We sought to examine the importance of mutations in the cardiac transcription factor gene NKX2-5in patients with an atrial septal defect (ASD), patent foramen ovale (PFO), or hypoplastic left heart syndrome (HLHS).

Mutations in NKX2-5have been found in families showing secundum ASD and atrioventricular (AV) conduction block and in some individuals with tetralogy of Fallot. The prevalence of NKX2-5mutations in sporadic cases of ASD/PFO and other forms of congenital heart disease is unknown.

A cohort of 146 individuals with secundum ASD, PFO complicated by paradoxical embolism, or HLHS were evaluated. Patients with ASD or PFO were ascertained irrespective of family history or associated cardiac abnormalities. The coding region of the NKX2-5locus was amplified by polymerase chain reaction and sequenced.

Among 102 ASD and 25 PFO patients screened, 13 patients (10%) had a positive family history and 5 patients (4%) had AV conduction block. We found one previously documented NKX2-5missense mutation, T178M, in members of a family with ASD without AV conduction block. One NKX2-5mutation-positive child from this family had HLHS, although no mutations were subsequently found in 18 patients with sporadic or familial HLHS. In a second ASD family without AV conduction block, we found a missense change, E21Q, previously reported as pathogenic. Because this change did not segregate with disease status, we propose that it is a non-disease–causing polymorphism.

Our findings suggest that NKX2-5mutations are a relatively infrequent cause of sporadic ASD and HLHS. Screening for NKX2-5mutations may be warranted in individuals with ASD and a positive family history, irrespective of the presence or absence of AV conduction block.