Novel Timothy syndrome mutation leading to increase in CACNA1C window current

Nicole J. Boczek, Erin M. Miller, Dan Ye, Vladislav V. Nesterenko, David J. Tester, Charles Antzelevitch, Richard J. Czosek, Michael J. Ackerman, Stephanie Ware

Research output: Contribution to journalArticle

34 Citations (Scopus)

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. CONCLUSION: 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.

Original languageEnglish
Pages (from-to)211-219
Number of pages9
JournalHeart Rhythm
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2015

Fingerprint

Mutation
Exome
Action Potentials
Exons
Syndactyly
L-Type Calcium Channels
Inborn Genetic Diseases
Timothy syndrome
Genetic Testing
Patch-Clamp Techniques
Missense Mutation
Neurologic Manifestations

Keywords

  • CACNA1C
  • Genetics
  • Timothy syndrome
  • Whole exome sequencing
  • Window current

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Medicine(all)

Cite this

Boczek, N. J., Miller, E. M., Ye, D., Nesterenko, V. V., Tester, D. J., Antzelevitch, C., ... Ware, S. (2015). Novel Timothy syndrome mutation leading to increase in CACNA1C window current. Heart Rhythm, 12(1), 211-219. https://doi.org/10.1016/j.hrthm.2014.09.051

Novel Timothy syndrome mutation leading to increase in CACNA1C window current. / Boczek, Nicole J.; Miller, Erin M.; Ye, Dan; Nesterenko, Vladislav V.; Tester, David J.; Antzelevitch, Charles; Czosek, Richard J.; Ackerman, Michael J.; Ware, Stephanie.

In: Heart Rhythm, Vol. 12, No. 1, 01.01.2015, p. 211-219.

Research output: Contribution to journalArticle

Boczek, NJ, Miller, EM, Ye, D, Nesterenko, VV, Tester, DJ, Antzelevitch, C, Czosek, RJ, Ackerman, MJ & Ware, S 2015, 'Novel Timothy syndrome mutation leading to increase in CACNA1C window current', Heart Rhythm, vol. 12, no. 1, pp. 211-219. https://doi.org/10.1016/j.hrthm.2014.09.051
Boczek NJ, Miller EM, Ye D, Nesterenko VV, Tester DJ, Antzelevitch C et al. Novel Timothy syndrome mutation leading to increase in CACNA1C window current. Heart Rhythm. 2015 Jan 1;12(1):211-219. https://doi.org/10.1016/j.hrthm.2014.09.051
Boczek, Nicole J. ; Miller, Erin M. ; Ye, Dan ; Nesterenko, Vladislav V. ; Tester, David J. ; Antzelevitch, Charles ; Czosek, Richard J. ; Ackerman, Michael J. ; Ware, Stephanie. / Novel Timothy syndrome mutation leading to increase in CACNA1C window current. In: Heart Rhythm. 2015 ; Vol. 12, No. 1. pp. 211-219.
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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. CONCLUSION: 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.",
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N2 - 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. CONCLUSION: 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.

AB - 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. CONCLUSION: 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.

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