Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways

TLDR

Heterozygous NKX2.5 mutations are linked to atrial septal defects and atrioventricular conduction block in post‑neonatal patients. The study aimed to identify additional NKX2.5 mutations in patients with cardiac anomalies and AV block. Seven novel NKX2.5 mutations were detected in 26 individuals, associated with AV block, septal defects, tetralogy of Fallot, and other tricuspid abnormalities, indicating the factor’s role in diverse cardiac developmental pathways.

Abstract

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.