Submission Details

The relationship between GDF2 (BMP9) and autosomal dominant Hereditary Hemorrhagic Telangiectasia, Type 5 (HHT5) was first reported by Wooderchak-Donahue et al. in 2013, PMID:23972370). HHT5 is defined broadly as any hereditary hemorrhagic telangiectasia in which the cause of the disease is a mutation in GDF2. HHT is diagnosed by the presence of 3 or more of the Curacao criteria (PMID:10751092). Given the large phenotypic spectrum from patients with GDF2 variants meeting HHT as defined by the Curacao criteria to patients displaying vascular defects with talengectasia and potential AVMs, the disorder may be more accurately described as "GDF2 related HHT-like syndrome". Interestingly, individuals with heterozygous missense variants and biallelic loss of function variants have been described, suggesting possible differences in the molecular mechanisms behind the disease. BMP9 is a circulating vascular quiescence factor. It acts on the TGF-β receptor system by interacting with ACVRL1 and ENG. Variants in ACVRL1 and ENG are known to cause HHT. Evidence supporting this gene-disease relationship includes case-level data and experimental data. In total, 9 variants were scored (missense, nonsense, and frameshift) from 9 probands reported in 4 publications (PMIDs: 23972370, 27081547, 33834622, 32669404, 34904380, 34611981). This gene-disease relationship is further supported by animal models, protein interaction with ACVRL1 and biochemical function. A number of mouse models have been developed to explore the relationship between BMP9 and HHT. Many show that BMP9 KO mice are phenotypically healthy compared to WT. However, double KO BMP9 and BMP10 blocked via immunoblocking or genetic knock out modeled HHT including the formation of AVMs. This resut may be explained by the fact that BMP10 can compensate for the loss of BMP9 in mice and that BMP10 and BMP9 may be functionaly equivelent during in vitro binding to ALK1. In summary, GDF2 is moderately associated with autosomal dominant hereditary hemorrhagic telangiectasia, type 5. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel on 04/03/2023 (SOP Version 9).

Of note, GDF2 is also definitively associated with pulmonary arterial hypertension (PAH) and was independently evaluated as of May 26, 2022 by the Pulmonary Hypertension GCEP. The GCEP scored three publications and 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.