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 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.

【摘要】TBX5基因（TBX5）与霍尔特-奥拉姆综合征（Holt-Oram syndrome）相关，先天性心脏缺损（CHD）与心房颤动（AF）为其两种主要心脏表型。然而，CHD合并AF患者中TBX5变异的患病率仍不明确。本研究对178例CHD合并AF患者的TBX5基因开展测序分析，在1例同时合并CHD、AF及主动脉瓣二叶畸形（BAV）的先证者中检出1种新型杂合变异：NM_000192.3: c.577G>T；p.(Gly193*)，其等位基因频率约为0.28%。对该先证者的家系进行遗传分析显示，该变异与疾病表型共分离。在292名无关健康对照个体中未检出该致病性变异。采用双荧光素酶报告基因检测系统开展功能分析发现，携带Gly193*突变的TBX5蛋白无法转录激活其靶基因MYH6与NPPA。此外，该突变消除了TBX5与GATA4及NKX2-5之间的协同反式激活作用。全外显子组测序分析未发现其他与该疾病相关的致病基因。本研究首次将TBX5基因的致病性变异与家族性CHD、AF及BAV关联起来，提示在部分患者中，CHD、AF与BAV共享共同的发育机制。