Genetic Etiology of Left-Sided Obstructive Heart Lesions: A Story in Development

J Am Heart Assoc. 2021 Jan 19;10(2):e019006. doi: 10.1161/JAHA.120.019006. Epub 2021 Jan 12.


Congenital heart disease is the most common congenital defect observed in newborns. Within the spectrum of congenital heart disease are left-sided obstructive lesions (LSOLs), which include hypoplastic left heart syndrome, aortic stenosis, bicuspid aortic valve, coarctation of the aorta, and interrupted aortic arch. These defects can arise in isolation or as a component of a defined syndrome; however, nonsyndromic defects are often observed in multiple family members and associated with high sibling recurrence risk. This clear evidence for a heritable basis has driven a lengthy search for disease-causing variants that has uncovered both rare and common variants in genes that, when perturbed in cardiac development, can result in LSOLs. Despite advancements in genetic sequencing platforms and broadening use of exome sequencing, the currently accepted LSOL-associated genes explain only 10% to 20% of patients. Further, the combinatorial effects of common and rare variants as a cause of LSOLs are emerging. In this review, we highlight the genes and variants associated with the different LSOLs and discuss the strengths and weaknesses of the present genetic associations. Furthermore, we discuss the research avenues needed to bridge the gaps in our current understanding of the genetic basis of nonsyndromic congenital heart disease.

Keywords: aortic stenosis; bicuspid aortic valve; coarctation of the aorta; congenital heart disease; hypoplastic left heart syndrome; interrupted aortic arch.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Aortic Diseases* / congenital
  • Aortic Diseases* / genetics
  • Genetic Predisposition to Disease
  • Genetic Testing / methods
  • Genetic Testing / trends
  • Heart Defects, Congenital / genetics*
  • Humans
  • Hypoplastic Left Heart Syndrome / genetics*
  • Sequence Analysis / methods
  • Sequence Analysis / trends
  • Vascular Malformations / genetics*