Dw. Benson et al., Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways, J CLIN INV, 104(11), 1999, pp. 1567-1573
Heterozygous mutations in NKX2.5, a homeobox transcription factor, were rep
orted to cause secundum atrial septal defects and result in atrioventricula
r (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, idiopa
thic AV block, or tetralogy of Fallot. We identified 7 novel mutations by s
equence analysis of the NKX2.5-coding region in 26 individuals. Associated
phenotypes included AV block, which was the primary manifestation of cardia
c disease in nearly a quarter of affected individuals, as well as atrial se
ptal defect and ventricular septal defect. Ventricular septal defect was as
sociated with tetralogy of Fallot or double-outlet right ventricle in 3 ind
ividuals. Ebstein's anomaly and other tricuspid valve abnormalities were al
so 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 variou
s congenital heart defects suggests that this transcription factor contribu
tes to diverse cardiac developmental pathways.