Rapid advances in the technology of next generation sequencing, coupled with falling costs, allows sequencing of the whole exome or whole genome to be applied at scale in rare diseases. In addition, the development of statistical approaches to analyze genomic data continues to improve our ability to detect rare and common genetic variation underlying these diseases.

Genetic studies over the last few years have revealed that heterozygous mutations in the gene encoding the bone morphogenetic protein type 2 receptor (BMPR2) are responsible for approximately 75% of cases of pulmonary arterial hypertension (PAH) that occurs in families, and for approximately 20% of apparently sporadic cases of idiopathic PAH. Studies have also confirmed the presence of mutations in additional BMPR2 pathways genes (ALK1, ENG, Smad1, Smad9), as well as mutations in KCNK3 (TASK1) and CAV-1.  Taken together these non-BMPR2 mutations account for less than 5% of PAH cases. Furthermore, mutations in EIF2AK4 (GCN2) have emerged as the dominant cause of pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH).

Although environmental factors may account for some cases of idiopathic PAH, it seems likely that additional novel rare genetic variation underlies a significant proportion of cases. Moreover, common or rare genetic variation may influence the penetrance of the known genes and the clinical course/response to therapy.

It is clear that only international collaborations, which are capable of generating thousands of samples from patients with idiopathic and heritable PAH, will have the statistical power to discover the complete genetic architecture of PAH, and to address the major questions regarding the role of genetic variation in disease penetrance, phenotype and the clinical course of disease.