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Genetic findings in patients with different forms of pulmonary hypertension

Background: A genetic predisposition has been identified in different forms of pulmonary arterial hypertension (PAH). Most pathogenic variants have been identified in BMPR2 in hereditary PAH. However, many further PAH genes have been described. Objective: The aim of this study was to screen for all known PAH genes in a large cohort of patients with PAH and other forms of PH who have been referred for genetic testing. Methods: DNA from 244 patients was extracted and sequenced using a PAH specific gene diagnostics panel for the genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4. Of these, 180 samples were also sequenced for ATP13A3, AQP1 and SOX17. Results: Of the 244 patients about 50% were classified as IPAH and 17% as HPAH. Further patients with associated PAH such as congenital heart disease or connective tissue disease patients, pulmonary veno-occlusive disease (PVOD) and patients with sarcoidosis associated PH were included. A total of 70 pathogenic variants were identified in 66 patients. The majority of the variants (56%) was located in the gene BMPR2 but the others were found across 10 other PAH genes. Most HPAH patients had pathogenic variants in BMPR2 but also in AQP1, KCNK3, SMAD9 and SOX17. Two sarcoidosis associated PH patients carried pathogenic variants in the genes GDF2 and SOX17. Conclusion: Pathogenic variants were located in BMPR2 and in further PAH genes. Genetic predisposition was not restricted to HPAH, IPAH and PVOD but could also be identified PH with sarcoidosis and other forms of associated PAH. Thus, genetic diagnostics might be useful in a larger patient cohort than currently recommended.