Pulmonary atresia (PA) is a rare congenital heart defect (CHD) with complex manifestations and a high mortality rate. Since the genetic determinants in the pathogenesis of PA remain elusive, a thorough identification of the genetic factors through whole exome sequencing (WES) will provide novel insights into underlying mechanisms of PA. We performed WES data from PA/VSD (n = 60), PA/IVS (n = 20), TOF/PA (n = 20) and 100 healthy controls. Rare variants and novel genes were identified using variant-based association and gene-based burden analysis. Then we explored the expression pattern of our candidate genes in endothelium cell lines, pulmonary artery tissues, and embryonic hearts. 56 rare damage variants of 7 novel candidate genes (DNAH10, DST, FAT1, HMCN1, HNRNPC, TEP1, and TYK2) were certified to have function in PA pathogenesis for the first time. In our research, the genetic pattern among PA/VSD, PA/IVS and TOF/PA were different to some degree. Taken together, our findings contribute new insights into the molecular basis of this rare congenital birth defect.

肺动脉闭锁（PA）是一种罕见的先天性心脏病（CHD），表现复杂且死亡率高。由于PA发病机理中的遗传决定因素仍然难以捉摸，因此通过全外显子组测序（WES）全面鉴定遗传因素将为PA的潜在机制提供新的见解。我们从PA / VSD（n = 60），PA / IVS（n = 20），TOF / PA（n = 20）和100个健康对照组中进行了WES数据分析。使用基于变体的关联和基于基因的负担分析来鉴定稀有变体和新基因。然后，我们探索了我们的候选基因在内皮细胞系，肺动脉组织和胚胎心脏中的表达模式。7种新候选基因（DNAH10，DST，FAT1，HMCN1，HNRNPC，TEP1和TYK2）的56种罕见损伤变体）首次被证明在PA发病机制中具有功能。在我们的研究中，PA / VSD，PA / IVS和TOF / PA之间的遗传模式有所不同。综上所述，我们的发现为这种罕见的先天性先天缺陷的分子基础提供了新的见解。