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Heterozygous mutations in NKX2.5, a homeobox transcription factor, were reported to cause secundum atrial septal defects and result in atrioventricular (AV) conduction block during postnatal life. To further characterize the role of NKX2.5 in cardiac morphogenesis, we sought additional mutations in groups of probands with cardiac anomalies and first-degree AV block, idiopathic AV block, or tetralogy of Fallot. We identified 7 novel mutations by sequence analysis of the NKX2.5-coding region in 26 individuals. Associated phenotypes included AV block, which was the primary manifestation of cardiac disease in nearly a quarter of affected individuals, as well as atrial septal defect and ventricular septal defect. Ventricular septal defect was associated with tetralogy of Fallot or double-outlet right ventricle in 3 individuals. Ebstein’s anomaly and other tricuspid valve abnormalities were also present. Mutations in human NKX2.5 cause a variety of cardiac anomalies and may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block. The coinheritance of NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways.


Article written by researchers from the Division of Pediatric Cardiology, Medical University of South Carolina;Division of Pediatric Cardiology, UHN 60 - Oregon Health Sciences University;Division of Pediatric Cardiology, Vanderbilt University Medical Center;Division of Pediatric Cardiology, University of Kentucky;Division of Pediatric Cardiology and Division of Medical Genetics, Department of Pediatrics, Washington University;Department of Genetics, Howard Hughes Medical Institute;Division of Pediatric Cardiology, University of New Mexico;and Division of Pediatric Cardiology, University of Nebraska and Creighton University. Published in the Journal of Clinical Investigation, December 1999, volume 104, number 11, pages 1567-1573. Includes abstract, references, tables, diagrams, and color photographic illustrations.