Infants with Turner syndrome (TS) and Down syndrome (DS) account for the vast majority of patients born with congenital heart defects (CHD), where those with TS have a 1 in 3 chance of having a bicuspid aortic valve (BAV) and aortopathy and those with DS have a 1 in 5 chance of having an atrioventricular septal defect (AVSD). These chromosomal aneuploidy’s associations with CHDs and observations of Mendelian inheritance patterns of CHDs in families provides strong evidence of a genetic component. Although the chromosomal aneuploidies that give rise to these syndromic forms of CHDs are well established, the additional genetic factors that determine which subset will develop a CHD is not understood. Additionally, CHDs can also occur sporadically, with no family history, and without any other defect as non-syndromic CHDs. Therefore, we also studied AVSD in the euploid population utilizing a case-control gene-burden analysis and a rare variant analysis. The information presented here is a collection of whole exome sequencing studies pertaining to the investigation of the genetic basis of congenital heart defects and diseases in both syndromic (TS and DS) and non-syndromic populations.