Principal Investigators:
Annick Rothschild MD and Azaria J-J.T. Rein MD

Abstract

Congenital heart defects (CHD) occur in about 8/1000 live births and represent the majority of clinically significant birth defects diagnosed. Determination of a specific genetic predisposition has been difficult and led to false results due to prior imprecise phenotype diagnosis. Today echocardiography is mainly used to establish a precise structural diagnosis of the defect. Over the last few years a number of genes have been discovered that are involved in heart development, e.g. TBX 5 in Holt-Oram syndrome. Transcription factors are increasingly recognized as playing key roles in the complex biological processes governing cardiac development.
The murine Nkx2.5 homeobox gene, also independently described as a cardiac-specific homeobox gene (CSX) is a vertebrate homologue of tinman a fruit fly (drosophila) gene. Targeted disruption of tinman results in the absence of the dorsal vessel, an insect equivalent of the vertebrate heart.
Nkx2.5 heterozygous mice have an atrial septal defect (ASD) (20%) together with conduction abnormalities, whereas in the knockout murine model, heart development is arrested at the stage of a primitive linear structure which fails to loop or to develop definitive chambers. Mutations in the Nkx2.5 gene leading to specific cardiac phenotypes have been recently described namely, in ASD, atrio-ventricular blocks, Ebstein anomaly of the tricuspid valve and even cono-truncal malformation such as tetralogy of Fallot. We hypothesize that the possibility to detect new mutations would be significantly increased by screening patients affected by a phenotype which would combine most of the above described defects. Indeed, {S,L,L} transposition of the great arteries (commonly called "corrected transposition of the great arteries") includes 4 of the 5 characteristic defects which have been associated with NKX2.5 gene mutations i.e., 1) VSD, 2) tricuspid valve anomalies (Ebstein or Ebstein-like defects in 30-70% of the cases), 3) AV conduction disturbances and 4) subpulmonic conal obstruction of the left ventricular outflow.
Results of this study of patients with corrected transposition will permit us to further characterize the role of NKX2.5 in cardiac morphogenesis.
In addition, the identification of Nkx2.5 gene mutations in these patients may provide a molecular diagnostic tool. The molecular tools might permit to give a more accurate pre- and postnatal genetic counseling in families at risk