Abstract

Pulmonary arterial hypertension (PAH) is a rare disorder that may be hereditable (HPAH), idiopathic (IPAH), or associated with either drug-toxin exposures or other medical conditions. Familial cases have long been recognized and are usually due to mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2), or, much less commonly, 2 other members of the transforming growth factor-beta superfamily, activin-like kinase-type 1 (ALK1) and endoglin (ENG), which are associated with hereditary hemorrhagic telangiectasia. In addition, approximately 20% of patients with IPAH carry mutations in BMPR2. We provide a summary of BMPR2 mutations associated with HPAH, most of which are unique to each family and are presumed to result in loss of function. We review the finding of missense variants and variants of unknown significance in BMPR2 in IPAH/HPAH, fenfluramine exposure, and PAH associated with congenital heart disease. Clinical testing for BMPR2 mutations is available and may be offered to HPAH and IPAH patients but should be preceded by genetic counseling, since lifetime penetrance is only 10% to 20%, and there are currently no known effective preventative measures. Identification of a familial mutation can be valuable in reproductive planning and identifying family members who are not mutation carriers and thus will not require lifelong surveillance. With advances in genomic technology and with international collaborative efforts, genome-wide association studies will be conducted to identify additional genes for HPAH, genetic modifiers for BMPR2 penetrance and genetic susceptibility to IPAH. In addition, collaborative studies of BMPR2 mutation carriers should enable identification of environmental modifiers, biomarkers for disease development and progression, and surrogate markers for efficacy end points in clinical drug development, thereby providing an invaluable resource for trials of PAH prevention.