wang Xing-Biao Qiu Xu Liu Shao-Hui Wu Yi-Qing Yang |
| author_sort | Wei-Feng Jiang |
| collection | DOAJ |
| description | Abstract TBX5 has been linked to Holt-Oram syndrome, with congenital heart defect (CHD) and atrial fibrillation (AF) being two major cardiac phenotypes. However, the prevalence of a TBX5 variation in patients with CHD and AF remains obscure. In this research, by sequencing analysis of TBX5 in 178 index patients with both CHD and AF, a novel heterozygous variation, NM_000192.3: c.577G>T; p.(Gly193*), was identified in one index patient with CHD and AF as well as bicuspid aortic valve (BAV), with an allele frequency of approximately 0.28%. Genetic analysis of the proband’s pedigree showed that the variation co-segregated with the diseases. The pathogenic variation was not detected in 292 unrelated healthy subjects. Functional analysis by using a dual-luciferase reporter assay system showed that the Gly193*-mutant TBX5 protein failed to transcriptionally activate its target genes MYH6 and NPPA. Moreover, the mutation nullified the synergistic transactivation between TBX5 and GATA4 as well as NKX2-5. Additionally, whole-exome sequencing analysis showed no other genes contributing to the diseases. This investigation firstly links a pathogenic variant in the TBX5 gene to familial CHD and AF as well as BAV, suggesting that CHD and AF as well as BAV share a common developmental basis in a subset of patients. |
| first_indexed | 2024-12-17T20:15:40Z |
| format | Article |
| id | doaj.art-71bf2bb6632741728ca55061e412dabb |
| institution | Directory Open Access Journal |
| issn | 1678-4685 |
| language | English |
| last_indexed | 2024-12-17T20:15:40Z |
| publishDate | 2020-11-01 |
| publisher | Sociedade Brasileira de Genética |
| record_format | Article |
| series | Genetics and Molecular Biology |
| spelling | doaj.art-71bf2bb6632741728ca55061e412dabb2022-12-21T21:34:07ZengSociedade Brasileira de GenéticaGenetics and Molecular Biology1678-46852020-11-0143410.1590/1678-4685-gmb-2020-0142A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valveWei-Feng JiangYing-Jia XuCui-Mei ZhaoXin-Hua WangXing-Biao QiuXu LiuShao-Hui WuYi-Qing Yanghttps://orcid.org/0000-0003-0291-8395Abstract TBX5 has been linked to Holt-Oram syndrome, with congenital heart defect (CHD) and atrial fibrillation (AF) being two major cardiac phenotypes. However, the prevalence of a TBX5 variation in patients with CHD and AF remains obscure. In this research, by sequencing analysis of TBX5 in 178 index patients with both CHD and AF, a novel heterozygous variation, NM_000192.3: c.577G>T; p.(Gly193*), was identified in one index patient with CHD and AF as well as bicuspid aortic valve (BAV), with an allele frequency of approximately 0.28%. Genetic analysis of the proband’s pedigree showed that the variation co-segregated with the diseases. The pathogenic variation was not detected in 292 unrelated healthy subjects. Functional analysis by using a dual-luciferase reporter assay system showed that the Gly193*-mutant TBX5 protein failed to transcriptionally activate its target genes MYH6 and NPPA. Moreover, the mutation nullified the synergistic transactivation between TBX5 and GATA4 as well as NKX2-5. Additionally, whole-exome sequencing analysis showed no other genes contributing to the diseases. This investigation firstly links a pathogenic variant in the TBX5 gene to familial CHD and AF as well as BAV, suggesting that CHD and AF as well as BAV share a common developmental basis in a subset of patients.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572020000600104&tlng=enCongenital heart diseaseatrial fibrillationbicuspid aortic valvemolecular geneticsTBX5 |
| spellingShingle | Wei-Feng Jiang Ying-Jia Xu Cui-Mei Zhao Xin-Hua Wang Xing-Biao Qiu Xu Liu Shao-Hui Wu Yi-Qing Yang A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve Genetics and Molecular Biology Congenital heart disease atrial fibrillation bicuspid aortic valve molecular genetics TBX5 |
| title | A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve |
| title_full | A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve |
| title_fullStr | A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve |
| title_full_unstemmed | A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve |
| title_short | A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve |
| title_sort | novel tbx5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve |
| topic | Congenital heart disease atrial fibrillation bicuspid aortic valve molecular genetics TBX5 |
| url | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572020000600104&tlng=en |
| work_keys_str_mv | AT weifengjiang anoveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT yingjiaxu anoveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT cuimeizhao anoveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT xinhuawang anoveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT xingbiaoqiu anoveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT xuliu anoveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT shaohuiwu anoveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT yiqingyang anoveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT weifengjiang noveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT yingjiaxu noveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT cuimeizhao noveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT xinhuawang noveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT xingbiaoqiu noveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT xuliu noveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT shaohuiwu noveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve AT yiqingyang noveltbx5mutationpredisposestofamilialcardiacseptaldefectsandatrialfibrillationaswellasbicuspidaorticvalve |