Pulmonary vascular phenotype identified in patients with GDF2 (BMP9) or BMP10 variants: An international multicentre study

<bold>Background:</bold> Bone morphogenetic proteins 9 and 10 (BMP9 and BMP10), encoded by <italic>GDF2</italic> and <italic>BMP10</italic>, play a pivotal role in pulmonary vascular regulation. <italic>GDF2</italic> variants have been reported in pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). However, the phenotype of <italic>GDF2</italic> and <italic>BMP10</italic> carriers remains largely unexplored. <bold>Methods:</bold> We report the characteristics and outcomes of PAH patients in <italic>GDF2</italic> and <italic>BMP10</italic> carriers from the French and Dutch PH registry. A literature review explored the phenotypic spectrum of these patients. <bold>Results:</bold> 26 PAH patients were identified: 20 harbouring heterozygous <italic>GDF2</italic> variants, 1 homozygous <italic>GDF2</italic> variant, 4 heterozygous <italic>BMP10</italic> variants, and 1 with both <italic>GDF2</italic> and <italic>BMP10</italic> variants. The prevalence of <italic>GDF2</italic> and <italic>BMP10</italic> variants was 1.3% and 0.4%. Median age at PAH diagnosis was 30 years, with a female-to-male ratio of 1.9. Congenital heart disease (CHD) was present in 15.4% of the patients. At diagnosis, most of the patients (61.5%) were in NYHA functional class III or IV with severe haemodynamic compromise (median PVR 9.0 WU, range 3.3-40.6 WU). Haemoptysis was reported in four patients, none met the HHT criteria. Two patients carrying <italic>BMP10</italic> variants underwent lung transplantation, revealing typical PAH histopathology. The literature analysis showed that 7.6% of <italic>GDF2</italic> carriers developed isolated HHT and identified cardiomyopathy and developmental disorders in <italic>BMP10</italic> carriers <bold>Conclusion:</bold> <italic>GDF2</italic> and <italic>BMP10</italic> pathogenic variants are rare among PAH patients, and occasionally associated with CHD. HHT cases among <italic>GDF2</italic> carriers are limited according to literature. <italic>BMP10</italic> full phenotypic ramifications warrant further investigation.