A novel variant in TBX20 (p.D176N) identified by whole-exome sequencing in combination with a congenital heart disease related gene filter is associated with familial atrial septal defect
A novel variant in TBX20 (p.D176N) identified by whole-exome sequencing in combination with a congenital heart disease related gene filter is associated with familial atrial septal defect
复制标题
通过全外显子组测序结合先天性心脏病相关基因过滤器鉴定出 TBX20 (p.D176N) 的新变异与家族性房间隔缺损相关
DOI：
10.1631/jzus.b1400062
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发表时间：
2014-09-01
影响因子：
5.1
通讯作者：
Yang, Yi-feng
中科院分区：
文献类型：
--
作者：
Liu, Ji-jia;Fan, Liang-liang;Yang, Yi-feng
Congenital heart disease (CHD) is the leading cause of birth defects, and its etiology is not completely understood. Atrial septal defect (ASD) is one of the most common defects of CHD. Previous studies have demonstrated that mutations in the transcription factor T-box 20 (TBX20) contribute to congenital ASD. Whole-exome sequencing in combination with a CHD-related gene filter was used to detect a family of three generations with ASD. A novel TBX20 mutation, c.526G>A (p.D176N), was identified and co-segregated in all affected members in this family. This mutation was predicted to be deleterious by bioinformatics programs (SIFT, Polyphen2, and MutationTaster). This mutation was also not presented in the current Single Nucleotide Polymorphism Database (dbSNP) or National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP). In conclusion, our finding expands the spectrum of TBX20 mutations and provides additional support that TBX20 plays important roles in cardiac development. Our study also provided a new and cost-effective analysis strategy for the genetic study in small CHD pedigree.概要研究目的寻求该房间隔缺损家系遗传致病原因。创新要点1. 鉴定出一个全新的家族性房间隔缺损相关性TBX20 突变; 2. 首次使用全外显子测序结合先天性心脏病相关基因过滤的方法来研究小家系遗传致病因素; 3. TBX20 的T-box DNA 结合域的突变与先天性心脏病有关。研究方法对一个临床发现的房间隔缺损家系(图1a)的先证者进行全外显子测序, 运用公共数据库过滤后, 使用先天性心脏病相关基因再次过滤, 得到了19 个候选基因; 然后, 运用SIFT、 Polyphen-2 和MutationTaster 等软件预测, 排除了13 个多态性位点(表2); 最后, 运用共分离检测(聚合酶链式反应产物直接测序), 找到该家系致病的遗传因素, 即TBX20 基因发生了错义突变(D176N)(图2), 该突变位点在ESP 和dbSNP 数据库中也未曾发现, 且该位点在多种生物中高度保守(图1c)。重要结论1. 本研究发现的TBX20 突变(D176N)是该房间隔缺损家系致病的原因, 同时该突变位点为世界上首次报道; 2. 全外显子测序结合先天性心脏病相关基因过滤是一个分析小家系遗传致病因素的有效又经济的方法。