One of the essential homeobox transcription factors orchestrating cardiac embryologic development is NKX2-5 (1). Mutations in NKX2-5 were initially discovered in inherited atrial septal defect (ASD) associated with atrioventricular block (AVB)(2), but were further found linked to other congenital heart defects and cardiomyopathies. However, it remains difficult to have a clear idea of the cardiac abnormalities caused by NKX2-5 mutations in large populations.

We describe the cardiac phenotype and long-term prognosis of a nationwide cohort of NKX2-5 mutated patients. This cohort included 50 patients (23 males) from 19 families. Cardiac phenotype was diagnosed at a median of 5 years of age (range: birth to 54 years) and median follow-up was 15 years (range: 0 years to 50 years). During the same period, a total of 450 NKX2. 5 gene screenings were performed. Thus, approximately 90% of the genetic analyses were negative. None of the 50 patients had a normal phenotype, although no cardiac or conduction defect was observed in 14 nonmutated other kindreds, suggesting high penetrance. The most frequent congenital heart defect was ostium secundum ASD (38 patients, 76%). Muscular or perimembraneous ventricular septal defect (VSD) was present in 11 patients (22%; 88% with ASD and/or VSD). No other relevant congenital heart disease was found in our population. Structural cardiomyopathy was observed in 14 patients (28%)(7 left ventricular noncompaction, 4 hypertrophic cardiomyopathy, 2 dilated cardiomyopathy [DCM], 1 restrictive/constrictive) with a preserved left ventricular ejection fraction in 44 of 48 patients. AVB was observed in 45 patients (94%), either at first observation or during follow-up (20 first degree, 12 second degree, and 13 third degree AVB). AVB was not related to ASD, surgery, age, or follow-up duration. Significant sinus bradycardia/pauses were observed in 23%. Electro-physiological investigation (18 patients) revealed suprahisian conduction disturbances (AH and HV intervals 167+ 48 and 47+ 22 ms).