Abstract 4407: Haplotype Sharing Analysis Identifies DPP6 as a Novel Gene for Familial Idiopathic Ventricular Fibrillation
Idiopathic Ventricular Fibrillation (IVF) is defined as spontaneous ventricular fibrillation (VF) without any structural or electrical heart disease of known cause. In up to 20% of cases a family history is present, suggesting that at least a subset of IVF is hereditary. No gene has been identified yet and since no cardiac abnormalities are present, family members that are at risk cannot easily be identified. We set out to localize the responsible gene in three families in which multiple individuals died suddenly, or were successfully resuscitated from VF. The families originate from the same area in the Netherlands and are distantly related. This enabled identification of the culprit gene by haplotype sharing analysis in affected individuals. This method identifies chromosomal segments that are identical-by-descent (IBD) and are likely to harbor the disease causing gene. We performed haplotype sharing analysis on DNA samples of three resuscitated patients, one from each family, using the Illumina 317K array. We identified a 2.5 Mb haplotype on chromosome 7q36 that was conserved in all three patients. Subsequent analysis of a group of 42 apparently unrelated IVF/OHCA patients revealed that this haplotype was shared by 7 additional patients, indicating that in approximately 20% of our cohort, IVF is caused by a founder mutation on chromosome 7q36. Haplotyping analysis in these additional families enabled us to narrow down the shared haplotype to 2 Mb. We subsequently analyzed two candidate genes (ACTR3B and DPP6) within this interval. DNA sequence analysis of coding regions from these two genes did not reveal any amino acid changing mutation. However quantitative RT-PCR on biopsies from 3 carriers of the risk haplotype demonstrated a 10 –20-fold increase in DPP6 mRNA levels in the patients compared to controls (n=11). The increase in DPP6 expression was due to increased expression from the risk haplotype allele. In conclusion, we propose DPP6 as a novel gene for IVF. Increased DPP6 expression in the myocardium is a likely pathogenetic mechanism in carriers of the risk haplotype.