Genetics of Pulmonary Arterial Hypertension

Abstract

Tremendous progress has been made in understanding the genetics of pulmonary arterial hypertension (PAH) since its description in the 1950s as a primary disorder of the pulmonary vasculature. Heterozygous germline mutations in the gene coding bone morphogenetic receptor type 2 (BMPR2) are detectable in the majority of cases of heritable PAH, and in approximately 20% of cases of idiopathic pulmonary arterial hypertension (IPAH). However, recent advances in gene discovery methods have facilitated the discovery of additional genes with mutations among those with and without familial PAH. Heritable PAH is an autosomal dominant disease characterized by reduced penetrance, variable expressivity, and female predominance. Biallelic germline mutations in the gene EIF2AK4 are now associated with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Growing genetic knowledge enhances our capacity to pursue and provide genetic counseling, although the issue remains complex given that the majority of carriers of PAH-related mutations will never be diagnosed with the disease.

Fig. 1

Condensed pedigree of an extended kindred with heritable pulmonary arterial hypertension (HPAH) due to a BMPR2 mutation. This pedigree contains 42 total patients with HPAH, as well as many known BMPR2 mutation carriers without HPAH. Solid symbols represent individuals with disease. Circles represent women, and squares represent men. Line through symbol represents death. Dot inside symbol represents obligate carrier of the BMPR2 mutation. Numbers below symbols represent age at death or current living age. Numbers inside symbols represent numbers of unaffected siblings of each gender. S inside symbol represents stillbirth. Diamond symbol represents sex unknown.

Fig. 2

Suggested approach to a relative of a pulmonary arterial hypertension (PAH) patient with known heritable PAH (HPAH). If the asymptomatic but at-risk relative has a detectable PH-specific mutation, that person should undergo clinical evaluation and echocardiographic imaging every 1 to 3 years. However, if the person lacks the family’s PH-specific mutation, further testing can be halted unless new clinical concerns emerge.