Commentary on “Ineffectiveness of Sotatercept Therapy in a Patient with Heritable Pulmonary Arterial Hypertension Associated with a Previously Unreported Missense Variant in GDF2, the Gene for Bone Morphogenic Protein-9”

Author Contributions

Author contributions: S.-F.L.: Methodology, Formal analysis, Writing—original draft; M.-Y.H.: Methodology, Writing—original draft; W.M.K.: Conceptualization, Methodology, Supervision, Writing—review & editing.

Ethics Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Funding

This research received no external funding.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

[1] Langleben D, Lesenko L, Fox BD, Eintracht S, Foulkes WD, Rosenblatt DS. Ineffectiveness of Sotatercept Therapy in a Patient With Heritable Pulmonary Arterial Hypertension Associated With a Previously Unreported Missense Variant in GDF2, the Gene for Bone Morphogenic Protein-9. Chest 2025, 167, e37-e39.

[2] Wang G, Fan R, Ji R, Zou W, Penny DJ, Varghese NP, et al. Novel homozygous BMP9 nonsense mutation causes pulmonary arterial hypertension: a case report. BMC Pulm. Med. 2016, 16, 17.

[3] Gräf S, Haimel M, Bleda M, Hadinnapola C, Southgate L, Li W, et al. Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. Nat. Commun. 2018, 9, 1416.

[4] Eyries M, Montani D, Nadaud S, Girerd B, Levy M, Bourdin A, et al. Widening the landscape of heritable pulmonary hypertension mutations in paediatric and adult cases. Eur. Respir. J. 2019, 14, 53.

[5] Wang XJ, Lian TY, Jiang X, Liu SF, Li SQ, Jiang R, et al. Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension. Eur. Respir. J. 2019, 3, 53.

[6] Hodgson J, Swietlik EM, Salmon RM, Hadinnapola C, Nikolic I, Wharton J, et al. Characterization of GDF 2 Mutations and Levels of BMP9 and BMP10 in Pulmonary Arterial Hypertension. Am. J. Respir. Crit. Care Med. 2020, 201, 575-585.

[7] van den Heuvel LM, Jansen SM, Alsters SI, Post MC, van der Smagt JJ, Handoko-De Man FS, et al. Genetic Evaluation in a Cohort of 126 Dutch Pulmonary Arterial Hypertension Patients. Genes 2020, 11, 1191.

[8] Hernandez-Gonzalez I, Tenorio-Castano J, Ochoa-Parra N, Gallego N, Pérez-Olivares C, Lago-Docampo M, et al. Novel Genetic and Molecular Pathways in Pulmonary Arterial Hypertension Associated with Connective Tissue Disease. Cells. 2021, 10, 1488.

[9] Hodgson J, Ruiz‐Llorente L, McDonald J, Quarrell O, Ugonna K, Bentham J, et al. Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an “HHT-like” syndrome in children. Mol. Genet. Genomic Med. 2021, 9, e1685.

[10] Zhu N, Swietlik EM, Welch CL, Pauciulo MW, Hagen JJ, Zhou X, et al. Correction to: Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH. Genome Med. 2021, 13, 106.

[11] Eichstaedt CA, Saßmannshausen Z, Shaukat M, Cao D, Xanthouli P, Gall H, et al. Gene panel diagnostics reveals new pathogenic variants in pulmonary arterial hypertension. Respir. Res. 2022, 23, 74.

[12] Chomette L, Hupkens E, Romitti M, Dewachter L, Vachiery JL, Bailly S, et al. Pediatric pulmonary arterial hypertension due to a novel homozygous GDF2 missense variant affecting BMP9 processing and activity. Am. J. Med. Genet. A 2023, 191, 2064-2073.

[13] 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. A 2023, 191, 228-233.

[14] Long L, Ormiston ML, Yang X, Southwood M, Gräf S, Machado RD, et al. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat. Med. 2015, 21, 777-785.

[15] Hoeper MM, Badesch DB, Ghofrani HA, Gibbs JS, Gomberg-Maitland M, McLaughlin VV, et al. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N. Engl. J. Med. 2023, 388, 1478-1490.

[16] Guignabert C, Savale L, Boucly A, Thuillet R, Tu L, Ottaviani M, et al. Serum and Pulmonary Expression Profiles of the Activin Signaling System in Pulmonary Arterial Hypertension. Circulation 2023, 147, 1809-1822.

[17] Grynblat J, Bogaard HJ, Eyries M, Meyrignac O, Savale L, Jaïs X, et al. Pulmonary vascular phenotype identified in patients with GDF2 (BMP9) or BMP10 variants: an international multicentre study. Eur. Respir. J. 2024, 4, 63.