Doctor's Name: 
Bezzina, Connie, PhD
Doctor's Name 2: 
Mulder, Barbara, MD
Academic Medical Center, Amsterdam, The Netherlands

Transposition of the great arteries (TGA) is a severe and life-threatening congenital (present at birth) heart defect (CHD). In this disorder, the aorta is connected to the right ventricle whereas the pulmonary artery is connected to the left ventricle: the opposite of a normal heart's anatomy. Because of this ‘swap’ two separate circuits are formed that do not mix: one that circulates oxygen-poor blood from the body back to the body, and another that recirculates oxygen-rich blood from the lungs back to the lungs.  The ‘arterial switch’ surgical procedure, which corrects the defect within the neonatal period, has led to a spectacular increase in life expectancy of individuals with TGA. However, survival of TGA patients into adulthood has brought with it new challenges in clinical management:

(1) Many TGA patients now live to reproductive age and our current lack of knowledge about the genetic underpinnings of TGA constitutes a major obstacle for reproductive counseling in these patients;

(2) The course of the disease and the type and severity of long-term clinical complications varies among TGA patients; however, it has been proven difficult to predict who will develop clinical complications and how severe these will be. We hypothesize that the nature and severity of late complications in TGA patients depends, at least in part, on the type of genetic defect causing TGA.

Progress on these two fronts is currently hindered by the current gap in knowledge concerning the genetic causes of TGA.

Novel methods of reading the DNA (genetic code) that have lately become available (so called next-generation sequencing, NGS) are now expected to provide an important impetus to the discovery of genes causing TGA, even in cases where there is no familial clustering. In this project we aim to use these technologies in a large set of patients with TGA (1600 patients) to identify the underlying genetic factors. In one approach we shall compare changes in the DNA sequence between the 1600 patients and a large sample from the general population to identify genetic variants that are more prevalent in the patients. In a second approach we shall study 30 affected child-parent trios to identify variants that have arisen in the affected child (so called de novo mutations) or which are inherited from both the father and the mother (so called recessive inheritance). Importantly, in the latter approach we shall study the ‘non-coding’ part of the genome, which although constituting 98% of our genome, is so far unexplored.

We expect that the results of our project will provide insight into the inheritance and genetics of TGA and will ultimately improve reproductive counseling and long-term treatment/management in patients with this disorder.

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