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Sci Rep. 2019 Feb 27;9(1):2959. doi: 10.1038/s41598-019-39648-7.

A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A.

Author information

1
Institute for Cardiogenetics, University Heart Centre Lübeck, University of Lübeck, DZHK (German Research Centre for Cardiovascular Research) partner site Hamburg/Lübeck/Kiel, D-23562, Lübeck, Germany.
2
Department of Cardiovascular Surgery, University Heart Centre Hamburg, D-20246, Hamburg, Germany.
3
Institute of Molecular Biology, Hannover Medical School, D-30625, Hannover, Germany.
4
Institute of Biochemistry and Biology, Potsdam University, D-14476, Potsdam, Germany.
5
Center for Public Health Genomics, University of Virginia, Charlottesville, VA, 22903, USA.
6
Institute of Anatomy and Embryology, UMG, Göttingen University, D-37075, Göttingen, Germany.
7
Department of Cardiovascular Diseases, German Heart Centre Munich, Technical University of Munich (TUM) and DZHK (German Research Centre for Cardiovascular Research) partner site, D-80636, Munich, Germany.
8
Institute for Cardiogenetics, University Heart Centre Lübeck, University of Lübeck, DZHK (German Research Centre for Cardiovascular Research) partner site Hamburg/Lübeck/Kiel, D-23562, Lübeck, Germany. jeanette.erdmann@uni-luebeck.de.
9
Institute of Molecular Biology, Hannover Medical School, D-30625, Hannover, Germany. salim.seyfried@uni-potsdam.de.
10
Institute of Biochemistry and Biology, Potsdam University, D-14476, Potsdam, Germany. salim.seyfried@uni-potsdam.de.

Abstract

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 nineteen family members carry a familial mutation [NM_004329.2:c.1328 G > A (p.R443H)] which encodes a predicted deleterious variant of BMPR1A. This mutation co-segregates with a linkage region on chromosome 1 that associates with the emergence of severe CHDs including Ebstein's anomaly, atrioventricular septal defect, and others. We show that the continuous overexpression of the zebrafish homologous mutation bmpr1aap.R438H within endocardium causes a reduced AV valve area, a downregulation of Wnt/ß-catenin signalling at the AV canal, and growth of additional tissue mass in adult zebrafish hearts. This finding opens the possibility of testing genetic interactions between BMPR1A and other candidate genes within linkage region 1 which may provide a first step towards unravelling more complex genetic patterns in cardiovascular disease aetiology.

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