Congenital heart defects (CHDs) are the most common congenital abnormalities. Analysis of large multigenerational families has led to the identification of a number of genes for CHDs. However, identifiable variations in these genes are the cause of a small proportion of cases of CHDs, suggesting significant genetic heterogeneity. In addition, large families with CHDs are rare, making the identification of additional genes difficult. Next-generation sequencing technologies will provide an opportunity to identify more genes in the future. However, the significant genetic variation between individuals will present a challenge to distinguish between ‘pathogenic’ and ‘benign’ variants. We have demonstrated that the analysis of multiple individuals in small families using combinations of algorithms can reduce the number of candidate variants to a small, manageable number. Thus, the analysis of small nuclear families or even distantly related ‘sporadic’ cases may begin to uncover the ‘dark matter’ of CHD genetics.