Familial Idiopathic Ventricular Fibrillation Linked to Chromosome 7q36 Harboring DPP6

Abstract

Background: Until recently it was impossible to identify presymptomatic family members at risk for fatal events in familial idiopathic ventricular fibrillation (IVF). We uncovered a large IVF-family and linked their arrhythmic events to a new arrhythmia gene on chromosome 7q36: DPP6. Methods and Results: We studied 169 carriers and 195 non-carriers. ECGs and echocardiography were normal. All-cause mortality or IVF/resuscitation occurred in 67 carriers and 7 non-carriers (no IVF/resuscitation). At 62 years of age, 50% of carriers had an event (p<0.001), the youngest 16 years old, males earlier than females (56 vs. 72 years, p<0.001). IVF was always elicited by monomorphic short-coupled extrasystoles from the right ventricular apex/lower free wall and an origin in the Purkinje network was suspected. Expression-studies showed overexpression of DPP6 mRNA in carriers (p<0.01). Expression-studies in non-diseased explanted human hearts showed higher DPP6 mRNA expression in Purkinje fiber than in any other region (p<0.01). Conclusions: A new arrhythmia gene on chromosome 7q36, DPP6, is linked to familial IVF and shows a very malignant phenotype. Short-coupled extrasystoles from the right-ventricular apex/free wall, presumably originating from the Purkinje network, trigger IVF. For the first time, only genetic predisposition can be used as a risk-marker for future events in IVF.