A novel TBX5 mutation predisposes to familial cardiac septal defects and atrial fibrillation as well as bicuspid aortic valve

• Published in: Genetics and molecular biology Vol. 43; no. 4; p. e20200142
• Main Authors: Jiang, Wei-Feng, Xu, Ying-Jia, Zhao, Cui-Mei, Wang, Xin-Hua, Qiu, Xing-Biao, Liu, Xu, Wu, Shao-Hui, Yang, Yi-Qing
• Format: Journal Article
• Language: English
• Published: Brazil Sociedade Brasileira de Genética 01.01.2020
• Subjects: atrial fibrillation; bicuspid aortic valve; BIOCHEMISTRY & MOLECULAR BIOLOGY; Congenital heart disease; GENETICS & HEREDITY; Human and Medical Genetics; molecular genetics; TBX5; molecular genetics; atrial fibrillation; Congenital heart disease; TBX5; bicuspid aortic valve
• ISSN: 1415-4757; 1678-4685; 1678-4685
• DOI: 10.1590/1678-4685-GMB-2020-0142

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.