Pulmonary hypertension is characterized by an increase in pulmonary pressure in the absence of a secondary cause explaining it (absence of associated pulmonary, cardiac or thromboembolic disease). It is a progressive disease associated with poor prognosis. The main cause is pulmonary arterial hypertension (PAH), which includes idiopathic PAH, familial (inherited) PAH and PAH related to other disorders (such as hemorrhagic hereditary telangiectasia, HHT).
In recent years, significant advances have been made regarding physiopathology and application of genetics in the management of patients suspected of the disease: many of the cases believed to be idiopathic are currently considered to have a genetic cause. The inheritance pattern in familial cases is autosomal dominant.
- Patients with suspected diagnosis of idiopathic or familial PAH, since it allows confirming the clinical diagnosis if a pathogenic mutation is identified.
- Performing an adequate and correct diagnosis allows for risk stratification in some cases. For example, patients who are carriers of pathogenic mutations in BMPR2 or ACVRL1 genes present a worse prognosis than non-carriers.
- For familial genetic screening when a pathogenic mutation is identified in the proband. This allows detecting carrier relatives at risk of developing the disease, while monitoring of non-carriers may be discontinued. The clinical variability and the incomplete penetrance of this disease need to be taken into account: carriers must undergo appropriate clinical monitoring, although not all cases will develop the disease.
- Aepc C, Society I, Uk SG, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2015:ehv317. doi:10.1093/Eur Heart J/ehv317.McDonald J, et al.
- Chung WK, Austin ED, Hunter Best D, Brown LM, Gregory Elliott C. Training/Practice When to Offer Genetic Testing for Pulmonary Arterial Hypertension. Can J Cardiol. 2015;31:544-547. doi:10.1016/j.cjca.2014.11.005.
The yield of the genetic testing on PAH through the use of massive sequencing panels has not been completely assessed. It is generally around 55%, being higher in cases with familial PAH or PAH related to other disorders (HHT), where it can reach values of over 80%.
Pulmonary Hypertension Panel
- BMPR2, the main gene associated with PAH, responsible for 75% of familial PAH cases and 25% of idiopathic PAH cases.
- Genes linked to PAH associated with other disorders such as hemorrhagic hereditary telangiectasia.
- Other secondary genes which have been recently associated with the disease, as well as candidate genes arising from a systematic review of the literature.
ACVRL1, BMPR2, ENG, BMPR1B, CAV1, KCNA5, KCNK3, NOTCH3, SMAD1, SMAD4, SMAD9, GDF2*
Notes on Genes:
Priority Genes: These genes include >70% of the mutations that have been previously associated with the development of hypertrophic cardiomyopathy and/or their testing is recommended by the guidelines. Secondary genes: Other genes related to the disease. *Candidate genes: With no evidence, but likely to be related to the phenotype.