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

BACKGROUND: Bone morphogenetic proteins 9 and 10 (BMP9 and BMP10), encoded by GDF2 and BMP10 , play a pivotal role in pulmonary vascular regulation. GDF2 variants have been reported in pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). However, the phenotype of GDF2 and BMP10 carriers remains largely unexplored.

METHODS: We report the characteristics and outcomes of PAH patients in GDF2 and BMP10 carriers from the French and Dutch PH registry. A literature review explored the phenotypic spectrum of these patients.

RESULTS: Twenty-six PAH patients were identified: 20 harbouring heterozygous GDF2 variants, 1 homozygous GDF2 variant, 4 heterozygous BMP10 variants, and one with both GDF2 and BMP10 variants. The prevalence of GDF2 and BMP10 variants was 1.3% and 0.4%, respectively. 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 pulmonary vascular resistance 9.0 WU, range 3.3-40.6) WU. Haemoptysis was reported in four patients, none met the HHT criteria. Two patients carrying BMP10 variants underwent lung transplantation, revealing typical PAH histopathology. The literature analysis showed that 7.6% of GDF2 carriers developed isolated HHT and identified cardiomyopathy and developmental disorders in BMP10 carriers . CONCLUSIONS: GDF2 and BMP10 pathogenic variants are rare among PAH patients, and occasionally associated with CHD. HHT cases among GDF2 carriers are limited according to literature. BMP10 full phenotypic ramifications warrant further investigation.