Rare and common variants in congenital heart disease A complex puzzle to solve?

Congenital heart disease (CHD) is the most common congenital anomaly. Genetic causes are identified in 20-30% of CHD cases, particularly in non-isolated and familial forms. About a third of all CHD comprise of cardiac outflow tract (OFT) defects, including tetralogy of Fallot (TOF) and dextro-transposition of the great arteries (D-TGA). Using whole exome sequencing and genome-wide association studies (GWAS) we investigated the role of rare and common genetic variants in OFT defects. This thesis expands on our knowledge about known CHD-genes (GATA6), and provides more (mechanistic) insight in new evolving disease-related genes (KDR). A GWAS performed in patients with D-TGA identified a susceptibility locus and showed that common variants contribute substantially to the risk of the disease. Moreover, we showed that applying a combined clinical and genetic risk score in D-TGA patients that had a atrial switch operation might help determine which patients are at high risk of a severe clinical outcome, which would have implications for their follow-up and treatment. Taken together, this thesis contributes to our understanding of the role of genetic variants in CHD, particularly OFT defects, and their underlying mechanisms.