rs200330818 — GDF2

Rare missense variant in BMP9/GDF2 that impairs processing of the mature BMP9 ligand, reducing ALK1 vascular signaling and predisposing carriers to hereditary hemorrhagic telangiectasia type 5 (HHT5)

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GDF2 Arg68Leu — When BMP9 Cannot Mature

Your blood vessels are not static pipes. They are living structures continuously reshaped by molecular signals — and one of the most important of those signals in the vascular system is BMP911 BMP9
BMP9 (bone morphogenetic protein 9) is a secreted ligand of the TGF-beta superfamily. Despite the name, it is primarily active in vascular biology, not bone — it is the physiological ligand for the endothelial receptor ALK1 and its co-receptor endoglin. The GDF2 gene encodes BMP9, and the p.Arg68Leu variant — a single amino acid substitution in the prodomain of the protein — disrupts BMP9's ability to mature into its active form, impairs signaling through the ALK1 pathway, and has been linked to a rare vascular malformation syndrome now classified as hereditary hemorrhagic telangiectasia type 5 (HHT5).

HHT is an autosomal dominant disorder affecting an estimated 1 in 5,000 people globally. It is characterized by abnormal blood vessel formations — telangiectases (tiny dilated vessels visible on skin and mucous membranes) and arteriovenous malformations (AVMs) in internal organs including the lungs, liver, and brain. Recurrent nosebleeds (epistaxis) are almost universally the first symptom. GDF2 variants account for a small fraction of HHT cases, and the clinical phenotype of HHT5 overlaps with but differs from the more common HHT1 (ENG) and HHT2 (ACVRL1) forms in ways that have clinical management implications.

The Mechanism

BMP9 is secreted as a large precursor — a prodomain22 prodomain
The prodomain is a regulatory segment that must be cleaved off to release the active mature ligand. For BMP9, the prodomain and the mature domain remain non-covalently associated after cleavage, forming what is called a 'procomplex' attached to a mature signaling domain. Cleavage by furin-family proteases releases the active mature BMP9 dimer, which then binds to ALK1 and its co-receptors (endoglin, BMPR2) on endothelial cell surfaces.

The Arg68 residue sits within the prodomain. In vitro expression studies of the p.Arg68Leu mutant showed that the precursor protein is expressed normally but fails to produce mature BMP9 dimer efficiently33 fails to produce mature BMP9 dimer efficiently
Processing to mature BMP9 was far less efficient for p.Arg68Leu than wild-type protein; in ALK1 signaling assays the variant showed approximately 79% of wild-type activity at 10 pg/ml and 79% at 30 pg/ml equivalent dilutions — a modest but consistent and reproducible reduction. The biological consequence is reduced BMP9/ALK1/SMAD1/5/8 signaling in endothelial cells, which normally suppresses pathological angiogenesis and maintains AV differentiation. Loss of this brake promotes disorganized vascular sprouting, telangiectasia formation, and AV fistula development.

The Evidence

The p.Arg68Leu variant was identified by Wooderchak-Donahue et al. (2013)44 Wooderchak-Donahue et al. (2013)
Wooderchak-Donahue WL et al. Am J Hum Genet 2013 93:530-7 — sequenced 191 patients with suspected HHT who were negative for ENG, ACVRL1, and SMAD4; identified three pathogenic GDF2 missense variants including Arg68Leu in a proband who met clinical HHT criteria (epistaxis and cutaneous telangiectases). The variant co-segregated with disease in family members: the proband's father and sister both carried p.Arg68Leu and reported epistaxis. Functional assays in C2C12 and ATDC5 cells transfected with ALK1 confirmed reduced BMP9 signaling. This variant was absent from 5,400 control exomes, 1000 Genomes, and dbSNP at time of publication, consistent with a rare pathogenic allele under negative selection.

The variant has since been documented in subsequent case literature. A 2025 pediatric HHT cohort study at CHOP identified the p.Arg68Leu variant in one patient (patient 6 in that series), who presented with epistaxis and mucocutaneous telangiectases; the patient's father, carrying the same variant, also had epistaxis — confirming the family segregation pattern originally described.

ClinVar (VCV000088651) classifies the G>T transversion (p.Arg68Leu) as "Likely Pathogenic" for HHT5, based on functional evidence of altered GDF2 protein processing and the clinical presentation of the carrier and affected family members. A second variant at the same codon — p.Arg68His (G>A, ClinVar VCV000646500) — is classified as "Uncertain Significance," highlighting that not every amino acid change at position 68 has the same functional impact.

Separate work has reinforced the dose-sensitivity of BMP9 signaling. Chomette et al. (2023)55 Chomette et al. (2023)
Chomette L et al. Am J Med Genet A 2023 191:2157-2167 — described a child with homozygous GDF2 missense at the cleavage site who had both PAH and HHT features; heterozygous parents were entirely asymptomatic, illustrating how homozygous loss of BMP9 is far more severe than haploinsufficiency showed that BMP9 processing mutations can cause pediatric PAH. Heterozygous parents of the affected child remained asymptomatic, consistent with variable expressivity in GDF2-HHT5 generally.

