Pulmonary arterial hypertension [25 genes]

Pulmonary hypertension is defined as an abnormal increase in pulmonary artery pressure, which can be idiopathic (with no known cause), hereditary, or associated with systemic diseases. It is a progressive disease usually associated with a poor prognosis.

In recent years, major advances have been achieved regarding its pathophysiology and the application of genetics to the management of patients suspected of this disease, leading to a decrease in the number of cases diagnosed as idiopathic. Among hereditary forms of pulmonary artery hypertension (PAH), approximately 70% of cases are due to mutations in the BMPR2 gene, for which an autosomal dominant inheritance pattern and incomplete penetrance have been described. Some diseases with autosomal recessive inheritance are also associated with PAH, such as pulmonary veno-occlusive disease/ pulmonary capillary hemangiomatosis (PVOD/PCH), associated with biallelic mutations in the EIF2AK4 gene. Pathogenic variants associated with this disease have been recently described in other genes, which are also included in this panel.

Pulmonary hypertension is a rare disease (with an estimated prevalence of between 5 and 52 cases per million inhabitants).

• Making an adequate diagnosis allows in some cases to establish a risk stratification and/or reclassify the disease, thus providing more appropriate management and follow-up to the patient. For example, patients carrying pathogenic mutations in the BMPR2 or ACVRL1 gene have a worse prognosis than non-carriers.
• Performing family genetic screening, when a causal pathogenic mutation is identified in the index case. This makes it possible to detect family members who are carriers at risk of developing the disease and avoid unnecessary follow-up with non-carriers. The clinical variability and incomplete penetrance of the disease must be considered: carriers must have adequate clinical follow-up, although not in all cases they will develop the disease.

The International Guidelines on Diagnosis and Treatment of Pulmonary Hypertension recommend genetic study and counseling for adults and children with PAH (sporadic or familial) or PVOD/PCH as well as family members at risk of being carriers.

Approximately 25-30% of patients with idiopathic pulmonary arterial hypertension have a Mendelian familial presentation 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 using massive sequencing panels has not been fully studied. In general terms, it oscillates around 55%, being higher in cases of familial PAH or associated with other disorders (THH), where it can reach more than 80%.