Abstract

The identification of the genetic basis of heritable pulmonary arterial hypertension (HPAH) was a landmark discovery in the field. Ten years later, investigators are making significant progress toward understanding how such mutations confer susceptibility to disease and using this information to devise new approaches to treatment. Still, much remains to be learned regarding the genetic architecture of severe pulmonary arterial hypertension (PAH) and the genetic contribution to disease susceptibility. Evidence of familial clustering in PAH was first reported by Dresdale in 1954. Familial PAH, observed in approximately 10% of all ascertained cases, has recently been redefined as HPAH to acknowledge the fact that a causal and transmissible genetic defect may underlie disease in as many as a third of all cases. PAH may also be idiopathic (IPAH), or observed in association with exposure to risk factors such as appetite suppressant drugs and a limited series of disorders, including connective tissue disease, congenital heart disease, human immunodeficiency virus infection, and thromboembolic disease.