1. ¹Laboratory of Human Molecular Genetics, Christian de Duve Institute of Cellular Pathology and Université catholique de Louvain, Brussels, Belgium
2. ²Division of Pediatric Cardiology and Cardiology, Cliniques universitaires St Luc, Université catholique de Louvain, Brussels, Belgium
3. ³Center for Human Genetics, University of Leuven, Leuven, Belgium
4. ⁴Department of Human Genetics, University Medical Center St Radboud, Nijmegen, The Netherlands

Correspondence: Dr M Vikkula, Laboratory of Human Molecular Genetics, Christian de Duve Institute of Cellular Pathology and Université catholique de Louvain, Avenue Hippocrate 74+5, bp 75.39, Brussels, B-1200, Belgium. E-mail: vikkula@bchm.ucl.ac.be

Received 15 July 2005; Revised 21 April 2006; Accepted 14 June 2006; Published online 9 August 2006.

Abstract

The prevalence of congenital heart defects is approximately 1% of all live births. Identifying the genes responsible for cardiac malformation is the first step to understand pathogenesis. Heterozygous mutations in the CSX/NKX2-5 (NKX2E) gene have been identified to cause atrial septal defect (ASD) and/or atrioventricular (AV) conduction disturbance in some families. However, there is great variability in expressivity of the phenotype between the patients with a CSX/NKX2-5 mutation.

We screened four sporadic patients and three index cases of families with ASD and/or conduction defects. In one of them, a CSX/NKX2-5 mutation was identified. This novel mutation (p.Tyr256X) was inherited in a three-generation family causing five individuals to have cardiac anomalies ranging from ASD to arrhythmias. Interestingly, all the observed AV conduction disturbances were at the nodal level, manifesting first as an AV block of the first degree and evolving toward a second-degree block. Atrial fibrillation, previously reported in three individuals with CSX/NKX2-5 mutations, was observed in three patients.