Human Genetics of Tetralogy of Fallot and Double-Outlet Right Ventricle

Adv Exp Med Biol. 2024:1441:629-644. doi: 10.1007/978-3-031-44087-8_36.


Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are conotruncal defects resulting from disturbances of the second heart field and the neural crest, which can occur as isolated malformations or as part of multiorgan syndromes. Their etiology is multifactorial and characterized by overlapping genetic causes. In this chapter, we present the different genetic alterations underlying the two diseases, which range from chromosomal abnormalities like aneuploidies and structural mutations to rare single nucleotide variations affecting distinct genes. For example, mutations in the cardiac transcription factors NKX2-5, GATA4, and HAND2 have been identified in isolated TOF cases, while mutations of TBX5 and 22q11 deletion, leading to haploinsufficiency of TBX1, cause Holt-Oram and DiGeorge syndrome, respectively. Moreover, genes involved in signaling pathways, laterality determination, and epigenetic mechanisms have also been found mutated in TOF and/or DORV patients. Finally, genome-wide association studies identified common single nucleotide polymorphisms associated with the risk for TOF.

Keywords: 22q11 deletion; 22q11 deletion syndrome; CFC1; CHARGE syndrome; CHD7; CNVs; Cat eye syndrome; Copy number variations; Cri du chat syndrome; DORV; DiGeorge syndrome; Double-outlet right ventricle; Down syndrome; Edwards syndrome; FOG2; GATA4; GDF1; Genome-wide association studies; HAND2; Heterotaxy; Holt–Oram syndrome; JAG1; Jacobsen syndrome; LEOPARD syndrome; Laterality defects; NKX2–5; NOTCH2; Patau syndrome; SNPs; Single nucleotide polymorphisms; TBX1; TBX5; TOF; Tetralogy of Fallot; Trisomy; Velocardiofacial syndrome; Williams–Beuren syndrome.

Publication types

  • Review

MeSH terms

  • Double Outlet Right Ventricle* / genetics
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study
  • Humans
  • Mutation
  • Polymorphism, Single Nucleotide / genetics
  • Tetralogy of Fallot* / genetics
  • Transcription Factors / genetics


  • Transcription Factors