Cardiovascular malformation (CVM) is the commonest cause of childhood death in developed countries. In the EU there are 51,000 new cases each year and two million affected individuals. Yet, despite intensive research, the cause of 80% of CVM remains elusive. The mission of CHeartED is to identify genetic and environmental pathways that can be modified with the goal of reducing preventable CVM incidence. Epidemiological studies have shown that the stress of maternal hypo or hyperglycaemia increases the incidence of CVM. We plan a genetic association study in individuals with and without CVM born to diabetic mothers, to test whether genetic variants are associated with CVM. A similar study, without prior risk hypothesis, addresses tetralogy of Fallot, a CVM, which requires surgery in early life. These studies will reveal common genetic variants associated with CVM and thus add to existing knowledge on the aetiology of CVM. Moreover, the identification of genetic factors that differ in the context of maternal diabetes will disclose any associations in genetic pathways influenced by environmental factors. RNA expression studies in the mouse to identify new genes and pathways involved in outflow tract malformations and maternal diabetes associated with CVM, will complement the human studies. Finally, we will develop a 3D atlas of gene expression patterns and cardiac morphology at key developmental stages that will serve as a morphological framework. Central to our proposal is the development of a bioinformatics tool complemented by an open-access Wiki-based database. The bioinformatics tool will combine the sequence data and expression data generated by the human and mouse studies with morphology and literature to prioritize genes and generate hypotheses. The Wiki, which will contain existing and new genetic and environmental knowledge on heart development, will be an aid for many groups working on cardiovascular development and a novel means of disseminating our findings