Abstract
BackgroundPulmonary 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.MethodsThe 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.ResultsSeventeen 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.ConclusionThis 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.
Highlights
Congenital heart disease (CHD) is the most common congenital disorder that affects about 1% liveborn infants [1]
21326, 16594, and 20230 SNPs and Indels were identified in pulmonary valvular stenosis (PS), Pulmonary atresia (PA)/IVS, PA with ventricular septal defect (PA/VSD), and tetralogy of Fallot (TOF), respectively
A previous study speculated that PA with intact ventricular septum (PA/IVS) was the extremely severe form of PS, and PA/VSD, another group of PA, was the extreme form of TOF [6,7,8]
Summary
Congenital heart disease (CHD) is the most common congenital disorder that affects about 1% liveborn infants [1]. Pulmonary atresia (PA), a rare malformation of complex cyanotic CHD characterized by right ventricular outflow tract obstruction (RVOTO), accounts for about 1.3–3.4% of all heart abnormalities [3]. TOF is a heart defects syndrome with heart malformations of TOF are VSD, right ventricular hypertrophy, variable obstruction of the right ventricular outflow tract, and overriding aorta [9, 10] Patients born with these diseases might need to relieve RVOTO by intervention or surgery [11, 12]. 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
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