Two siblings diagnosed with pulmonary arterial hypertension (PAH) presented with a rare homozygous missense pathogenic variant in GDF2, the gene encoding bone morphogenetic protein 9 (BMP9).

The case report was published in the American Journal of Medical Genetics Part A.

“We recently presented the first plasma BMP9 measurements in 2 children with homozygous GDF2 nonsense variants, 1 child with PAH and the other with diffuse pulmonary artery venous malformations, both with atypical facial telangiectasias,” the authors said. “Here, we add to this rare genetic cohort, showing that 2 pediatric siblings with homozygous p.S320C missense variants have PAH and an absence of measurable BMP9.”

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The mutation was shown to impair BMP9 proprotein processing and reduce growth factor domain availability. Neither of the siblings had detectable levels of BMP9, whereas their parents, who were heterozygous for the variant, showed low BMP9 levels compared with sex-matched controls.

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On the other hand, the levels of BMP10 were detectable and the authors observed serum-dependent endothelial BMP activity. BMP10 was investigated because previous studies suggested a correlation between the circulating levels of BMP9 and BMP10, as well as the potential occurrence of BMP9/BMP10 heterodimers.

The 2 siblings, a boy and a girl, were diagnosed with idiopathic PAH at 3 months and 4 years of age, respectively. The boy was classified as World Health Organization class 2 as he complained of shortness of breath with exercise. He remained stable on therapy up to the time of blood sampling for the study at 11 years old. His sister was 8 years old by that time.

The parents were apparently healthy, with normal right and left ventricles on echocardiographic assessment. Moreover, they had no family history of epistaxis, telangiectasias, or arteriovenous malformations.


Upton P, Richards S, Bates A, Niederhoffer KY, Morrell NW, Christian S. A rare homozygous missense GDF2 (BMP9) mutation causing PAH in siblings: does BMP10 status contribute? Am J Med Genet Part A. Published online October 19, 2022. doi: