Identification of TBX5 Mutations in a Series of 94 Patients With Tetralogy of Fallot
Identification of TBX5 Mutations in a Series of 94 Patients With Tetralogy of Fallot
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DOI：
10.1002/ajmg.a.36783
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发表时间：
2014-12-01
影响因子：
2
通讯作者：
Pongiglione, Giacomo
中科院分区：
文献类型：
--
作者：
Baban, Anwar;Postma, Alex Vincent;Pongiglione, Giacomo
法洛四联症 (TOF) (OMIM #187500) 是最常见的圆锥干先天性心脏病 (CHD)，具有一系列心内和心外表型。 TBX5 是一种转录因子，在心脏和前肢发育中具有明确的作用，TBX5 的突变与 Holt-Oram 综合征 (HOS) (OMIM#142900) 相关。在此，我们报告了对 94 名 TOF 患者进行 TBX5、NKX2.5 和 GATA4 基因突变的筛查。我们在 TBX5 中发现了两个杂合突变。在一名摩洛哥患者中检测到一种突变，该患者患有 TOF、大继发孔房间隔缺损和完全性房室传导阻滞，以及 HOS 的特征，包括双侧三指拇指和第五指斜指。该患者携带先前描述的位于外显子 8 的从头终止密码子突变 (p.R279X)，导致蛋白质过早截短。在来自意大利的第二例患有 TOF、继发孔房间隔缺损和心电图进行性心律失常改变的患者中，我们在外显子 9 中发现了母系遗传的新突变，该突变导致氨基酸位置 372 处的丝氨酸被亮氨酸取代（p.S372L，c.1115C>T）。母亲的临床评估显示频繁的室性早搏和房间隔动脉瘤。体格检查和手部 X 光片显示，孩子或母亲都没有明显的骨骼缺陷。 p.S372L 突变的分子评估显示出功能获得表型。我们还回顾了 TOF 和 HOS 同时出现的文献，强调了其相关性。这是首次对 TOF 患者的 TBX5 突变进行系统筛查，在 94 名患者中检测到了 2 名 (2.1%) 患者的突变。 (c) 2014 年 Wiley 期刊公司。
Tetralogy of Fallot (TOF) (OMIM #187500) is the most frequent conotruncal congenital heart defect (CHD) with a range of intra- and extracardiac phenotypes. TBX5 is a transcription factor with well-defined roles in heart and forelimb development, and mutations in TBX5 are associated with Holt-Oram syndrome (HOS) (OMIM#142900). Here we report on the screening of 94 TOF patients for mutations in TBX5, NKX2.5 and GATA4 genes. We identified two heterozygous mutations in TBX5. One mutation was detected in a Moroccan patient with TOF, a large ostium secundum atrial septal defect and complete atrioventricular block, and features of HOS including bilateral triphalangeal thumbs and fifth finger clinodactyly. This patient carried a previously described de novo, stop codon mutation (p.R279X) located in exon 8 causing a premature truncated protein. In a second patient from Italy with TOF, ostium secundum atrial septal defect and progressive arrhythmic changes on ECG, we identified a maternally inherited novel mutation in exon 9, which caused a substitution of a serine with a leucine at amino acid position 372 (p.S372L, c.1115C>T). The mother's clinical evaluation demonstrated frequent ventricular extrasystoles and an atrial septal aneurysm. Physical examination and radiographs of the hands showed no apparent skeletal defects in either child or mother. Molecular evaluation of the p.S372L mutation demonstrated a gain-of-function phenotype. We also review the literature on the co-occurrence of TOF and HOS, highlighting its relevance. This is the first systematic screening for TBX5 mutations in TOF patients which detected mutations in two of 94 (2.1%) patients. (c) 2014 Wiley Periodicals, Inc.