title: Use of whole exome sequencing for the identification of Ito-based arrhythmia mechanism and therapy.
abstract: BACKGROUND
  Identified genetic variants are insufficient to explain all cases of inherited arrhythmia. We tested whether the integration of whole exome sequencing with well-established clinical, translational, and basic science platforms could provide rapid and novel insight into human arrhythmia pathophysiology and disease treatment.
  
  
  RESULTS
  We report a proband with recurrent ventricular fibrillation, resistant to standard therapeutic interventions. Using whole-exome sequencing, we identified a variant in a previously unidentified exon of the dipeptidyl aminopeptidase-like protein-6 (DPP6) gene. This variant is the first identified coding mutation in DPP6 and augments cardiac repolarizing current (Ito) causing pathological changes in Ito and action potential morphology. We designed a therapeutic regimen incorporating dalfampridine to target Ito. Dalfampridine, approved for multiple sclerosis, normalized the ECG and reduced arrhythmia burden in the proband by >90-fold. This was combined with cilostazol to accelerate the heart rate to minimize the reverse-rate dependence of augmented Ito.
  
  
  CONCLUSIONS
  We describe a novel arrhythmia mechanism and therapeutic approach to ameliorate the disease. Specifically, we identify the first coding variant of DPP6 in human ventricular fibrillation. These findings illustrate the power of genetic approaches for the elucidation and treatment of disease when carefully integrated with clinical and basic/translational research teams.
authors.affiliation: The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Internal Medicine, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., P.F.B., R.W., S.V.R., T.J.H., P.J.M.).
authors.forename: Amy C
authors.initials: AC
authors.lastname: Sturm
authors.affiliation: The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (C.F.K., J.C., P.L.J., P.J.M.).
authors.forename: Crystal F
authors.initials: CF
authors.lastname: Kline
authors.affiliation: The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Surgery, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (P.G., A.K., R.D.H.).
authors.forename: Patric
authors.initials: P
authors.lastname: Glynn
authors.affiliation: The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.).
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Johnson
authors.affiliation: The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (C.F.K., J.C., P.L.J., P.J.M.).
authors.forename: Jerry
authors.initials: J
authors.lastname: Curran
authors.affiliation: The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Surgery, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (P.G., A.K., R.D.H.).
authors.forename: Ahmet
authors.initials: A
authors.lastname: Kilic
authors.affiliation: The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Surgery, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (P.G., A.K., R.D.H.).
authors.forename: Robert S D
authors.initials: RS
authors.lastname: Higgins
authors.affiliation: The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Internal Medicine, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., P.F.B., R.W., S.V.R., T.J.H., P.J.M.).
authors.forename: Philip F
authors.initials: PF
authors.lastname: Binkley
authors.affiliation: The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (C.F.K., J.C., P.L.J., P.J.M.).
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.affiliation: The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Internal Medicine, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., P.F.B., R.W., S.V.R., T.J.H., P.J.M.).
authors.forename: Raul
authors.initials: R
authors.lastname: Weiss
authors.affiliation: The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Internal Medicine, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., P.F.B., R.W., S.V.R., T.J.H., P.J.M.).
authors.forename: Subha V
authors.initials: SV
authors.lastname: Raman
authors.affiliation: Cardiovascular Genetics Program, Clinical Cardiac Electrophysiology, New York University Langone Medical Center, New York, NY (S.J.F., S.G.P.) Leon H. Charney Division of Cardiology, New York University Langone Medical Center, New York, NY (S.J.F.).
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Fowler
authors.affiliation: Cardiovascular Genetics Program, Clinical Cardiac Electrophysiology, New York University Langone Medical Center, New York, NY (S.J.F., S.G.P.) Molecular Cardiology, IRCCS Fondazione Salvatore Maugeri, University of Pavia, Italy (S.G.P.) Department of Cardiology, University of Pavia, Italy (S.G.P.).
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
authors.affiliation: The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Internal Medicine, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., P.F.B., R.W., S.V.R., T.J.H., P.J.M.) Department of Biomedical Engineering, The Ohio State University, Columbus, OH (T.J.H.).
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.affiliation: The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) College of Pharmacy, Columbus, OH (C.A.C.).
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Carnes
authors.affiliation: The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., C.F.K., P.G., B.L.J., J.C., A.K., R.D.H., P.F.B., P.L.J., R.W., S.V.R., T.J.H., C.A.C., P.J.M.) Department of Internal Medicine, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (A.C.S., P.F.B., R.W., S.V.R., T.J.H., P.J.M.) Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, The Ohio State University College of Engineering, Columbus, OH (C.F.K., J.C., P.L.J., P.J.M.).
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
mesh_terms: D015761:4-Aminopyridine / Q000627:therapeutic use; D000200:Action Potentials / Q000187:drug effects*; D000328:Adult; D000077407:Cilostazol; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics*; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D059472:Exome / Q000235:genetics; D014644:Genetic Variation; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D015221:Potassium Channels / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013777:Tetrazoles / Q000627:therapeutic use; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000627:therapeutic use*; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*
chemical_list: D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013777:Tetrazoles; D014665:Vasodilator Agents; D015761:4-Aminopyridine; C503535:DPP6 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D000077407:Cilostazol
keywords: arrhythmia; genetics; ion channel