Genetic Origins of Tetralogy of Fallot

Cardiol Rev. 2018 Mar/Apr;26(2):86-92. doi: 10.1097/CRD.0000000000000170.


Due to improved survival and clinical outcomes, congenital heart disease (CHD) is an area of growing importance within the medical community. As these patients reach adulthood and have children, there has been a growing appreciation for the increased risk of CHD among their offspring, strongly implying a genetic element. Given the growing wealth of genetic data available and these clinical implications, this review serves to reexamine the role of genetics within CHD, using Tetralogy of Fallot as a model pathology. Tetralogy of Fallot (TOF) is one of the oldest documented CHDs, with a growing prevalence of adult patients, and thus serves as an excellent model for this review. Given the complex nature of cardiac development, it is not surprising that multiple transcription factors and signaling molecules responsible for cardiogenesis have been implicated in TOF, with additional, previously nonimplicated genes being routinely reported within the literature. This review focuses on the well-characterized genes gata4, nkx2.5, jag1, foxc2, tbx5, and tbx1, which have been previously implicated in TOF. Furthermore, this article will attempt to summarize the specific clinical implications associated with the affected genes, such as right-sided aortic arches, associated syndromic presentations, and parental carrier states.

Publication types

  • Review

MeSH terms

  • Genetic Predisposition to Disease
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Tetralogy of Fallot / etiology
  • Tetralogy of Fallot / genetics*
  • Tetralogy of Fallot / metabolism
  • Transcription Factors / genetics


  • Intercellular Signaling Peptides and Proteins
  • Transcription Factors