A Genetic Variant in DPP10 Linked to Inherited J-Wave Syndrome Associated with Sudden Cardiac Death by Augmentation of Kv4.3 Channel Current

Background Mutations in genes encoding the α ( KCND3 ) and β ( KCNE3 ) subunits of genes encoding the cardiac transient outward potassium (I to ) have been associated with inherited cardiac arrhythmia syndromes such as Brugada syndrome (BrS) and sudden infant death syndromes (SIDS). Here, we identify and characterize a novel genetic variant in DPP10 associated with severe pediatric J-wave syndrome (JWS) characterized by early repolarization syndrome (ERS). Methods and Results The proband, a 14-year-old female, presented with atrial fibrillation. At age 16 she developed accentuated J waves in all ECG leads and multiple episodes of polymorphic ventricular tachycardia/ventricular fibrillation (VT/VF; type 3 ERS), resulting in appropriate ICD shocks. Cilostazol proved effective in quieting VT/VF. She died of an electrical storm at age 21. Genetic screening using Next Gen and Sanger methods uncovered a genetic variant in DPP10 but no variants in any other JWS susceptibility genes. Transversion of thymine for guanine at nucleotide 15 predicted substitution of aspartic acid (D) for glutamine acid (E) at position 5 in exon 1b in the N-terminal of DPP10 . The variation was present in 5 of 448 ethnically matched healthy controls (1.1%). E5 is highly conserved among species. The E5D rare polymorphism was found in the proband's aunt who was asymptomatic but displayed ER pattern in select ECG leads. Wild-type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques at 37°C. Coexpression of KCND3 + KChIP2 + DPP10 /E5D generated Kv4.3 current density (I to ) 169.9% and 70.6% greater compared with KCND3 + KChIP2 + DPP10 /WT when homozygously and heterozygously expressed, respectively (n = 9–12, P to and recovery from inactivation was slower in E5D channels. Quinidine (5 μM) and cilostazol (5 μM) inhibited I to by approximately 50% at +20 mV in E5D channels but less so (20 %) in WT channels. Conclusions Our results provide, for the first time, evidence supporting the hypothesis that DDP10 is a novel susceptibility gene for life-threatening arrhythmias associated with ERS. Our data suggest that DPP10- E5D contributes to generation of a pathogenic substrate by boosting I to and that quinidine and cilostazol serve as therapeutic options in this setting by reducing I to .