BMPR2 – Congenital Heart Disease

Heterozygous missense variants in BMPR2 have been identified in patients with congenital heart disease (CHD), particularly those with pulmonary arterial hypertension (PAH)/CHD syndromes. In a mixed cohort of 40 adults and 66 children with PAH and CHD, six unrelated probands (3 adults, 3 children) with complete type C atrioventricular canals, septal defects, patent ductus arteriosus, partial anomalous pulmonary venous return, and aortopulmonary windows harbored novel BMPR2 missense mutations (6% mutation rate) (PMID:15358693). In a separate study of 294 CHD patients with pulmonary vascular disease (PVD) and 161 without PVD, BMPR2 variants were detected in 22 (7.5%) and 2 (1.2%) individuals, respectively, demonstrating a significant enrichment in the CHD-PVD group (P=0.004) (PMID:27002414). No segregation data are reported, and all variants identified in CHD cohorts are missense substitutions such as c.556A>G (p.Met186Val).

Experimental models support the role of BMP signaling in cardiac morphogenesis. Mouse perturbation of BMP/TGF-β pathway components recapitulates human atrioventricular canal, septal, and conotruncal anomalies analogous to those seen in BMPR2-variant carriers. These in vivo data reinforce a plausible mechanism whereby BMPR2 insufficiency disrupts endocardial-mesenchymal signaling during septation. However, evidence is limited by small sample sizes and absence of familial segregation.

Key Take-Home: While BMPR2 variants occur in a subset of CHD patients with complex septal and conotruncal defects, further studies are needed before routine clinical screening.

References

• The European respiratory journal • 2004 • BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease PMID:15358693
• International journal of cardiology • 2016 • BMPR2 mutation is a potential predisposing genetic risk factor for congenital heart disease associated pulmonary vascular disease PMID:27002414

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