GDF2

Inheritance Pattern: SD

Disease ID:MONDO:0014217

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: ClinGen

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.

Inheritance Pattern: Unknown

Disease ID:MONDO:0014217

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014217

Submitter: ClinGen

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). HHT is diagnosed by the presence of 3 or more of the Curacao criteria (PMID: 10751092); it is characterized by telangiectases and arteriovenous malformations (AVMs). Hallmark features are recurrent epistaxis due to telangiectases of the nasal mucosa; telangiectases on the lips, hands, and oral mucosa; and solid-organ AVMs, particularly of the lungs, liver, and brain. Variants in *GDF2* have been described to result in a vascular-anomaly syndrome phenotypically overlapping with HHT but there is a large phenotypic spectrum from patients meeting HHT as defined by the Curacao criteria to patients displaying only vascular defects with talengectasia and potential AVMs. Thus, 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, 10 variants were scored (missense and frameshift) from 10 probands reported in 8 publications (PMIDs: 23972370, 27081547, 32669404, 34904380, 34611981, 39151291, 40429357, 40930918). 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, in the 129/Ola background, the deletion of Bmp9 is sufficient to induce spontaneous AVMs (PMID: 38502919). 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 originally approved by the ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel on 04/03/2023 (SOP Version 9). It was reevaluated on 06/01/2026 and while new genetic (PMID: 39151291, 40429357, 40930918) and experimental (PMID: 38502919) evidence was identified, it remained at a Moderate classification. 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.

Inheritance Pattern: AR

Disease ID:MONDO:0014217

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0014217

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0014217

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0008535

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0019180

Submitter: Orphanet