Phd ceremony Ms. W.S. Kerstjens-Frederikse: Congenital heart defects and pulmonary arterial hypertension. Genes, environment and heredity

In this thesis we describe our search for genetic and non-genetic causes of congenital heart defects and high blood pressure in the lungs (pulmonary arterial hypertension).Congenital heart defects occur in 8 per 1000 live births (1:130) and have a great impact on the life of the child and his or her family. We show that a (previously unknown) heart defect is present in a parent or a sibling in 20% of the children with a certain kind of heart defect. We conclude that the heart defect is hereditary in these children, and in some (7%) this is caused by a mutation in the NOTCH1 gene.In two patients with an unknown syndrome including a heart defect we have identified a new gene (SMO).Apart from genetic factors we investigated environmental factors by analysing data of a Birth Defects Registry (EUROCAT). We conclude that women who smoke and are overweight have an increased risk of congenital heart defects in their children.Pulmonary arterial hypertension in children is a rare, serious pulmonary vessel disease, leading to heart failure and a yearly death rate of 15% of the affected children. We have identified mutations in the TBX4 gene in children with this disease. Previously, mutations in the same gene had been reported as a cause of skeletal defects.Based on our results we can advise relatives on targeted investigations that may prevent morbidity or even sudden cardiac death. In addition, we have gained more insight in the aetiology of both diseases.