Assessing the contribution of rare variants to congenital heart disease through a large-scale case-control exome study.

Several studies have demonstrated the value of large-scale human exome and genome data analysis to maximise gene discovery in rare diseases. Using this approach, we have analysed the exomes of 4747 cases and 52,881 controls to identify genes which confer a substantial risk of congenital heart disease (CHD). We identified both rare loss-of-function and missense coding variants in 14 genes, which reached genome-wide significance at FDR 5%. Ten genes have been associated with CHD, whereas four genes (PBX1, KAT6B, SHOX2, HCAR1) have not been reported as genome-wide significant so far. We highlight distinct genetic contributions to syndromic and non-syndromic CHD by independently analysing probands from these two groups. In addition, by integrative analysis of exome data with single-cell transcriptomics data from human embryonic hearts, we identified cardiac-specific cells, such as neural crest cells and endothelial cells, as well as putative biological processes underlying the pathogenesis of CHD. In summary, our findings strengthen the association of known CHD genes and have identified additional novel disease genes contributing to the aetiology of CHD.