Introduction: Mutations in genes encoding the α (KCND3) and β (KCNE3) subunits of genes encoding the cardiac transient outward potassium (Ito) have been associated with inherited cardiac arrhythmia syndromes such as Brugada Syndrome (BrS) and Sudden Infant Death Syndromes (SIDS).
Hypothesis: Novel genetic variant in DPP10 associated with severe pediatric J Wave Syndrome (JWS), IVF and SIDS.
Methods: The proband, a 16 year-old female, presented with atrial fibrillation and atrial septal defect. Subsequently she developed accentuated J waves in all ECG leads leading to repeated episodes of VT/VF (Type 3 ERS). Cilostazol proved effective in quieting VT/VF. She died of an electrical storm at 21 years of old. Genetic screening using Next Gen and Sanger methods uncovered a genetic variant in DPP10 but no variants in any other JWS susceptibility genes.
Results: 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 (E5D). The variation E5D was present in 5 unrelated patients with ERS (2), IVF (1) and BrS (3). E5D is highly conserved among species. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques at 37°C. Co-expression of KCND3+KChIP2+DPP10/E5D generated Kv4.3 current density (Ito) 169.9% and 70.6% greater compared with KCND3+KChIP2+DPP10/WT when homozygously and heterozygously expressed, respectively (n=9-12, p<0.01). Inactivation of Ito and recovery from inactivation was slower in E5D channels. Quinidine (5 μM) and cilostazol (5 μM) inhibited Ito 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 in support for the hypothesis that DDP10 is a novel susceptibility gene for life threatening arrhythmias associated with JWS. Our data suggest that DPP10-E5D contributes to the generation of a pathogenic substrate by boosting Ito and that Quinidine and Cilostazol serve as therapeutic options in this setting by reducing Ito.