A novel stop mutation truncating critical regions of the cardiac transcription factor NKX2-5 in a large family with autosomal-dominant inherited congenital heart disease.

We report on a familial screen of five female members in three generations affected by an autosomal-dominant inherited atrioventricular (AV) conduction block associated with atrial septal defects (ASD) and other congenital cardiovascular diseases (CCVD), such as pulmonary artery stenosis (PAS), patent foramen ovale (PFO) and ventricular septal defect (VSD). We tested the cardiac transcription factor NKX2-5 which is known to cause CCVD with variable phenotype and penetrance by direct sequencing of the two NKX2-5 coding exons in the index patient and identified a novel heterozygous c.325G> T mutation in exon 1 of the gene. This mutation co-segregated with the disease in the family and was present in all five affected family members, but not in 100 control chromosomes. The c.325G > T mutation is predicted to introduce a stop codon at amino-acid position 109 (p.E109X). The truncated protein lacks all of the functionally important domains of the cardiac transcription factor. Therefore, it is very likely that this novel mutation causes a complete loss of NKX2-5 function and haploinsufficiency is the pathophysiological mechanism underlying the disease in the family.