Pulmonary hypertension (PAH) 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 the application of genetics to the patient management, leading to a decrease in the number of cases diagnosed as idiopathic. Among hereditary forms of pulmonary arterial 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 an autosomal recessive inheritance pattern 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.
Indication for genetic testing:
- 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 accurate 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. The clinical variability and incomplete penetrance of this disease must be taken into account: carriers must receive adequate clinical follow-up, even though not all of them are expected to develop the disease.
Yield of genetic testing: 55%
- The yield of genetic testing for PAH by massive sequencing panels has not been fully studied. Its overall yield is around 55%, while it can exceed 80% for familial PAH cases and for those associated with other disorders (HHT).
BMPR2, the main gene related to PAH, accounting for 75% of familial PAH cases and 25% of idiopathic cases.
Genes related to PAH associated with other disorders, such as hereditary hemorrhagic telangiectasia (ACVRL1, ENG), alveolar capillary dysplasia with misalignment of the pulmonary veins (FOXF1), or pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (EIF2AK4).
Other secondary genes that have been recently related to the disease, as well as candidate genes gathered from a systematic literature review.
- Aepc C, Society I, Uk SG, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2015; 46:903-975.
- Frost A, Badesch D, Gibbs JSR, et al. Diagnosis of pulmonary hypertension. Eur Respir J. 2019; 53: 1801904.
- Morrell NW, Aldred MA, Chung WK, et al. Genetics and genomics of pulmonary arterial hypertension. Eur Respir J 2019; 53: 1801899.