BMP10 – Pulmonary Arterial Hypertension

Heterozygous variants in BMP10 have been identified as a rare cause of autosomal-dominant pulmonary arterial hypertension (PAH) through independent pediatric and adult cohorts. Initial whole-exome sequencing of 18 childhood-onset PAH probands revealed BMP10 as a novel risk gene in one individual (PMID:33187088). A targeted panel of 26 PAH/PVOD genes in 263 unselected cases identified two sporadic female PAH patients harboring BMP10 truncating or predicted loss-of-function variants (PMID:30578383). An international multicentre registry of 26 PAH patients further detected four additional carriers of heterozygous BMP10 variants (prevalence 0.4%) with severe hemodynamic compromise; two underwent lung transplantation demonstrating classic PAH histopathology (PMID:38514094).

All BMP10 variants reported in PAH are rare, heterozygous, and predicted to abrogate protein function, consistent with haploinsufficiency. Across three independent studies, at least seven unrelated PAH probands have been reported with BMP10 variants; none have documented segregation beyond the proband and all variants are absent from population controls. This cumulative evidence supports a pattern of autosomal-dominant inheritance with incomplete penetrance and no recurrent founder alleles.

Mechanistic studies corroborate a loss-of-function model. In vitro assays demonstrate that BMP10 binds endoglin with high affinity, modulating TGF-β signaling in endothelial cells (PMID:21737454). Bmp10-conditional knockout mice under chronic hypoxia exhibit cardiac remodeling and altered pulmonary vascular resistance, mirroring human PAH features (PMID:34086873). Plasma measurements in PAH patients with GDF2 mutations revealed significantly reduced BMP10 levels, linking BMP10 insufficiency to disease severity (PMID:31661308).

No studies to date have refuted this association, and the concordant genetic and functional data satisfy ClinGen criteria for a Moderate gene–disease relationship. Additional family studies and segregation analyses are needed to attain a definitive classification. BMP10 testing can inform molecular diagnosis and guide early surveillance in at-risk individuals.

Key Take-home: BMP10 haploinsufficiency underlies a rare form of autosomal-dominant PAH, supporting its inclusion in clinical gene panels for molecular diagnosis.

References

• Genes • 2020 • Whole Exome Sequence Analysis Provides Novel Insights into the Genetic Framework of Childhood-Onset Pulmonary Arterial Hypertension. PMID:33187088
• The European respiratory journal • 2019 • Widening the landscape of heritable pulmonary hypertension mutations in paediatric and adult cases. PMID:30578383
• The European respiratory journal • 2024 • Pulmonary vascular phenotype identified in patients with GDF2 (BMP9) or BMP10 variants: an international multicentre study. PMID:38514094
• The Journal of biological chemistry • 2011 • Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth. PMID:21737454
• Cardiovascular research • 2022 • Different cardiovascular and pulmonary phenotypes for single- and double-knock-out mice deficient in BMP9 and BMP10. PMID:34086873
• 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

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