Haplotype-sharing analysis implicates chromosome 7q36 harboring DPP6 in familial idiopathic ventricular fibrillation.
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.
Alders
Marielle
M
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
Koopmann
Tamara T
TT
Christiaans
Imke
I
Postema
Pieter G
PG
Beekman
Leander
L
Tanck
Michael W T
MW
Zeppenfeld
Katja
K
Loh
Peter
P
Koch
Karel T
KT
Demolombe
Sophie
S
Mannens
Marcel M A M
MM
Bezzina
Connie R
CR
Wilde
Arthur A M
AA
D000328:Adult; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D016757:Death, Sudden, Cardiac / Q000209:etiology; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D004562:Electrocardiography; D005260:Female; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010447:Peptide Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D014693:Ventricular Fibrillation / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D055815:Young Adult
D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D012333:RNA, Messenger; C503535:DPP6 protein, human; D010447:Peptide Hydrolases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases