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

Abstract

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.

• Authors: Marielle Alders, Tamara T Koopmann, Imke Christiaans, Pieter G Postema, Leander Beekman, Michael W T Tanck, Katja Zeppenfeld, Peter Loh, Karel T Koch, Sophie Demolombe, Marcel M A M Mannens, Connie R Bezzina, Arthur A M Wilde
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 84 Issue 4 Pg. 468-76 (Apr 2009) ISSN: 1537-6605 [Electronic] United States
• PMID: 19285295 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Tissue Proteins
• Potassium Channels
• RNA, Messenger
• DPP6 protein, human
• Peptide Hydrolases
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases

Topics

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