P933Novel missense variant in DPP6 in familial ventricular fibrillation
Authors: Rossetti A , Spatjens R L H , Seyen S R , Helderman-Van Den Enden A T J , Wilde A A M , Volders P G A 
Published: June 2020

Abstract

Funding Acknowledgements
This work was supported by an ESC Research Grant to A.R., and by The Netherlands CardioVascular Research Initiative (CVON PREDICT2), Den Haag, The N

Background
The DPP6 gene, encoding dipeptidyl aminopeptidase-like protein-6, has been associated with familial ventricular fibrillation (VF) and early repolarization. The DPP6 protein is part of the macromolecular Ito-channel complex and functionally expressed in ventricular myocytes (VM) and Purkinje cells (PC). Here we report a novel missense variant in DPP6 identified in a family with sudden cardiac death/arrest due to VF.

Purpose
To examine the consequences of the novel DPP6 variant c.821G &gt; A, p.(R274H) for cardiac Ito and their potential contribution to a VF substrate.

Methods: Clinical
Co-segregation of DPP6-R274H with major adverse cardiac events in the family members was investigated. Ambulatory ECGs, echocardiograms, exercise tests and ICD recordings were systematically analyzed.

Cellular
Chinese hamster ovary cells were transiently transfected with Ito α and β subunits in order to mimic the VM (Kv4.3 + KChIP2) or the PC phenotype (Kv4.3 + NCS1). Additionally, DPP6 wild type (WT) or variant was transfected. Ito was assessed by patch clamping.

Results: Clinical
DPP6-R274H, affecting a conserved region in the extracellular protein domain segregated with an autosomal dominant pattern of inheritance. The female index patient experienced first VF at 17 years, and subsequent ICD therapy, after her brother had died suddenly at 13 years. Both carriers were also known with mitral-valve prolapse (MVP), but otherwise without structural heart disease. A third sibling without arrhythmia, but with mild MVP, did not carry the DPP6 variant. No other pathogenic mutations were found by next generation sequencing in the index patient. ECGs of the index patient revealed dynamic early repolarization, U waves with varying amplitudes and pause-dependent prominence, and &gt;8000/24 h superimposed premature ventricular complexes (PVCs) and (non)sustained VT. PVCs (QRS duration 120 ms) displayed both a left posterior (80%) and anterior (20%) fascicular origin. PVC burden was higher during daytime and exercise, with pause-dependent occurrence.

Cellular
In the PC model DPP6-R274H markedly decreased Ito density (at +30 mV: 291 pA/pF vs 995 pA/pF in WT; p &lt; 0.001), whereas it did not in the VM model. In VM, but not in PC, Ito inactivation was slowed by the variant (Tau at 0 mV: 91 ms vs 49 ms in WT; p &lt; 0.001).

Conclusions
The novel DPP6 variant R274H has differential effects on Ito in cellular models of VM versus PC. Our main finding of a loss-of-function in the PC model combined with a slowed Ito inactivation in the VM phenotype may exaggerate electrical heterogeneity, especially at the PC-VM junction. Ito loss in PC would prolong action-potential duration and promote early afterdepolarizations, consistent with the dynamic patterns of T-U-dispersion and (fascicular) ectopy in the index case. Mechano-electric influences by the MVP further promote arrhythmogenesis.