Familial congenital heart disease, progressive atrioventricular block and the cardiac homeobox transcription factor gene NKX2.5:

Abstract

D. Woodrow Benson Cincinnati Children’s Hospital Medical Center Cincinnati, OH, USA Sirs: Congenital heart disease has the highest incidence of all birth defects affecting about 6–8/1000 live births. These heart malformations are believed to arise during cardiac development, but there is little known about the underlying mechanisms of disease [12]. Cardiac development is a complex process, and in recent years, the role of transcription factors as possible navigators of development has been frequently investigated [7, 10, 19]. The cardiac transcription factor NKX2.5 was identified as the first genetic cause of nonsyndromic congenital heart disease [22]. A total of 33 heterozygous mutations in NKX2.5 have been reported in individuals with a variety of congenital heart malformations, including atrial septal defect, ventricular septal defect, tetralogy of Fallot and abnormalities of the tricuspid valve [2, 6, 8, 9, 11, 13, 14, 16, 18, 21–23]. Specific types of mutations result in progressive atrioventricular (AV) conduction disturbance, requiring pacemaker implantation. These studies have provided important insight into the genetic origins of cardiac malformations and, by providing tools for the developmental biologist, have contributed to improved insights into the pathogenesis of congenital heart disease [3, 5]. As such, these results are important to pediatricians, cardiologists and surgeons who diagnose, treat and provide longterm follow-up to these patients. Here we report a novel NKX2.5 mutation in a small family where progressive AV block and congenital heart disease was identified in two generations.