Two novel frameshift mutations in NKX2.5 result in novel features including visceral inversus and sinus venosus type ASD.

Recently, heterozygous mutations of human NKX2.5 were identified in patients with congenital heart disease. 2 The most common phenotypes were progressive atrioventricular conduction delays (AV block) and secundum atrial septal defect (ASD), but other anatomical abnormalities, such as ventricular septal defect, tetralogy of Fallot, or tricuspid valve abnormalities, including Ebstein’s anomaly, and progressive left ventricular failure, were also reported. These findings strongly suggest that NKX2.5 is important in the later stages of heart development and maturation in addition to its role in cardiac progenitor commitment and patterning in the developing heart. To characterise further the genotype-phenotype correlation of NKX2.5 mutations, we used NKX2.5 as a candidate gene in two kindreds where subjects in multiple generations had congenital heart disease and AV block. In this report, we describe phenotypes in two families with novel frameshift mutations in NKX2.5. The findings suggest an expanded population of subjects who could now be examined for mutations within this transcription factor and its upstream and downstream regulatory elements.