Prevalence and spectrum of GATA5 mutations associated with congenital heart disease

Abstract

Congenital heart disease (CHD) is the most prevalent form of developmental abnormality with an incidence of approximately 1% in live newborns, and is the leading non-infectious cause of infant mortality with more than 29% of neonates who die of birth defects having cardiac anomalies [ [1] Roger V.L. Go A.S. Lloyd-Jones D.M. et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation. 2012; 125: e2-e220 Crossref PubMed Scopus (0) Google Scholar ]. Despite its striking prevalence and important clinical significance, the etiology responsible for CHD remains largely unknown. Now it is generally understood that abnormal cardiovascular development during embryogenesis may be attributed to an aberrant biological process that is heterogeneous and complex, with both environmental and genetic risk factors involved [ [2] Bruneau B.G. The developmental genetics of congenital heart disease. Nature. 2008; 451: 943-948 Crossref PubMed Scopus (565) Google Scholar ]. Great advance in developmental biology has contributed to the discovery of numerous transcriptional regulators, signaling molecules and structural proteins that are crucial for normal cardiogenesis. This mechanistic understanding of cardiac morphogenesis results in the identification of multiple CHD related genes by using positional cloning or direct candidate gene strategies [ [3] Cecchetto A. Rampazzo A. Angelini A. et al. From molecular mechanisms of cardiac development to genetic substrate of congenital heart diseases. Future Cardiol. 2010; 6: 373-393 Crossref PubMed Scopus (16) Google Scholar ]. Aggregating evidence demonstrates that cardiac transcription factor genes GATA4 and NKX2-5 are most commonly causally implicated in the pathogenesis of CHD [ [4] McCulley D.J. Black B.L. Transcription factor pathways and congenital heart disease. Curr Top Dev Biol. 2012; 100: 253-277 Crossref PubMed Scopus (211) Google Scholar ]. Nevertheless, CHD is genetically heterogeneous and the genetic determinants underlying CHD in a vast majority of patients are still to be identified.