Around one per cent of newborn babies have a congenital heart defect – it is the most common organ in which to have an abnormality. Congenital heart disease can be treated and managed better now than ever before - which is why those affected are increasingly becoming adults who can then start their own families. For this reason, doctors and scientists are becoming ever more interested in the causes of these diseases in order to improve diagnosis and treatment.
Interaction of several gene alterations
A large number of genes are involved in causing the formation of the heart. A gene is a portion of DNA that contains the blueprint for a protein. Scientists have identified a small number of congenital heart defects that are caused by an alteration in just one gene, while it is assumed that the majority are caused by a number of alterations in more than one gene, all occurring at the same time. One of the most urgent challenges in the search for the causes of congenital heart defects is therefore to better understand the interaction of these multiple gene changes.
The research team from Germany was able to prove that studying families with the latest DNA sequencing technology can identify complex causes, from more than one gene. They then recreated these genetic changes in zebrafish and were able to show how this affects the heart.
The participating scientists from the University Hospital Hamburg-Eppendorf, the Hanover Medical School, the German Heart Centre Munich, the University Medicine Göttingen, the University of Lübeck and the University of Potsdam are publishing data from a family with different complex congenital heart defects, including the Ebstein anomaly, the atrioventricular septal defect and others. A total of 12 of the 19 family members carry a family-specific variation in the BMPR1A gene on chromosome 10. Furthermore, this variation appears commonly alongside a variation on a region of chromosome 1 and leads to the development of such severe heart abnormalities.
Smaller heart valves in zebrafish
The protein BMPR1A is involved in passing chemical signals from the cell’s membrane to its nucleus and this regulates how the cell grows and divides, as well as the activity of certain genes. In zebrafish, it has now been shown that variations in human BMPR1A are associated with the development of smaller heart valves, lead to changes in a signaling pathway important for heart development (Wnt/ß-catenin signaling), and also cause abnormal tissue growth in the heart valves. This is a clear sign that BMPR1A is involved in heart development.
This finding opens up the possibility of testing the genetic interactions between BMPR1A and other genes within the important region on chromosome 1 and thus detecting more complex genetic causes of congenital heart disease.
Modern sequencing methods led to a breakthrough
Prof. Jeanette Erdmann from the University of Lübeck explains: "The study is a prime example of perseverance in research, because the beginnings date back to 1996, when the first member of the family came to the university hospital in Regensburg. Only the rapid technological developments of the last few years, especially the so-called Next-Generation-Sequencing method, could lead to a positive outcome of the study. In addition, the patience and continuing support from the family was essential.
Prof. Salim Seyfried from the University of Potsdam adds: "The zebrafish studies were absolutely crucial to prove the disease significance of the candidate mutation. This cooperation, funded by the German Centre for Cardiovascular Research, shows how important the interdisciplinary cooperation of working groups has become for modern biomedicine".
The project has been funded by the REBIRTH excellence cluster, the German Centre for Cardiovascular Research (DZHK), the University of Lübeck, the German Heart Foundation and the DFG.
Prof. Dr. Salim Seyfried
MHH Institute of Molecular Biology and University of Potsdam
Telephone (0511) 532 5933 or (0331) 977 5540
Prof. Dr. Jeanette Erdmann
University of Lübeck / UKSH, Campus Lübeck
Institute for Cardiogenetics
Phone: (0451) 3101 8300
Original publication: A familial congenital heart disease with a possible multigenic origin involving a mutation in BMPR1A. Scientific Reports (2019)