Single gene mutations in Gata4 and Nkx2.5 genes have been identified as a causative factor for various clinical forms of hereditary congenital heart diseases (CHDs), especially for cardiac septal defects. However, the role of Gata4 and Nkx2.5 mutations in familial CHD is not clear yet. We report 5 cases of familial CHD with a positive history of cardiac septal defects. Our data suggest that mutations of either the Gata4 or Nkx2.5 genes are very uncommonly found in familial cases of CHD, supporting the genetic heterogeneity of cardiac congenital defects and the limitation of genetic testing in clinical setting.