Rare Copy Number Variants Identify Novel Genes in Sporadic Total Anomalous Pulmonary Vein Connection.

Xin Shi,Jing Wang,Sun Chen,Yulai Liang,Qihua Fu,Liangping Cheng,Jing Sun,Zixiong Li,Bo Chen,Yanan Lu,Wei Liu,Yuejuan Xu,Gang Liu,Xianting Jiao

doi:10.3389/fgene.2018.00559

Abstract

Total anomalous pulmonary venous connection (TAPVC) is a rare congenital heart anomaly. Several genes have been associated TAPVC but the mechanisms remain elusive. To search novel CNVs and candidate genes, we screened a cohort of 78 TAPVC cases and 100 healthy controls for rare copy number variants (CNVs) using whole exome sequencing (WES). Then we identified pathogenic CNVs by statistical comparisons between case and control groups. After that, we identified altogether eight pathogenic CNVs of seven candidate genes (PCSK7, RRP7A, SERHL, TARP, TTN, SERHL2, and NBPF3). All these seven genes have not been described previously to be related to TAPVC. After network analysis of these candidate genes and 27 known pathogenic genes derived from the literature and publicly database, PCSK7 and TTN were the most important genes for TAPVC than other genes. Our study provides novel candidate genes potentially related to this rare congenital birth defect (CHD) which should be further fundamentally researched and discloses the possible molecular pathogenesis of TAPVC.

Highlights

Total anomalous pulmonary venous connection (TAPVC) is a rare but heterogeneous congenital heart anomaly in which pulmonary veins do not connect routinely to the left atrium but abnormally connect to the right atrium or systemic venous system
Total anomalous pulmonary venous connection is a rare congenital heart defect characterized by the misconnection of all four pulmonary veins, which could cause severe morbidity and mortality (Bando et al, 1996)
To detect the underlying mechanism of TAPVC, we screened a cohort of 78 TAPVC cases and 100 healthy controls for rare copy number variants (CNVs) and novel candidate genes, using whole exome sequencing (WES)

Summary

Introduction

Total anomalous pulmonary venous connection (TAPVC) is a rare but heterogeneous congenital heart anomaly in which pulmonary veins do not connect routinely to the left atrium but abnormally connect to the right atrium or systemic venous system. The incidence of TAPVC is approximately 1 out of 15,000 live births (Ammash et al, 1997; Bjornard et al, 2013; Thummar et al, 2014). The molecular mechanism of TAPVC remains unknown. Only a few genes have been demonstrated as pathogenic genes for TAPVC and these genes are just a partial explanation for some patients. Bleyl et al (2006) used genetic linkage analysis found a locus for TAPVR at 4p13-q12 called total anomalous pulmonary venous return 1 (TAPVR1) and other important pathogenic genes in this region include vascular endothelial growth factor Only a few genes have been demonstrated as pathogenic genes for TAPVC and these genes are just a partial explanation for some patients. Bleyl et al (2006) used genetic linkage analysis found a locus for TAPVR at 4p13-q12 called total anomalous pulmonary venous return 1 (TAPVR1) and other important pathogenic genes in this region include vascular endothelial growth factor

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Results

Conclusion