New Gene Mutations Identified in Heritable Pulmonary Arterial Hypertension - Pulmonology Advisor

January 28, 2019

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A gene panel was designed to focus on all exons and included BMPR-2, EIF2AK4, TBX4, CAV1, SMAD9, KCNK3, ACVRL1, BMP9, ENG, and BMP10.

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 TBX4, BMP9, 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- 2, EIF2AK4, TBX4, CAV1, SMAD9, KCNK3, ACVRL1, BMP9, ENG, 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.

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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.

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.

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

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