Novel Point Mutations in the NKX2.5 Gene in Pediatric Patients with Non-Familial Congenital Heart Disease

: Congenital heart disease (CHD) is the most common birth abnormality in the structure or function of the heart that affects approximately 1% of all newborns. Despite its prevalence and clinical importance, the etiology of CHD remains mainly unknown. Somatic and germline mutations in cardiac specific transcription factor genes have been identified as the factors responsible for various forms of CHD, particularly ventricular septal defects (VSDs), tetralogy of Fallot (TOF), and atrial septal defects (ASDs). p. NKX2.5 is a homeodomain protein that controls many of the physiological processes in cardiac development including specification and proliferation of cardiac precursors. The aim of our study was to evaluate the gene mutations in sporadic pediatric patients with clinical diagnosis of congenital heart malformations. : In this study, we investigated mutations of the gene's coding region in 105 Iranian pediatric patients with non-familial CHD by polymerase chain reaction-single stranded conformation polymorphism (PCR-SSCP) and direct sequencing. : We observed a total of four mutations, of which, two were novel DNA sequence variants in the coding region of exon 1 (c. 95 A > T and c. 93 A > T) and two others were previously reported as single-nucleotide polymorphisms (SNPs), namely rs72554028 (c. 2357 G > A) and rs3729753 (c. 606 G > C) in exon 2. Further, observed mutations are completely absent in normal healthy individuals ( = 92). : These results suggest that mutations are highly rare in CHD patients. However, in silico analysis proves that c.95 A > T missense mutation in gene is probably pathogenic and may be contributing to the risk of sporadic CHD in the Iranian population.