Genetic analysis of the NKX2.5 Arg25Cys mutation in Tetralogy of Fallot: Indian scenario

Tetralogy of Fallot (TOF) is a structural congenital heart defect with functional significance, occurring 1 in 3,300 live births. Several studies have reported mutations in essential transcription factors responsible for the development of TOF. NKX2.5 is a homeobox containing transcription factor, expresses at various stages of heart development. The rationale of this study was to estimate the frequency of NKX2.5 Arg25Cys mutation in TOF children from India. Using PCR-RFLP the frequency was estimated in TOF and controls. Clinical characteristics and maternal data from 84 unrelated TOF patients was collected and evaluated in comparison with 117 healthy individuals. TOF patients were tested for 22q11.2 micro deletion for the inclusion of sporadic cases. In 6% of TOF cases (n=84) a positive family history of congenital heart defects was revealed and 85.7% of children had various clinical symptoms. Significant reproductive history such as abortions, intrauterine and perinatal deaths were seen in 31% (n=26) of patient’s mothers. NKX2.5 Arg25Cys mutation was observed only in TOF children with a frequency of 5.9% TT (homozygous) and 10.7% CT (heterozygous) respectively. None of the controls showed the presence of mutation. Hence the present study concludes that the mutation Arg25Cys was segregated with disease pathology with reduced penetrance and variable expressivity.