Pulmonary arterial hypertension (PAH)

Pulmonary arterial hypertension (PAH) is characterised by progressive remodelling of the pulmonary vasculature, resulting in increased pulmonary vascular resistance. Initial symptoms are non-specific and typically develop gradually, including exertional dyspnoea, fatigue, chest pain and palpitations. Clinical presentation ranges from isolated (non-syndromic) PAH to syndromic forms in which pulmonary vascular disease occurs alongside additional organ manifestations. Hereditary haemorrhagic telangiectasia is one such example; skeletal and airway anomalies may occur in others. Heritable forms can present from childhood to late adulthood.

Reported prevalence for PAH estimates range from 11 to 60 cases per million adults across different registries. These estimates include both genetic and non-genetic forms of pulmonary arterial hypertension and therefore do not reflect the prevalence of heritable pulmonary arterial hypertension specifically.

Genetic causes of pulmonary arterial hypertension comprise both isolated (non-syndromic) and syndromic forms. The most common genetic cause is a germline pathogenic variant in BMPR2, which encodes a receptor involved in transforming growth factor beta signalling. Other important causes of isolated PAH include pathogenic variants in genes involved in the BMP/TGF-β signalling pathway, such as ACVRL1, ENG, SMAD9 and GDF2. Syndromic forms include ACVRL1-related hereditary haemorrhagic telangiectasia and TBX4 syndrome, which may present with pulmonary arterial hypertension and skeletal anomalies. Rare genetically related pulmonary vascular disorders include EIF2AK4-related pulmonary veno-occlusive disease and FOXF1-related alveolar capillary dysplasia.

The genetic conditions associated with pulmonary arterial hypertension predominantly follow autosomal dominant inheritance. Both isolated and syndromic entities occur within this spectrum. Less commonly, pulmonary vascular disease may be inherited in an autosomal recessive manner.

• Establishing the diagnosis and informing management: Identification of a pathogenic variant in a disease-associated gene can confirm a genetic diagnosis and may support condition-specific monitoring and management.
• Family risk assessment and reproductive counselling: Identification of the causative variant enables predictive testing of at-risk relatives and provides information relevant to family planning

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• Eichstaedt CA, Belge C, Chung WK, Gräf S, Grünig E, Montani D, et al. Genetic counselling and testing in pulmonary arterial hypertension: a consensus statement on behalf of the International Consortium for Genetic Studies in PAH. Eur Respir J. 2023;61(2):2201471. PMID: .