GDF2 – Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy characterized by obliterative remodeling of small pulmonary arteries, leading to elevated pulmonary vascular resistance and right heart failure. Genetic predisposition underlies many heritable and idiopathic PAH cases, with variants in BMPR2 and related TGF-β pathway genes accounting for the majority of familial forms. The NIH ClinGen Expert Panel has classified GDF2, encoding BMP9, as having definitive evidence for causal association with PAH (PMID:37422716).

Autosomal dominant inheritance with incomplete penetrance is the predominant mode for adult PAH–associated GDF2 variants, whereas rare homozygous or compound heterozygous cases present with early-onset severe PAH. To date, 25 unrelated probands have been reported carrying heterozygous or homozygous GDF2 variants: 21 heterozygous carriers in multicenter registries (PMID:38514094), two siblings with homozygous c.946A>G (p.Arg316Gly) (PMID:36259599), one pediatric case with homozygous c.946A>G (p.Arg316Gly) (PMID:37249087), and a single 5-year-old with homozygous c.76C>T (p.Gln26Ter) (PMID:26801773). Segregation analysis identified two affected siblings, consistent with semi-dominant transmission but incomplete penetrance in heterozygous relatives.

The variant spectrum in PAH encompasses loss-of-function changes—nonsense (e.g., c.76C>T (p.Gln26Ter)), frameshift, and splice—and rare missense alleles impairing BMP9 proprotein processing. Recurrent variants include c.329G>A (p.Arg110Gln) in multiple cohorts, and novel variants like c.946A>G (p.Arg316Gly) disrupting the furin cleavage site. Most variants are ultra-rare or private, with no clear founder effect identified.

Functional studies demonstrate that GDF2 mutations cause BMP9 loss of function via impaired secretion and reduced ligand-receptor signaling. In vitro expression of missense mutants shows defective processing and endothelial signaling, with patient plasma exhibiting low BMP9 and BMP10 levels and reduced SMAD-dependent activity (PMID:31661308). Animal models further support pathogenicity: combined Bmp9/Bmp10 knockout in mice leads to pulmonary vascular remodeling and high-output heart failure under hypoxia, mirroring human PAH features (PMID:34086873).

Incomplete penetrance is evidenced by asymptomatic heterozygous carriers in multiple families, suggesting the need for additional genetic or environmental modifiers. No studies have refuted the association, and concordant genetic, biochemical, and in vivo data firmly establish GDF2 as a definitive PAH gene.

Key take-home: Screening for GDF2 variants in PAH patients can inform diagnosis, risk stratification, and guide potential BMP9/BMP10–based therapeutic approaches.

References

• Genetics in Medicine • 2023 • Defining the clinical validity of genes reported to cause pulmonary arterial hypertension PMID:37422716
• The European respiratory journal • 2024 • Pulmonary vascular phenotype identified in patients with GDF2 (BMP9) or BMP10 variants: an international multicentre study PMID:38514094
• American journal of medical genetics. Part A • 2023 • A rare homozygous missense GDF2 (BMP9) mutation causing PAH in siblings: Does BMP10 status contribute? PMID:36259599
• American journal of medical genetics. Part A • 2023 • Pediatric pulmonary arterial hypertension due to a novel homozygous GDF2 missense variant affecting BMP9 processing and activity PMID:37249087
• American journal of respiratory and critical care medicine • 2020 • Characterization of GDF2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension PMID:31661308
• Cardiovascular research • 2022 • Different cardiovascular and pulmonary phenotypes for single- and double-knock-out mice deficient in BMP9 and BMP10 PMID:34086873
• BMC pulmonary medicine • 2016 • Novel homozygous BMP9 nonsense mutation causes pulmonary arterial hypertension: a case report. PMID:26801773

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