Genetic counselling and testing in pulmonary arterial hypertension: a consensus statement on behalf of the International Consortium for Genetic Studies in PAH

Abstract

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered.

FIGURE 1

Main genes recommended to be included in genetic testing of pulmonary arterial hypertension (PAH) patients and their relatives. The underlined genes are the genes which should definitely be included in the PAH gene panel. The other genes may be included but results should be interpreted with caution as they await further supporting evidence. ^#: genes associated with hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu disease); ^¶: gene associated with pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis; ⁺: genes associated with lung development abnormalities. BMP: bone morphogenetic protein; TGF: transforming growth factor. Protein symbols/names/aliases are given in brackets.

FIGURE 2

Genetic counselling path for pulmonary arterial hypertension (PAH) patients and their relatives. Patients should receive genetic counselling before and after genetic testing. If a (likely) pathogenic variant is identified, family testing should be encouraged. If asymptomatic carriers are identified they should undergo regular clinical follow-up. IPAH: idiopathic PAH; FPAH: familial PAH; PVOD: pulmonary veno-occlusive disease; PCH: pulmonary capillary haemangiomatosis; CHD APAH: congenital heart disease-associated PAH; CPET: cardiopulmonary exercise testing; TTE: transthoracic echocardiography.