Identification of Rare Variants in Right Ventricular Outflow Tract Obstruction Congenital Heart Disease by Whole-Exome Sequencing

Yue Zhou; Kai Bai; Yu Wang; Zhuo Meng; Shuang Zhou; Shiwei Jiang; Hualin Wang; Jian Wang; Mei Yang; Qingjie Wang; Kun Sun; Sun Chen

doi:10.3389/fcvm.2021.811156

Identification of Rare Variants in Right Ventricular Outflow Tract Obstruction Congenital Heart Disease by Whole-Exome Sequencing

Front Cardiovasc Med. 2022 Jan 24:8:811156. doi: 10.3389/fcvm.2021.811156. eCollection 2021.

Authors

Yue Zhou¹, Kai Bai¹, Yu Wang^{1

2}, Zhuo Meng¹, Shuang Zhou¹, Shiwei Jiang¹, Hualin Wang¹, Jian Wang¹, Mei Yang¹, Qingjie Wang¹, Kun Sun¹, Sun Chen¹

Affiliations

¹ Department of Pediatric Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Department of Pediatric Cardiology, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Abstract

Background: Pulmonary atresia (PA) is a kind of congenital heart disease characterized by right ventricular outflow tract obstruction. It is divided into PA with intact ventricular septum (PA/IVS) whose favorable form is pulmonary valvular stenosis (PS), and PA with ventricular septal defect (PA/VSD) whose favorable form is tetralogy of Fallot (TOF). Due to limitations in genetics etiology, whole-exome sequencing (WES) was utilized to identify new variants associated with the diseases.

Methods: The data from PS-PA/IVS (n = 74), TOF-PA/VSD (n = 100), and 100 controls were obtained. The common sites between PS and PA/IVS, PA/VSD and TOF, were compared. The novel rare damage variants, and candidate genes were identified by gene-based burden analysis. Finally, the enrichment analysis of differential genes was conducted between case and control groups.

Results: Seventeen rare damage variants located in seven genes were predicted to be associated with the PS through burden analysis. Enrichment analysis identified that the Wnt and cadherin signaling pathways were relevant to PS-PA/IVS.

Conclusion: This study put forth seven candidate genes (APC, PPP1R12A, PCK2, SOS2, TNR, MED13, and TIAM1), resulting in PS-PA/IVS. The Wnt and cadherin signaling pathways were identified to be related to PS-PA/IVS by enrichment analysis. This study provides new evidence for exploring the genetic mechanism of PS-PA/IVS.

Keywords: congenital heart disease; pulmonary atresia with intact ventricular septum; pulmonary valvular stenosis; right ventricular outflow tract obstruction; single nucleotide polymorphism; whole-exome sequencing.