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Human Genetics of Tetralogy of Fallot and Double Outlet Right Ventricle

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Congenital Heart Diseases: The Broken Heart

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Abstract

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.

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Acknowledgments

This work was supported by the European Community’s Seventh Framework Programme contract (“CardioNeT”) grant 289600 to S.R.S and the German Research Foundation (Heisenberg professorship and grant 574157 to S.R.S.). This work was also supported by the Berlin Institute of Health (BIH-CRG2-ConDi to S.R.S.).

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  1. Cardiovascular Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany

    Cornelia Dorn, Andreas Perrot & Silke Rickert-Sperling

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  1. Cornelia Dorn
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  2. Andreas Perrot
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  3. Silke Rickert-Sperling
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Correspondence to Silke Rickert-Sperling .

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  1. Cardiovascular Genetics, Charité - Universitätsmedizin Berlin , Berlin, Germany

    Silke Rickert-Sperling

  2. Developmental Biology, Inst. of Marseilles, Aix-Marseille Univ. , Marseille, France

    Robert G. Kelly

  3. Dpt. of Pediatrics Div.of Pediatric Card, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

    David J. Driscoll

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Dorn, C., Perrot, A., Rickert-Sperling, S. (2016). Human Genetics of Tetralogy of Fallot and Double Outlet Right Ventricle. In: Rickert-Sperling, S., Kelly, R., Driscoll, D. (eds) Congenital Heart Diseases: The Broken Heart. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1883-2_32

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