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.

中文翻译：

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一种新的 TBX5 突变易患家族性心脏间隔缺损和心房颤动以及二叶主动脉瓣

TBX5 与 Holt-Oram 综合征有关，先天性心脏缺陷 (CHD) 和心房颤动 (AF) 是两种主要的心脏表型。然而，在 CHD 和 AF 患者中 TBX5 变异的流行率仍然不明确。本研究通过对 178 名 CHD 和 AF 指标患者的 TBX5 进行测序分析，发现一个新的杂合变异，NM_000192.3：c.577G>T；p.(Gly193*)，在一名患有 CHD 和 AF 以及二叶主动脉瓣 (BAV) 的指标患者中被发现，等位基因频率约为 0.28%。先证者系谱的遗传分析表明，变异与疾病共同分离。在 292 名无关的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* 突变体 TBX5 蛋白未能转录激活其靶基因 MYH6 和 NPPA。此外，该突变使 TBX5 和 GATA4 以及 NKX2-5 之间的协同反式激活无效。此外，全外显子组测序分析显示没有其他基因导致这些疾病。该研究首先将 TBX5 基因中的致病性变异与家族性 CHD 和 AF 以及 BAV 联系起来，表明 CHD 和 AF 以及 BAV 在一部分患者中具有共同的发育基础。