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Phenotype – genotype associations in a large cohort of patients with pulmonary arterial hypertension



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Hadinnapola, Charaka Mayura Bandara  ORCID logo


Idiopathic and heritable pulmonary arterial hypertension (PAH) are rare diseases with a poor prognosis. There is significant heterogeneity in clinical features at diagnosis, and in a proportion of patients there is a genetic cause of the disease. This clinical and genetic heterogeneity has hindered accurate risk stratification and the development of personalised treatments.

The National Institute of Health Research BioResource – Rare Diseases PAH Study and the Medical Research Council / British Heart Foundation National Cohort Study of Idiopathic and Heritable PAH were established to investigate disease pathogenesis through whole genome sequencing and deep phenotyping. One thousand and seventy patients were sequenced and 391 clinical variables were captured for each patient.

In patients with idiopathic PAH the age at diagnosis, gender, right atrial pressure and the transfer coefficient for carbon monoxide were identified as independent prognostic variables. However, the presence of rare and predicted deleterious variants in BMPR2 was not of prognostic significance. Variants in genes previously associated with disease pathogenesis were identified in 204 patients (19 %). Patients with variants in BMPR2 were younger at diagnosis and had more severe pulmonary haemodynamic impairment compared to patients with idiopathic PAH. Novel associations between BMPR2 variant status and both haemoglobin concentration and white blood cell count were observed. Four patients carried variants in both SMAD9 and either BMPR2 or EIF2AK4. The clinical significance of this requires further study. Unexpectedly, biallelic variants in EIF2AK4 were identified in patients with a clinical diagnosis of idiopathic PAH. These patients had a significantly worse prognosis compared to patients with idiopathic PAH. The spectrum of phenotypic, radiological and histological changes associated with biallelic EIF2AK4 variants was broader than previously recognised.

As these datasets mature, further analyses assessing the response to specific treatments and the outcomes of specific subgroups will be possible.





Morrell, Nicholas
Stefan, Graf


Pulmonary arterial hypertension, Pulmonary veno-occlusive disease, BMPR2, EIF2AK4


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge