The purpose of this study was to estimate the frequency of NKX2.5mutations in specific cardiovascular anomalies and investigate genotype-phenotype correlations in individuals with NKX2.5mutations.

Recent reports have implicated mutations in the transcription factor NKX2.5as a cause of various congenital heart defects (CHD).

We tested genomic deoxyribonucleic acid from 608 prospectively recruited patients with conotruncal anomalies (n = 370), left-sided lesions (n = 160), secundum atrial septal defect (ASD) (n = 71), and Ebstein's malformation (n = 7) for NKX2.5mutations.

Twelve distinct mutations in the NKX2.5coding region were identified in 18 of 608 patients (3%), including 9 of 201 (4%) with tetralogy of Fallot, 3 of 71 (4%) with a secundum ASD, one each with truncus arteriosus, double-outlet right ventricle, L-transposition of the great arteries, interrupted aortic arch, hypoplastic left heart syndrome, and aortic coarctation, but in no patients with D-transposition of the great arteries (n = 86) or valvar aortic stenosis (n = 21). Eleven of the mutations were amino acid-altering missense nucleotide substitutions or deletions, and one was predicted to cause premature termination of translation. None of the mutations were in the homeodomain. Sixteen of the 18 individuals with NKX2.5mutations in this study had no family history of congenital cardiovascular anomalies, and one had first-degree atrioventricular (AV) block.

NKX2.5mutations occur in a small percentage of patients with various CHD. Most of the mutations identified in this study were missense, outside the homeodomain, and not associated with AV block. These findings suggest that NKX2.5mutations in non-homeodomain regions may be important in the development of human structural cardiac defects.