Novel and highly lethal NKX2.5 missense mutation in a family with sudden death and ventricular arrhythmia.

To date, several disease-related mutations in NKX2-5, a cardiac-specific homeobox gene, have been documented in patients with a variety of congenital heart diseases (CHDs). The most commonly reported phenotypes are secundum atrial septal defect (ASD) and atrioventricular conduction disease (AVCD). Reports of sudden cardiac death (SCD) have been attributed to progressive conduction disease preventable with pacemaker therapy. A retrospective chart review of individuals from three generations of a family with a novel NKX2-5 mutation associated with CHD, ventricular arrhythmias, and SCD despite pacemaker therapy was conducted. The review documented NKX2-5 Gln181His missense mutation in 11 phenotypically affected members of a single family with a strong family history of SCD, CHD, and AVCD. Before genotyping, four family members died suddenly, two despite pacemaker therapy. The ages at SCD were respectively 23, 29, 44, and 45 years. Observed phenotypic characteristics of genotype-positive patients included ASD, ventricular septal defect, aortic coarctation, tricuspid atresia, supraventricular tachycardia, progressive AVCD, and ventricular tachycardia documented on implantable cardiac defibrillator (ICD) recording. The age at presentation ranged from 5 months to 44 years, and AVCD was seen as early as infancy. Four phenotypically unaffected family members tested negative for the mutation. The findings of this review strongly suggest a new association of this NKX2-5 mutation with SCD from ventricular arrhythmia. This observation has significant implications for the choice of therapy for affected individuals, specifically the use of ICDs, and broadens the observed phenotypic spectrum of NKX2-5 mutations.