Heritable pulmonary arterial hypertension (PAH) involves mutations in genes other than Bone Morphogenetic Protein Receptor Type 2 (BMPR-2), according to a study published in the European Respiratory Journal. The roles of TBX4BMP9, and BMP10, a new gene in PAH, have been bolstered by this research.

This study included 268 participants with PAH that was familial or sporadic (n=181), induced by toxins or drugs (n=13), linked with a familial history (n=11), or sporadic pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (PVOD/PCH; n=63). A gene panel was designed to focus on all exons and included BMPR- 2EIF2AK4TBX4CAV1SMAD9KCNK3ACVRL1BMP9ENG, and BMP10. Using this gene panel, all genes could receive simultaneous analysis. A non-parametric Mann and Whitney test or chi-squared test was used to compare data, as they were not normally distributed.

Of the 268 participants in the study, 49 had mutations: 19.4% in those with sporadic PAH, 54.5% in those with familial PAH, and 12.5% in those with sporadic PVOD/PCH. The majority of mutations occurred in BMPR-2, with the next highest number in TBX4. Participants with PVOD/PCH exclusively presented with EIF2AK4 biallelic mutations, whereas 1.2% of adults with PAH presented with BMP9 mutations. The BMP10 gene mutation was identified in 2 female participants with PAH.

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The researchers concluded that their findings “confirm that mutations are found in genes beyond BMPR2 in hPAH and emphasize the role of TBX4 and BMP9, and designate BMP10 as a new PAH gene …. Indeed, imputing pathogenic role in [pulmonary arterial hypertension] to heterozygous mutations makes no doubt for major genes such as BMPR-2 and TBX4, but may be more difficult for other genes, for which less data are available on PAH.”

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Disclosures: Certain authors report financial contributions from pharmaceutical companies and other institutions. For a full list of disclosures, see the reference.


Eyries M, Montani D, Nadaud S, et al. Widening the landscape of heritable pulmonary hypertension mutations in pediatric and adult cases [published online December 21, 2018]. Eur Respir J doi:10.1183/13993003.01371-2018