Pulmonary arterial hypertension [25 genes]

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

• The ESC/ERS 2015 guidelines on diagnosis and treatment of pulmonary hypertension recommend genetic testing and counselling for adults and children with PAH (both sporadic and familial) or PVOD/PCH, as well as for relatives at risk of being carriers.
• In some cases, an adequate diagnosis allows establishing risk stratification and/or reclassifying the disease, therefore providing the patient with a more suitable management and follow-up. For example, patients carrying pathogenic mutations in genes BMPR2 or ACVRL1 show a poorer prognosis than non-carriers.
• Performing familial genetic screening when a causative pathogenic mutation is found in the index case allows detecting carrier relatives at risk of developing the disease and avoiding unnecessary follow-up of non-carrier relatives. Clinical variability and incomplete penetrance of this disease must be taken into account: carriers must undergo adequate clinical follow-up, even though not all of them will develop the disease.

The yield of genetic testing for PAH by massive sequencing panels has not been fully studied. Generally, it is around 55%, while it is higher for familial PAH cases and for those associated with other disorders (HHT), where it can exceed 80%..