Somatic mutations in NKX2-5, GATA4, and HAND1 are not a common cause of tetralogy of Fallot or hypoplastic left heart

• Published in: American journal of medical genetics. Part A 2011-10, Vol.155A (10), p.2416-2421
• Main Authors: Esposito, Giorgia, Butler, Tanya L., Blue, Gillian M., Cole, Andrew D., Sholler, Gary F., Kirk, Edwin P., Grossfeld, Paul, Perryman, Benjamin M., Harvey, Richard P., Winlaw, David S.
• Format: Article
• Language: English
• Subjects: Base Sequence; Basic Helix-Loop-Helix Transcription Factors - genetics; Biological and medical sciences; Cardiology. Vascular system; congenital heart disease; Congenital heart diseases. Malformations of the aorta, pulmonary vessels and vena cava; DNA - blood; DNA - metabolism; Environmental factors; Etiology; GATA4 Transcription Factor - genetics; Genetics; Heart; Heart diseases; Homeobox Protein Nkx-2.5; Homeodomain Proteins - genetics; Humans; Hypoplastic Left Heart Syndrome - genetics; Medical genetics; Medical sciences; Molecular Sequence Data; Mutation; Mutation - genetics; Myocardium; Myocardium - metabolism; NKX2-5; Nkx2.5 protein; Sequence Analysis, DNA; somatic mutation; tetralogy of Fallot; Tetralogy of Fallot - genetics; Transcription Factors - genetics; Ventricle
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.34187

The majority of congenital heart disease (CHD) occurs as a sporadic finding, with a minority of cases associated with a known genetic abnormality. Combinations of genetic and environmental factors are implicated, with the recent and intriguing hypothesis that an apparently high rate of somatic mutations might explain some sporadic CHD. We used samples of right ventricular myocardium from patients undergoing surgical repair of tetralogy of Fallot (TOF) and hypoplastic left heart (HLH) to examine the incidence of somatic mutation in cardiac tissue. TOF is a common form of cyanotic CHD, occurring in 3.3 per 10,000 live births. HLH is a rare defect in which the left side of the heart is severely under‐developed. Both are severe malformations whose genetic etiology is largely unknown. We carried out direct sequence analysis of the NKX2–5 and GATA4 genes from fresh frozen cardiac tissues and matched blood samples of nine TOF patients. Analysis of NKX2–5, GATA4, and HAND1 was performed from cardiac tissue of 24 HLH patients and three matched blood samples. No somatic or germline mutations were identified in the TOF or HLH patients. Although limited by sample size, our study suggests that somatic mutations in NKX2–5 and GATA4 are not a common cause of isolated TOF or HLH. © 2011 Wiley‐Liss, Inc.