For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
11
views
24
references
 Top references
cited by
40
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      73
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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 S NAI1, 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.

          Related collections

          Most cited references24

          • Record: found
          • Abstract: found
          • Article: not found

          The incidence of congenital heart disease.

          Julien Hoffman, Samuel Kaplan (2002)
          This study was designed to determine the reasons for the variability of the incidence of congenital heart disease (CHD), estimate its true value and provide data about the incidence of specific major forms of CHD. The incidence of CHD in different studies varies from about 4/1,000 to 50/1,000 live births. The relative frequency of different major forms of CHD also differs greatly from study to study. In addition, another 20/1,000 live births have bicuspid aortic valves, isolated anomalous lobar pulmonary veins or a silent patent ductus arteriosus. The incidences reported in 62 studies published after 1955 were examined. Attention was paid to the ways in which the studies were conducted, with special reference to the increased use of echocardiography in the neonatal nursery. The total incidence of CHD was related to the relative frequency of ventricular septal defects (VSDs), the most common type of CHD. The incidences of individual major forms of CHD were determined from 44 studies. The incidence of CHD depends primarily on the number of small VSDs included in the series, and this number in turn depends upon how early the diagnosis is made. If major forms of CHD are stratified into trivial, moderate and severe categories, the variation in incidence depends mainly on the number of trivial lesions included. The incidence of moderate and severe forms of CHD is about 6/1,000 live births (19/1,000 live births if the potentially serious bicuspid aortic valve is included), and of all forms increases to 75/1,000 live births if tiny muscular VSDs present at birth and other trivial lesions are included. Given the causes of variation, there is no evidence for differences in incidence in different countries or times.
          Article 0 comments Cited 461 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Genetics of congenital heart disease: the glass half empty.

            Akl Fahed, Bruce Gelb, J G Seidman … (2013)
            Congenital heart disease (CHD) is the most common congenital anomaly in newborn babies. Cardiac malformations have been produced in multiple experimental animal models, by perturbing selected molecules that function in the developmental pathways involved in myocyte specification, differentiation, or cardiac morphogenesis. In contrast, the precise genetic, epigenetic, or environmental basis for these perturbations in humans remains poorly understood. Over the past few decades, researchers have tried to bridge this knowledge gap through conventional genome-wide analyses of rare Mendelian CHD families, and by sequencing candidate genes in CHD cohorts. Although yielding few, usually highly penetrant, disease gene mutations, these discoveries provided 3 notable insights. First, human CHD mutations impact a heterogeneous set of molecules that orchestrate cardiac development. Second, CHD mutations often alter gene/protein dosage. Third, identical pathogenic CHD mutations cause a variety of distinct malformations, implying that higher order interactions account for particular CHD phenotypes. The advent of contemporary genomic technologies including single nucleotide polymorphism arrays, next-generation sequencing, and copy number variant platforms are accelerating the discovery of genetic causes of CHD. Importantly, these approaches enable study of sporadic cases, the most common presentation of CHD. Emerging results from ongoing genomic efforts have validated earlier observations learned from the monogenic CHD families. In this review, we explore how continued use of these technologies and integration of systems biology is expected to expand our understanding of the genetic architecture of CHD.
            Article 0 comments Cited 165 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition.

              Sylvie Thuault, Héctor Peinado, Amparo Cano … (2008)
              Epithelial-mesenchymal transition (EMT) is important during embryonic cell layer movement and tumor cell invasiveness. EMT converts adherent epithelial cells to motile mesenchymal cells, favoring metastasis in the context of cancer progression. Transforming growth factor-beta (TGF-beta) triggers EMT via intracellular Smad transducers and other signaling proteins. We previously reported that the high mobility group A2 (HMGA2) gene is required for TGF-beta to elicit EMT in mammary epithelial cells. In the present study we investigated the molecular mechanisms by which HMGA2 induces EMT. We found that HMGA2 regulates expression of many important repressors of E-cadherin. Among these, we analyzed in detail the zinc-finger transcription factor SNAIL1, which plays key roles in tumor progression and EMT. We demonstrate that HMGA2 directly binds to the SNAIL1 promoter and acts as a transcriptional regulator of SNAIL1 expression. Furthermore, we observed that HMGA2 cooperates with the TGF-beta/Smad pathway in regulating SNAIL1 gene expression. The mechanism behind this cooperation involves physical interaction between these factors, leading to an increased binding of Smads to the SNAIL1 promoter. SNAIL1 seems to play the role of a master effector downstream of HMGA2 for induction of EMT, as SNAIL1 knock-down partially reverts HMGA2-induced loss of epithelial differentiation. The data propose that HMGA2 acts in a gene-specific manner to orchestrate the transcriptional network necessary for the EMT program.
              Article 0 comments Cited 143 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Kun Sun
                Sun Chen
                Yu Yu
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 16 November 2018
                Publication date Collection: December 2018
                Publication date (Electronic): 16 November 2018
                Volume: 38
                Pages: 217-227
                Affiliations
                [a ]Department of Pediatric Cardiovascular, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
                [b ]Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
                [c ]Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tong Ji University School of Medicine, Shanghai 200433, China
                Author notes
                [* ]Corresponding authors at: Department of Pediatric Cardiology, Xin Hua Hospital, 1665 Kongjiang Road, Shanghai 200092, China sunkun@ 123456xinhuamed.com.cn chensun@ 123456xinhuamed.com.cn yuyu@ 123456xinhuamed.com.cn
                [1]

                Co-first authors

                Article
                Publisher ID: S2352-3964(18)30501-2
                DOI: 10.1016/j.ebiom.2018.11.008
                PMC ID: 6306349
                PubMed ID: 30448225
                SO-VID: 2021008e-74a4-43ab-af46-7a52bffc5ed5
                Copyright © © 2018 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 3 September 2018
                Date revision received : 22 October 2018
                Date accepted : 3 November 2018
                Categories
                Subject: Research paper

                Keywords: congenital heart defects,total anomalous pulmonary venous connection,whole exome sequencing,target sequencing,rare variants
                Data availability:
                Keywords: congenital heart defects, total anomalous pulmonary venous connection, whole exome sequencing, target sequencing, rare variants

                Comments

                Comment on this article

                scite_

                Similar content73

                See all similar

                Cited by43

                See all cited by

                Most referenced authors1,427

                See all reference authors