Research

Genetic Origin of Congenital Cardiac Disease

Scientists conduct research into gene mutations in a 19-member family

A team of German researchers applied the most advanced gene analysis techniques to demonstrate that several genes are responsible for complex congenital cardiac diseases and how these genetic mutations interact. For this, the team observed a 19-member family for many years, of which 12 carried a particular genetic trait. The researchers published their findings in the Scientific Reports journal.

Congenital cardiac diseases are the most common causes of organ malformations found among roughly one percent of newborns. Corrections of such malformations have been improving, which is why many of those affected decide to raise their own families. Physicians and biologists are increasingly interested in the underlying molecular causes of these illnesses, in order to improve their therapeutic and diagnostic options.

Interplay among several gene mutations

A host of genes are involved in any congenital cardiac abnormality. Only a small number of such diseases originate from mutations of individual genes, so-called monogenic mutations. A gene is defined as a segment of DNA that provides the coded instructions for synthesis of a protein. There is relatively good evidence that numerous congenital cardiac abnormalities arise from simultaneous mutations of diverse genes. Hence, one of the most urgent challenges in the search for the origins of congenital cardiac diseases is to better comprehend the interactions within this multitude of genetic mutations.

By using the most advanced DNA sequencing techniques to study members of a family, the German team of researchers was also able to identify complex, or multigene, origins. The team then modelled the gene mutations in zebra fish to illustrate how they impact the heart.

The research group included scientists from the University Medical Centre of Hamburg-Eppendorf, Medical University of Hanover, German Heart Centre Munich, University Medical Centre Göttingen, Universität zu Lübeck and the University of Potsdam. The team presented the sequencing data on the family exhibiting a diversity of complex congenital abnormalities, including the Ebstein anomaly, atrioventricular septal defect and others. Of the 19 family members, 12 of them had a family-specific mutation in the BMPR1A gene on chromosome 10. This mutation involves a mutation within the region of chromosome 1, which was previously unknown and which gives rise to these severe cardiac abnormalities.

Smaller cardiac valves in zebra fish

The protein receptor BMPR1A and its ligands are involved in the transfer of chemical signals from the cell membrane to the core, thereby regulating cellular growth and fission as well as activities of certain genes. In zebra fish, it was possible to show that continued overexpression of the human BMPR1A mutation is associated with the development of smaller cardiac valves, leads to reduced regulation of the Wnt/ß-Catenin signal pathway that is crucial for cardiogenesis, and causes tissue excrescence of the cardiac valve. This indicates that BMPR1A is a part of cardiogenesis.

This finding opens up the possibility to test genetic interactions between BMPR1A and other candidate genes within the region of chromosome 1, and thereby identify more complex genetic origins of congenital cardiac abnormalities.

Breakthrough facilitated by modern sequencing processes

Prof. Jeanette Erdmann at our Universität zu Lübeck elucidates: “This study is also a classic example of perseverance in research, since we started way back in 1996 as the first patient from this family was presented at the University Medical Center Regensburg. Rapid technological advancements led to the findings, in this case primarily the next generation sequencing process. Naturally, the unending patience of the family is not to be overlooked.”

Prof. Salim Seyfried from the University of Potsdam added: “Investigations into the zebra fish finally enabled us to prove the relevance of candidate mutations to the disease. This collaboration, with funding from the German Centre for Cardiovascular Research, underpins how important it has become for groups with different expertise to work together on advanced issues in biomedicine.”

The project was funded over the last few years by the REBIRTH Centre of Excellence, German Centre for Cardiovascular Research (DZHK), our Universität zu Lübeck, German Heart Foundation and DFG (German Society of Research).

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For scientific information, please contact:

Prof. Dr Jeanette Erdmann
Universität zu Lübeck / UKSH, Campus Lübeck
Institute for Cardiogenetics
Tel.: (0451) 3101 8300
jeanette.erdmann(at)uni-luebeck(dot)de

Prof. Dr Salim Seyfried
MHH Institute for Molecular Biology and University of Potsdam
Tel.: (0511) 532 5933 or (0331) 977 5540
salim.seyfried@uni-potsdam.de

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Original publication:

A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A. Scientific Reports (2019)