Next-generation sequencing identifies novel genes with rare variants in total anomalous pulmonary venous connectionResearch in context
Xin Shi,
Tao Huang,
Jing Wang,
Yulai Liang,
Chang Gu,
Yuejuan Xu,
Jing Sun,
Yanan Lu,
Kun Sun,
Sun Chen,
Yu Yu
Affiliations
Xin Shi
Department of Pediatric Cardiovascular, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
Tao Huang
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Jing Wang
Department of Pediatric Cardiovascular, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
Yulai Liang
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
Chang Gu
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tong Ji University School of Medicine, Shanghai 200433, China
Yuejuan Xu
Department of Pediatric Cardiovascular, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
Jing Sun
Department of Pediatric Cardiovascular, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
Yanan Lu
Department of Pediatric Cardiovascular, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
Kun Sun
Department of Pediatric Cardiovascular, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Corresponding authors at: Department of Pediatric Cardiology, Xin Hua Hospital, 1665 Kongjiang Road, Shanghai 200092, China
Sun Chen
Department of Pediatric Cardiovascular, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Corresponding authors at: Department of Pediatric Cardiology, Xin Hua Hospital, 1665 Kongjiang Road, Shanghai 200092, China
Yu Yu
Department of Pediatric Cardiovascular, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China; Corresponding authors at: Department of Pediatric Cardiology, Xin Hua Hospital, 1665 Kongjiang Road, Shanghai 200092, China
Background: Total anomalous pulmonary venous connection (TAPVC) is recognized as a rare congenital heart defect (CHD). With a high mortality rate of approximately 80%, the survival rate and outcomes of TAPVC patients are not satisfactory. However, the genetic aetiology and mechanism of TAPVC remain elusive. This study aimed to investigate the underlying genomic risks of TAPVC through next-generation sequencing (NGS). Methods: Rare variants were identified through whole exome sequencing (WES) of 78 sporadic TAPVC cases and 100 healthy controls using Fisher's exact test and gene-based burden test. We then detected candidate gene expression patterns in cells, pulmonary vein tissues, and embryos. Finally, we validated these genes using target sequencing (TS) in another 100 TAPVC cases. Findings: We identified 42 rare variants of 7 genes (CLTCL1, CST3, GXYLT1, HMGA2, SNAI1, VAV2, ZDHHC8) in TAPVC cases compared with controls. These genes were highly expressed in human umbilical vein endothelial cells (HUVECs), mouse pulmonary veins and human embryonic hearts. mRNA levels of these genes in human pulmonary vein samples were significantly different between cases and controls. Through network analysis and expression patterns in zebrafish embryos, we revealed that SNAI1, HMGA2 and VAV2 are the most important genes for TAPVC. Interpretation: Our study identifies novel candidate genes potentially related to TAPVC and elucidates the possible molecular pathogenesis of this rare congenital birth defect. Furthermore, SNAI1, HMGA2 and VAV2 are novel TAPVC candidate genes that have not been reported previously in either humans or animals. Fund: National Natural Science Foundation of China. Keywords: Congenital heart defects, Total anomalous pulmonary venous connection, Whole exome sequencing, Target sequencing, Rare variants