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Next-generation sequencing identifies novel genes with rare variants in total anomalous pulmonary venous connection.

ABSTRACT: 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.

SUBMITTER: Shi X

PROVIDER: S-EPMC6306349 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Next-generation sequencing identifies novel genes with rare variants in total anomalous pulmonary venous connection.

Shi Xin X Huang Tao T Wang Jing J Liang Yulai Y Gu Chang C Xu Yuejuan Y Sun Jing J Lu Yanan Y Sun Kun K Chen Sun S Yu Yu Y

EBioMedicine 20181116

<h4>Background</h4>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).<h4>Methods</h4>Rare variants were identified through whole exome sequenc ...[more]

PMID: 30448225

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Project description:ObjectivesA meta-analysis was performed to investigate the risk factors for postoperative pulmonary venous obstruction (PVO) after surgical repair of total anomalous pulmonary venous connection (TAPVC).MethodsData bases including PubMed, Embase, Web of Science and Cochrane Library were searched systematically. The goal was to discuss the risk factors for postoperative PVO after TAPVC. Publications were screened by 2 authors independently for criteria inclusion, methodological quality assessment and data extraction. The Newcastle-Ottawa Scale and the Agency for Healthcare Research and Quality checklist were obtained to assess the quality of the studies. Data were pooled by the random effect model or the fixed effect model according to the heterogeneity test.ResultsA total of 16 studies (2,385 participants) were included in the meta-analysis. All included studies were retrospective studies. Six potential risk factors were pooled, 5 of which were significantly associated with postoperative PVO. Patients with preoperative PVO were more likely to suffer from postoperative PVO [odds ratio (OR)=5.27, 95% confidence interval (CI) = (2.75, 10.11), P < 0.01]. Compared with a sutureless procedure, the conventional operative procedure was associated with postoperative PVO [OR = 1.80, 95% CI=(1.20, 2.71), P < 0.01]. A mixed type TAPVC plays a critical role in postoperative PVO [OR = 3.78, 95% CI=(1.08, 13.18), P = 0.04]. Inverse variance analysis showed that longer cardiopulmonary bypass time [hazard ratio (HR)=1.01, 95% CI=(1.01, 1.02), P < 0.00001] and aortic cross-clamp time [HR = 1.01, 95% CI=(1.01, 1.02), P < 0.01] were significantly associated with postoperative PVO. Heterotaxy [OR = 1.18, 95% CI = 0.13, 10.45, P = 0.88] was not statistically significant as a risk factor for postoperative PVO.ConclusionsThis meta-analysis may provide a perspective on the risk factors for postoperative PVO after TAPVC, thus leading to more studies predicting postoperative PVO after TAPVC with our findings.

Dataset Information

Next-generation sequencing identifies novel genes with rare variants in total anomalous pulmonary venous connection.

Publications

Next-generation sequencing identifies novel genes with rare variants in total anomalous pulmonary venous connection.

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