Pulmonary arterial hypertension [25 genes]

Pulmonary arterial hypertension (PAH) is defined by an abnormal increase in pulmonary arterial pressure, which can be of idiopathic origin (of unknown cause), inherited, or associated with systemic diseases. It is a progressive disease that is usually associated with a bad prognosis. In the last few years, important advances have been made regarding its pathophysiology and the applications of genetics to the management of patients with suspicion of this disease, which has allowed reducing the number of cases diagnosed as idiopathic. Among the hereditary forms of pulmonary arterial hypertension (PAH), a large proportion of cases are due to mutations in the BMPR2 gene, in which an autosomal dominant inheritance pattern with incomplete penetrance has been described.

Diseases with a recessive autosomal inheritance pattern associated with PAH also exist, such as pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (PVOD/PCH), associated with biallelic mutations in the EIF2AK4 gene. Recently, pathogenic variants associated with PAH have been described in other genes, which have been included in this panel.

• Rare disease, with an estimated prevalence between 5-52/1.000.000 individuals.

• In some cases, reaching an adequate diagnosis allows establishing risk stratification and/or reclassifying the disease, thus providing patients with a more adequate management and follow-up. For example, patients who carry pathogenic variants in the BMPR2 or ACVRL1 genes have a worse prognosis than non-carriers.
• Performing a familial genetic screening when a causal pathogenic mutation is identified in the index case allows detecting carrier relatives at risk of developing the disease and preventing unnecessary follow-up of non-carriers. The clinical variability and incomplete penetrance of the disease must be taken into account: carriers must undergo adequate clinical follow-up, even if disease is not expected to develop in all cases.

The international guidelines on the diagnosis and treatment of pulmonary arterial hypertension recommend genetic testing and counseling in adults and children with PAH (sporadic or familiar) or PVOD/PCH, as well as for relatives at risk of carrying the mutation.

Approximately 25-30% of patients with idiopathic pulmonary arterial hypertension show a familial presentation following a mendelian pattern and are classified as hereditary pulmonary arterial hypertension. In 70-80% of cases, the causal genetic variant affects the BMPR2 gene.

The performance of the genetic study in PAH through the use of massive sequencing panels has not been thoroughly assessed. In general terms, it is around 55%, being higher in cases of familial PAH or when associated with other disorders (HHT), where it can reach values over 80%.