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

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...

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Bibliographic Details
Published in:Scientific reports 2019-02, Vol.9 (1), p.2959-2959, Article 2959
Main Authors: Demal, Till Joscha, Heise, Melina, Reiz, Benedikt, Dogra, Deepika, Brænne, Ingrid, Reichenspurner, Hermann, Männer, Jörg, Aherrahrou, Zouhair, Schunkert, Heribert, Erdmann, Jeanette, Abdelilah-Seyfried, Salim
Format: Article
Language:English
Subjects:
Cardiovascular diseases
Chromosome 1
Congenital diseases
Coronary artery disease
Danio rerio
Heart diseases
Mutation
Rheumatic heart disease
Wnt protein
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Summary: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 bmpr1aa 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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-39648-7