Genes Associated With Development of Pulmonary Arterial Hypertension in Patients With Congenital Shunt Lesions

Genes Associated With Development of Pulmonary Arterial Hypertension in Patients With Congenital Shunt Lesions

Prospective, Monocentric Pilot Study for the Identification of Known or Novel Genes Associated With Development of Pulmonary Arterial Hypertension in Patients With Congenital Shunt Lesions

Pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD) is associated with considerable morbidity and even mortality. Next to environmental risk factors, the investigators believe that there is an important role of genetic predisposition to develop PAH in CHD. There often is a discrepancy between the severity of PAH and the CHD, where it is useful to screen for PAH gene mutations. The investigators hypothesize that the genotype is partly responsible for the phenotypic variability in patients with congenital shunt lesions, where some develop PAH and others do not. If a genetic predisposition for PAH in CHD could be identified, then genetic screening could be a useful additional tool for early detection of patients at risk of pulmonary vascular disease and PAH development, with new opportunities for prevention or early treatment.

Pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD) usually develops secondary to chronic volume overload of the pulmonary circulation following left to right shunt. This overload leads to elevated pulmonary artery pressure (PAP) and later to increased pulmonary vascular resistance. This causes pressure overload in the right heart, and thereby right ventricular and right atrial dysfunction, which may implicate considerable morbidity and even mortality. Since PAH nowadays is mostly detected when symptoms occur and PAP are elevated, the disease already evolved to an advanced (partially irreversible) stage and treatment is often initiated too late. Next to environmental risk factors, the investigators believe that there is an important role of genetic predisposition to develop PAH in CHD. In the past, certain genes have been identified that play a role in the development of atrial septal defect (ASD). There are also a lot of genes identified that play a role in PAH. Until now, not many research groups have studied a genetic link between CHD and PAH development. But it becomes more and more clear that there often is a discrepancy between the severity of PAH and the CHD, where it is useful to screen for PAH gene mutations. The investigators hypothesize that mutations in some of these known PAH genes or in other, still unidentified, genes are partly responsible for the phenotypic variability in patients with congenital shunt lesions, where some develop PAH and others do not. If a genetic predisposition for PAH in CHD could be identified, then genetic screening could be a useful additional tool for early detection of patients at risk of pulmonary vascular disease and PAH development, with new opportunities for prevention or early treatment.

In a first step, known PAH genes (BMPR2, ALK1 and endoglin) will be screened for mutations. In a second step, known ASD genes will be screened. If step 1 and 2 remain negative, exome sequencing will be performed.

Inclusion Criteria: Previous diagnosis of secundum atrial septal defect (ASD) or ventricular septal defect (VSD), with or without repair Development of PAH, defined as mean PAP ≥ 25 mmHg by right heart catheterization, in combination with a pulmonary wedge pressure of ≤ 15 mmHg and a PVR (pulmonary vascular resistance) of > 3 Wood units Preferably, families with congenital shunt lesions (at least three family members affected with ASD or VSD) will be considered for inclusion Exclusion Criteria: Other congenital heart disease Mental retardation Dysmorphic characteristics Chronic lung disease or total lung capacity < 80% of predicted value History of pulmonary embolism