Pulmonary Vascular Phenotype Identified in Patients Withgdf2(bmp9) Orbmp10variants: an International Multicentre Study

BackgroundBone morphogenetic proteins 9 and 10 (BMP9 and BMP10), encoded byGDF2andBMP10, respectively, play a pivotal role in pulmonary vascular regulation.GDF2variants have been reported in pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). However, the phenotype ofGDF2andBMP10carriers remains largely unexplored.MethodsWe report the characteristics and outcomes of PAH patients inGDF2andBMP10carriers from the French and Dutch pulmonary hypertension registries. A literature review explored the phenotypic spectrum of these patients.Results26 PAH patients were identified: 20 harbouring heterozygousGDF2variants, one homozygousGDF2variant, four heterozygousBMP10variants, and one with bothGDF2andBMP10variants. The prevalence ofGDF2andBMP10variants was 1.3% and 0.4%, respectively. Median age at PAH diagnosis was 30 years, with a female/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 New York Heart Association Functional Class III or IV with severe haemodynamic compromise (median (range) pulmonary vascular resistance 9.0 (3.3–40.6) WU). Haemoptysis was reported in four patients; none met the HHT criteria. Two patients carryingBMP10variants underwent lung transplantation, revealing typical PAH histopathology. The literature analysis showed that 7.6% ofGDF2carriers developed isolated HHT, and identified cardiomyopathy and developmental disorders inBMP10carriers.ConclusionsGDF2andBMP10pathogenic variants are rare among PAH patients, and occasionally associated with CHD. HHT cases amongGDF2carriers are limited according to the literature.BMP10full phenotypic ramifications warrant further investigation.