19285295

pubmed:Citation

4

Idiopathic Ventricular Fibrillation (IVF) is defined as spontaneous VF without any known structural or electrical heart disease. A family history is present in up to 20% of probands with the disorder, suggesting that at least a subset of IVF is hereditary. A genome-wide haplotype-sharing analysis was performed for identification of the responsible gene in three distantly related families in which multiple individuals died suddenly or were successfully resuscitated at young age. We identified a haplotype, on chromosome 7q36, that was conserved in these three families and was also shared by 7 of 42 independent IVF patients. The shared chromosomal segment harbors part of the DPP6 gene, which encodes a putative component of the transient outward current in the heart. We demonstrated a 20-fold increase in DPP6 mRNA levels in the myocardium of carriers as compared to controls. Clinical evaluation of 84 risk-haplotype carriers and 71 noncarriers revealed no ECG or structural parameters indicative of cardiac disease. Penetrance of IVF was high; 50% of risk-haplotype carriers experienced (aborted) sudden cardiac death before the age of 58 years. We propose DPP6 as a gene for IVF and increased DPP6 expression as the likely pathogenetic mechanism.

eng

IM

MEDLINE

1537-6605

Electronic

NLM

468-76

pubmed-meshheading:19285295-Adult, pubmed-meshheading:19285295-Case-Control Studies, pubmed-meshheading:19285295-Chromosome Mapping, pubmed-meshheading:19285295-Chromosomes, Human, Pair 7, pubmed-meshheading:19285295-Death, Sudden, Cardiac, pubmed-meshheading:19285295-Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, pubmed-meshheading:19285295-Electrocardiography, pubmed-meshheading:19285295-Female, pubmed-meshheading:19285295-Gene Expression, pubmed-meshheading:19285295-Genome-Wide Association Study, pubmed-meshheading:19285295-Haplotypes, pubmed-meshheading:19285295-Humans, pubmed-meshheading:19285295-Male, pubmed-meshheading:19285295-Middle Aged, pubmed-meshheading:19285295-Myocardium, pubmed-meshheading:19285295-Nerve Tissue Proteins, pubmed-meshheading:19285295-Pedigree, pubmed-meshheading:19285295-Peptide Hydrolases, pubmed-meshheading:19285295-Polymorphism, Single Nucleotide, pubmed-meshheading:19285295-Potassium Channels, pubmed-meshheading:19285295-RNA, Messenger, pubmed-meshheading:19285295-Risk Factors, pubmed-meshheading:19285295-Ventricular Fibrillation, pubmed-meshheading:19285295-Young Adult

Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation.

Journal Article, Research Support, Non-U.S. Gov't