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

Shi, X., Huang, T., Wang, J., Liang, Y., Gu, C., Xu, Y., Sun, J., Lu, Y., Sun, K., Chen, S., Yu, Y.
EBioMedicine   38: 217-227 (Journal)
Registered Authors
Liang, Yulai
Congenital heart defects, Rare variants, Target sequencing, Total anomalous pulmonary venous connection, Whole exome sequencing
MeSH Terms
  • Alleles
  • Amino Acid Substitution
  • Animals
  • Child, Preschool
  • Computational Biology/methods
  • Computed Tomography Angiography
  • Female
  • Gene Expression
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Genetic Association Studies*
  • Genetic Testing
  • Genetic Variation*
  • Genome, Human
  • Genome-Wide Association Study
  • Heart Defects, Congenital/diagnosis*
  • Heart Defects, Congenital/genetics*
  • Heart Defects, Congenital/mortality
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Infant
  • Male
  • Mutation
  • Phenotype*
  • Polymorphism, Single Nucleotide
  • Pulmonary Veins/abnormalities*
  • Survival Rate
  • Whole Genome Sequencing
  • Zebrafish
30448225 Full text @ EBioMedicine
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).
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.
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.
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.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes