Submission Details

GDF2 encodes an endothelial cell specific circulating ligand, BMP9, that activates the BMP signalling pathway by promoting the phosphorylation of Smads 1/5/8 (David et al. 2007). To date, three publications have identified a total of 30 independent variants predicted to be deleterious of which eight predict premature truncation in the autosomal dominant form of pulmonary hypertension (Graf et al. 2018, Wang et al. 2019, Eyries et al. 2019). The gene disease relationship is supported by both mutation-specific in vitro studies (n=6), demonstration of aberrant BMP9 expression in patient cells (Wang et al, 2019), and rescue of PAH phenotypes by treatment of BMPR2 mutant mice with wild-type BMP9. No contradictory evidence has been reported. Recuration three years after the initial gene discovery report (March 16th, 2022) identified four additional PAH patients with heterozygous variants, three of which were missense variants with in vitro evidence of loss of function, and one nonsense variant (PMID 31661308, 33066286). Furthermore, a combined analysis of the PAH Biobank and the UK NIHR PAH cohort identified GDF2 as one of seven genes that were significantly associated with IPAH on a genome-wide basis (PMID 33971972). In summary, the evidence for GDF2 in the aetiology of pulmonary arterial hypertension is designated as definitive.