Practical Actions

HHT5 is actionable: vascular screening detects AVMs before they become symptomatic emergencies. Pulmonary AVMs can cause paradoxical emboli (stroke) and hemoptysis. Brain AVMs risk hemorrhagic stroke. Hepatic AVMs cause high-output heart failure in advanced disease. Screening protocols adapted from HHT1/HHT2 guidelines are applied to GDF2 carriers.

The phenotype of GDF2-HHT5 may be milder and less penetrant than HHT1/HHT2 — some carriers have only epistaxis with no solid organ AVMs. Nonetheless, clinical evaluation and baseline screening are warranted in all confirmed or suspected carriers, as visceral AVMs are present in a meaningful proportion of published cases and can be clinically silent until they cause an acute event.

Genetic counseling is essential: HHT5 is autosomal dominant, meaning each first-degree relative of a carrier has a 50% chance of inheriting the variant. The variable expressivity means a parent with only mild epistaxis can have a child with pulmonary AVMs.

Interactions

GDF2 (BMP9) signals through the same endothelial receptor complex as ENG (HHT1) and ACVRL1/ALK1 (HHT2). Variants in ENG and ACVRL1 that reduce receptor availability or signaling would be expected to compound with GDF2 loss-of-function, though digenic HHT from GDF2 plus ENG/ACVRL1 has not been formally documented in published case series. Similarly, SMAD4 loss-of-function (HHT-juvenile polyposis overlap syndrome) disrupts the downstream effector of the same pathway.

BMPR2 is the type II receptor for BMP9, and pathogenic BMPR2 variants are the most common cause of hereditary pulmonary arterial hypertension (hPAH). GDF2 variants can cause both HHT5 and PAH through reduced BMP9/ALK1 signaling, suggesting that concurrent BMPR2 variants might amplify PAH risk in GDF2 carriers, though this interaction has not been systematically studied.

Genotype Interpretations

What each possible genotype means for this variant.

GG No Arg68Leu Variant Normal

No GDF2 Arg68Leu variant — standard vascular risk from this SNP

You carry two copies of the reference GDF2 allele at this position and do not have the p.Arg68Leu (c.203G>T) variant associated with HHT5. Your risk of hereditary hemorrhagic telangiectasia from this specific GDF2 variant is not elevated. This genotype is found in essentially all of the general population — the T allele is absent from major population databases and present in fewer than 1 in 50,000 individuals in TOPMed data.

GT Arg68Leu Carrier High Risk

Carries one copy of GDF2 Arg68Leu — associated with hereditary hemorrhagic telangiectasia type 5

The p.Arg68Leu substitution replaces arginine — a positively charged, bulky residue — with leucine, a hydrophobic residue, at position 68 of the GDF2 prodomain. This residue is highly conserved across species. In vitro expression studies showed the mutant precursor protein is produced but fails to be cleaved efficiently into the active mature BMP9 dimer. When the mutant was expressed in C2C12 or ATDC5 cells alongside ALK1, BMP9 signaling activity (measured by SMAD1/5/8 phosphorylation and downstream reporters) was approximately 79% of wild-type at physiological ligand concentrations. This is a modest but consistent reduction that, in the context of a haploinsufficiency mechanism, predicts roughly half-normal circulating active BMP9 ligand in carriers.

BMP9 is the principal circulating activating ligand for ALK1 on vascular endothelial cells. ALK1/endoglin/BMPR2 signaling promotes endothelial quiescence, maintains arterial-venous identity, and suppresses pathological angiogenesis. When this pathway is impaired below a threshold, endothelial cells lose their ability to suppress hyperdilated capillary loops and AV connections — the biological substrate of telangiectases and AVMs.

Published cases of p.Arg68Leu carriers show: - Epistaxis: the most consistent feature, present in all identified carriers - Mucocutaneous telangiectases: present in most, though sometimes atypical in distribution (upper body/trunk rather than classic hands/face pattern) - Family segregation: co-segregates with epistaxis in family members - Pulmonary AVM: reported in a subset of GDF2-HHT5 cases - Pulmonary arterial hypertension: elevated frequency in pediatric GDF2-HHT5 cohorts compared to ENG/ACVRL1-related HHT

Clinical penetrance in heterozygotes appears variable and may be lower than in HHT1 or HHT2. The GDF2-HHT5 phenotype was described by GeneReviews as "an overlapping but potentially distinct disorder" from classic HHT. Management parallels HHT protocols adapted for the GDF2-specific risk profile.

TT Homozygous Arg68Leu Homozygous

Carries two copies of GDF2 Arg68Leu — extreme rarity, severe BMP9 signaling impairment expected

You carry two copies of the GDF2 p.Arg68Leu variant, one on each chromosome 10. This genotype has not been described in the published literature — homozygosity would require both parents to carry the variant, which is itself ultra-rare in the general population. By analogy with homozygous variants in other HHT genes (ACVRL1, ENG) and with the related homozygous GDF2 cleavage-site variant described in a pediatric PAH case, complete bilateral loss of functional BMP9 production would be expected to cause severe, early-onset vascular disease including pulmonary arterial hypertension, extensive AVMs, and HHT features significantly more severe than heterozygous carriers. Urgent clinical evaluation is warranted.