JZUS - Journal of Zhejiang University SCIENCE

Journal of Zhejiang University SCIENCE B

Accepted manuscript available online (unedited version)

A novel variant in (p.D176N) identified by whole-exome sequencing in combination with a congenital heart disease related gene filter is associated with familial atrial septal defect

Author(s): Ji-jia Liu¹, Liang-liang Fan², Jin-lan Chen¹, Zhi-ping Tan³, Yi-feng Yang¹
Affiliation(s): 1. Department of Cardiothoracic Surgery, the Second Xiangya Hospital, Central South University, Changsha 410011, China;2. Department of Cell Biology, School of Life Sciences, Central South University, Changsha 410013, China;3. Center of Clinical Gene Diagnosis and Therapy, the State Key Laboratory of Medical Genetics, the Second Xiangya Hospital, Central South University, Changsha 410011, China
Corresponding email(s): yangyifengcsuxy@gmail.com
Key Words: Congenital heart disease (CHD), Atrial septal defect (ASD), Whole-exome sequencing, CHD-related gene filter,

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Ji-jia Liu, Liang-liang Fan, Jin-lan Chen, Zhi-ping Tan, Yi-feng Yang. 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[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B1400062

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author="Ji-jia Liu, Liang-liang Fan, Jin-lan Chen, Zhi-ping Tan, Yi-feng Yang",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B1400062"
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%0 Journal Article
%T 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 Ji-jia Liu
%A Liang-liang Fan
%A Jin-lan Chen
%A Zhi-ping Tan
%A Yi-feng Yang
%J Journal of Zhejiang University SCIENCE B
%P 830-837
%@ 1673-1581
%D in press
%I Zhejiang University Press & Springer
doi="https://doi.org/10.1631/jzus.B1400062"

TY - JOUR
T1 - 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
A1 - Ji-jia Liu
A1 - Liang-liang Fan
A1 - Jin-lan Chen
A1 - Zhi-ping Tan
A1 - Yi-feng Yang
J0 - Journal of Zhejiang University Science B
SP - 830
EP - 837
%@ 1673-1581
Y1 - in press
PB - Zhejiang University Press & Springer
ER -
doi="https://doi.org/10.1631/jzus.B1400062"

Abstract
Chinese Summary
Academic Network
Reviewer Comment

Abstract: 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.

全外显子测序结合先天性心脏病相关基因过滤在一家族性房间隔缺损家系中检测出新的致病突变TBX20（D176N）

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-boxDNA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。
先天性心脏病；房间隔缺损；全外显子测序；先天性心脏病相关基因；TBX20

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全外显子测序结合先天性心脏病相关基因过滤在一家族性房间隔缺损家系中检测出新的致病突变TBX20（D176N）

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References