Jiang Wei-Feng, Xu Ying-Jia, Zhao Cui-Mei, Wang Xin-Hua, Qiu Xing-Biao, Liu Xu, Wu Shao-Hui, Yang Yi-Qing
Shanghai Jiao Tong University, Department of Cardiology, Shanghai Chest Hospital, Shanghai, China.
Fudan University, Department of Cardiology, Shanghai Fifth People's Hospital, Shanghai, China.
Genet Mol Biol. 2020 Nov 13;43(4):e20200142. doi: 10.1590/1678-4685-GMB-2020-0142. eCollection 2020.
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.
TBX5与霍尔特-奥拉姆综合征有关，先天性心脏病（CHD）和心房颤动（AF）是两种主要的心脏表型。然而，CHD和AF患者中TBX5变异的患病率仍不清楚。在本研究中，通过对178例CHD和AF患者的索引病例进行TBX5测序分析，在1例患有CHD、AF以及二叶式主动脉瓣（BAV）的索引病例中鉴定出一种新的杂合变异，NM_000192.3:c.577G>T；p.(Gly193*)，等位基因频率约为0.28%。先证者家系的遗传分析表明，该变异与疾病共分离。在292名无关健康受试者中未检测到致病变异。使用双荧光素酶报告基因检测系统进行的功能分析表明，Gly193*突变的TBX5蛋白无法转录激活其靶基因MYH6和NPPA。此外，该突变消除了TBX5与GATA4以及NKX2-5之间的协同反式激活作用。此外，全外显子组测序分析未显示其他基因与疾病有关。本研究首次将TBX5基因中的一个致病变异与家族性CHD、AF以及BAV联系起来，表明CHD、AF以及BAV在一部分患者中具有共同的发育基础。
