The most common phenotype associated with NKX2.5 mutations are atrial septal defect (ASD) and atrioventricular block (AVB). These abnormalities are highly penetrant, however some patients may have ASD or AVB alone. Many different forms of congenital heart disease can arise from NKX2.5 gene mutations including: ventral septal defect, tetralogy of fallot, hypoplastic left heart, pulmonic stenosis, anomalous pulmonary venous return, tricuspid valve abnormalities, Ebstein’s anomaly, interrupted aortic arch, L-transposition of the great arteries, mitral valve abnormalities, coarctation of the aorta, and double outlet right ventricle. In addition, there are some forms of heart block that also arise from NKX2.5 gene mutations without additional congenital heart disease. Conduction system disease is often seen in individuals with NKX2.5mutations. AVB is the most common manifestation, but the severity and age of onset differs among individuals and can be progressive with age.
Mutations in NKX2.5 cause autosomal dominant non-syndromic congenital heart disease. Recurrence risk for affected individuals and carrier parents is 50%. Not all family members with NKX2.5 mutations have cardiac defects, consistent with decreased penetrance. Thus, individuals with isolated CHD and conduction system disease with or without family history should be considered for this analysis.
To date, no deletions or duplications in the NKX2.5 gene as causative of isolated congenital heart defects have been reported.