Atrial septal defect (ASD) is a common cardiovascular malformation, affecting over 1 in 1000 live births, accounting for 10% of congenital heart defects (CHD).¹ ASD refers to a communication between the right and left atria, anatomically classified into the deficient atrial septum structure. ASD ostium secundum (ASDos) is the prevalent defect, representing 85% of all ASDs.² ASD may be isolated or associated with other CHDs, such as pulmonary valve stenosis (PVS), ventricular septal defect (VSD), or conduction defects. In addition, persistent left to right blood shunt may result in atrial and ventricular dysfunctions and atrial arrhythmias, in the absence of surgical or catheter based repair.

The atrial septum is one of the cardiac structures most sensitive to environmental or genetic factors. Several lines of evidence have highlighted a role for different proteins and transcription factors in the septogenesis process;³ however, only two genes, encoding for the transcription factors NKX2.5 and GATA4, have been implicated so far in non-syndromic ASDs.^4,5 Clinical and molecular analyses have shown that mutations in these two genes are responsible for ASDs in association with distinct cardiac features.^4–15 Mutations in NKX2.5, a member of the NK-2 class of homeobox genes, have been described in autosomal dominant ASDos with progressive atrioventricular (AV) block, and in 1–4% of sporadic ASD patients.^4,6–12 Most of these mutations occur within the homeodomain, a critical protein domain that interacts specifically with DNA, and are associated with conduction anomalies. Low penetrance NKX2.5 gene mutations, mainly outside the homeodomain, have been found in 5% of patients with tetralogy of Fallot, and in a number of individuals with other CHDs and normal conduction.^4,6,9–13 Recently, heterozygous mutations in the GATA4 zinc finger transcription factor gene have been identified in three families with …