A Familial Congenital Heart Disease with a Possible Multigenic Origin Involving a Mutation in BMPR1A

Objectives: The genetics of many congenital heart diseases (CHDs) can only unsatisfactorily be explained by known chromosomal or Mendelian syndromes. Here, we present sequencing data of a family with a potentially multigenic origin of CHD. Twelve of 19 family members carry a familial mutation (NM_004329.2:c.1328G>A [p.R443H]) which encodes a predicted variant of BMPR1A. This mutation cosegregates with a linkage region on chromosome 1 that associates with the emergence of severe CHDs including Ebstein’s anomaly, atrioventricular septal defect, and others. As BMPR1A plays an essential role in cardiac development, we investigated a possible causal connection between BMPR1A^p.R443H and the emergence of CHDs.

Methods: We performed morphological and functional analyses in transgenic zebrafish with an endocardial-specific expression of the homologous zebrafish bmpr1aa gene carrying the equivalent of the human BMPR1A^p.R443H mutation.

Results: The continuous overexpression of the zebrafish homologous mutation bmpr1aa^p.R438H within endocardium causes a reduced AV valve area (p.R443H: 94,639µm², n = 13; WT: 136,352µm², n = 12; p = 0.003) and a downregulation of Wnt/β-catenin signaling at the AV canal of adult zebrafish hearts. Furthermore, electron-microscopic analysis revealed growth of valvular neoplasms in these transgenic zebrafish hearts.

Conclusion: Since endocardial expression of the bmpr1aa^p.R438H mutation corresponded with a reduced AV valve size in zebrafish, this mutation is a candidate for playing a key role in CHD among presented family members. One mechanism by which BMPR1A^p.R443H may cause reduced AV valves could be due to low levels of Wnt signaling, which is a mitogenic trigger at the AV valves. This finding opens the possibility of testing genetic interactions between BMPR1A and other candidate genes within the linkage region on chromosome 1 which may provide a first step toward unraveling more complex genetic patterns in cardiovascular disease etiology.