Background: Globally, 1% of all live births are affected by some form of congenital heart anomaly. Genetics and the environment both play a role in its causation, but very few of these aspects have been explored in the Indian subcontinent. One of the first and key transcription factors required for the formation of the heart during fetal development is NKX2-5. Several mutations in this gene have been identified for CHDs. In this study, we screened for known and novel variants to understand their role in CHDs.

Methods: Two exons and flanking 3’ and 5’ UTR regions of NKX2-5 were sequenced in n= 71 CHD cases, followed by a case–control test of association and a haplotype study.

Results: Only three known variants, namely rs2277923 (c.63A> G), rs3729753 (c.606G>C), and rs703752 (c.61G>T), were identified in a total of n= 69 cases. The case–control test of association revealed no significant allelic or haplotypic association. A genotypic association was observed for rs703752 in a recessive model (χ2 = 4.4702; p=0.03; risk score=0.33), along with a trend of association for rs3729753 (χ2 = 3.73; p=0.053; risk score=1.68) and rs703752 (p=0.082).

Discussion: Although we did not identify any new mutations in the coding regions of NKX2-5 gene, our findings are important observations for establishing an association between NKX2-5 variants and cardiac defects in the context of the north Indian population. There is a need to explore the roles of other transcription factors and cardiac developmental pathways and establish their interaction and role in disease biology in the Indian subcontinent.