title: Novel Timothy syndrome mutation leading to increase in CACNA1C window current.
abstract: BACKGROUND
  Timothy syndrome (TS) is a rare multisystem genetic disorder characterized by a myriad of abnormalities, including QT prolongation, syndactyly, and neurologic symptoms. The predominant genetic causes are recurrent de novo missense mutations in exon 8/8A of the CACNA1C-encoded L-type calcium channel; however, some cases remain genetically elusive.
  
  
  OBJECTIVE
  The purpose of this study was to identify the genetic cause of TS in a patient who did not harbor a CACNA1C mutation in exon 8/A, and was negative for all other plausible genetic substrates.
  
  
  METHODS
  Diagnostic exome sequencing was used to identify the genetic substrate responsible for our case of TS. The identified mutation was characterized using whole-cell patch-clamp technique, and the results of these analyses were modeled using a modified Luo-Rudy dynamic model to determine the effects on the cardiac action potential.
  
  
  RESULTS
  Whole exome sequencing revealed a novel CACNA1C mutation, p.Ile1166Thr, in a young male with diagnosed TS. Functional electrophysiologic analysis identified a novel mechanism of TS-mediated disease, with an overall loss of current density and a gain-of-function shift in activation, leading to an increased window current. Modeling studies of this variant predicted prolongation of the action potential as well as the development of spontaneous early afterdepolarizations.
  
  
  CONCLUSIONS
  Through expanded whole exome sequencing, we identified a novel genetic substrate for TS, p.Ile1166Thr-CACNA1C. Electrophysiologic experiments combined with modeling studies have identified a novel TS mechanism through increased window current. Therefore, expanded genetic testing in cases of TS to the entire CACNA1C coding region, if initial targeted testing is negative, may be warranted.
authors.affiliation: Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota; Mayo Graduate School, Mayo Clinic, Rochester, Minnesota.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Boczek
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Miller
authors.affiliation: Department Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota.
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.affiliation: Department of Pharmacology, Masonic Medical Research Laboratory, Utica, New York.
authors.forename: Vladislav V
authors.initials: VV
authors.lastname: Nesterenko
authors.affiliation: Department Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.affiliation: Department of Pharmacology, Masonic Medical Research Laboratory, Utica, New York.
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.affiliation: The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Czosek
authors.affiliation: Department Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota; Department of Medicine (Division of Cardiovascular Diseases), Mayo Clinic, Rochester, Minnesota; Department of Pediatrics (Division of Pediatric Cardiology), Mayo Clinic, Rochester, Minnesota. Electronic address: ackerman.michael@mayo.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.affiliation: Departments of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, Herman B Wells Center for Pediatric Research, Indianapolis, Indiana. Electronic address: stware@iu.edu.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Ware
mesh_terms: D001321:Autistic Disorder; D020746:Calcium Channels, L-Type / Q000235:genetics*; D006327:Heart Block / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D013576:Syndactyly / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type
keywords: CACNA1C; Genetics; Timothy syndrome; Whole exome sequencing; Window current