| Several inter-related lines of research related to the genetics of cardiac arrhythmias and predisposition to sudden cardiac death have been developed over recent years. Genetics of monogenic arrhythmia syndromes: Within this line of research, in 2006, using multiplex ligation-dependent probe amplification we identified the first large gene rearrangement consisting of a tandem duplication of 3.7 kb in the KCNH2 gene responsible for Long QT Syndrome in a Dutch family. Mouse models of primary arrhythmia syndromes enabling an integrated approach to the study of arrhythmia mechanisms (NHS 2003B195): In 2006 we reported our findings on a knock-in mouse model we generated carrying the murine equivalent of a founder mutation in the cardiac Na-channel gene (SCN5A). We demonstrated that mice carrying this mutation display bradycardia, right ventricular conduction slowing, and QT prolongation, similar to the human phenotype, demonstrating that the presence of a single SCN5A mutation is indeed sufficient to cause an overlap syndrome of cardiac Na-channel disease. Genetics of acquired (polygenic) arrhythmia syndromes (NHS 2000.059, NHS 2005/T024, Leducq 05 CVD 01): Through this line we identified the first genetic variant controlling cardiac conduction. This is an SCN5A gene promoter haplotype that accounts for a remarkable proportion of variance in conduction parameters and predicts variable response to pharmacological sodium channel blockade in Asians. Furthermore, in 2006 in a case-control study in acute myocardial infarction patients we demonstrated that familial sudden death is an important risk factor for primary ventricular fibrillation. |
