Genetic testing in pulmonary hypertension: how should our clinical practice reflect recent advances?

In this issue of the European Respiratory Journal , Girerd et al. [1] summarise their experience to date with genetic testing for reported mutations in cohorts of patients with familial pulmonary arterial hypertension (PAH), idiopathic PAH, pulmonary veno-occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH). This collective work from the French Referral Centre of Pulmonary Hypertension represents a current state of the art in a fast moving and complex area from a group with considerable experience. In the last decade, we have moved from a simple and unequivocal association of one gene; heterozygous germline mutations in the bone morphogenetic protein receptor type 2 (BMPR2) [2, 3], to multiple hits in the BMPR2 signalling pathway [4–8], to additional genes in non-canonical BMP pathways of uncertain clinical significance or definitively agreed frequencies [9–11]. How to test, what to test and how to counsel is already a potential minefield. It is only likely to become more complicated in the immediate future given the technological advances and rapidly decreasing costs involved in large-scale genetic studies. So for now, we have a well-delineated step-wise model set out, in which patients are first tested for BMPR2 and, if negative, a sub-selected population proceeded to activin receptor-like kinase (ALK)1 and endoglin testing. EIF2AK4 (eukaryotic translation initiation factor 2 alpha kinase 4) was only screened in patients suspected of having PVOD/PCH. This is not dissimilar to the recent change to guidelines where it is now recommend that genetic testing should be offered in PVOD/PCH, familial and sporadic PAH, but largely leave the specifics of this to local guidelines and regulations. If BMPR2 testing is negative, it is suggested that endoglin/ALK1 should be considered for patients aged under 40 years or with a history (or family history) of hereditary haemorrhagic telangiectasia (HHT) [12]. In a French cohort, those with a familial history were also tested for SMAD9, KCNK3 and CAV-1of PAH if negative for BMPR2/ALK1/endoglin. The largest genetic screen to date shows that some pulmonary hypertension patients should be offered genetic testing