Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death

Elena Burashnikov, Ryan Pfeiffer, Hctor Barajas-Martinez, Eva Delpn, Dan Hu, Mayurika Desai, Martin Borggrefe, Michel Hissaguerre, Ronald Kanter, Guido D. Pollevick, Alejandra Guerchicoff, Ruben Laio, Mark Marieb, Koonlawee Nademanee, Gi Byoung Nam, Roberto Robles, Rainer Schimpf, Dwight D. Stapleton, Sami Viskin, Stephen WintersChristian Wolpert, Samuel Zimmern, Christian Veltmann, Charles Antzelevitch

Research output: Contribution to journalArticle

276 Citations (Scopus)

Abstract

Background L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death. Objective The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Cav1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing. Methods/Results Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, β2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval. Conclusion The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Ca v genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.

Original languageEnglish (US)
Pages (from-to)1872-1882
Number of pages11
JournalHeart Rhythm
Volume7
Issue number12
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

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Brugada Syndrome
L-Type Calcium Channels
Sudden Cardiac Death
Mutation
Genes
Genetic Testing
Calcium Channels
Cardiac Arrhythmias

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Burashnikov, E., Pfeiffer, R., Barajas-Martinez, H., Delpn, E., Hu, D., Desai, M., ... Antzelevitch, C. (2010). Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. Heart Rhythm, 7(12), 1872-1882. https://doi.org/10.1016/j.hrthm.2010.08.026
Burashnikov, Elena ; Pfeiffer, Ryan ; Barajas-Martinez, Hctor ; Delpn, Eva ; Hu, Dan ; Desai, Mayurika ; Borggrefe, Martin ; Hissaguerre, Michel ; Kanter, Ronald ; Pollevick, Guido D. ; Guerchicoff, Alejandra ; Laio, Ruben ; Marieb, Mark ; Nademanee, Koonlawee ; Nam, Gi Byoung ; Robles, Roberto ; Schimpf, Rainer ; Stapleton, Dwight D. ; Viskin, Sami ; Winters, Stephen ; Wolpert, Christian ; Zimmern, Samuel ; Veltmann, Christian ; Antzelevitch, Charles. / Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. In: Heart Rhythm. 2010 ; Vol. 7, No. 12. pp. 1872-1882.
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abstract = "Background L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death. Objective The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Cav1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing. Methods/Results Overall, 23 distinct mutations were identified. A total of 12.3{\%}, 5.2{\%}, and 16{\%} of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, β2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9{\%}, 21{\%}, and 29.1{\%} for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval. Conclusion The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Ca v genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.",
author = "Elena Burashnikov and Ryan Pfeiffer and Hctor Barajas-Martinez and Eva Delpn and Dan Hu and Mayurika Desai and Martin Borggrefe and Michel Hissaguerre and Ronald Kanter and Pollevick, {Guido D.} and Alejandra Guerchicoff and Ruben Laio and Mark Marieb and Koonlawee Nademanee and Nam, {Gi Byoung} and Roberto Robles and Rainer Schimpf and Stapleton, {Dwight D.} and Sami Viskin and Stephen Winters and Christian Wolpert and Samuel Zimmern and Christian Veltmann and Charles Antzelevitch",
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Burashnikov, E, Pfeiffer, R, Barajas-Martinez, H, Delpn, E, Hu, D, Desai, M, Borggrefe, M, Hissaguerre, M, Kanter, R, Pollevick, GD, Guerchicoff, A, Laio, R, Marieb, M, Nademanee, K, Nam, GB, Robles, R, Schimpf, R, Stapleton, DD, Viskin, S, Winters, S, Wolpert, C, Zimmern, S, Veltmann, C & Antzelevitch, C 2010, 'Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death', Heart Rhythm, vol. 7, no. 12, pp. 1872-1882. https://doi.org/10.1016/j.hrthm.2010.08.026

Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. / Burashnikov, Elena; Pfeiffer, Ryan; Barajas-Martinez, Hctor; Delpn, Eva; Hu, Dan; Desai, Mayurika; Borggrefe, Martin; Hissaguerre, Michel; Kanter, Ronald; Pollevick, Guido D.; Guerchicoff, Alejandra; Laio, Ruben; Marieb, Mark; Nademanee, Koonlawee; Nam, Gi Byoung; Robles, Roberto; Schimpf, Rainer; Stapleton, Dwight D.; Viskin, Sami; Winters, Stephen; Wolpert, Christian; Zimmern, Samuel; Veltmann, Christian; Antzelevitch, Charles.

In: Heart Rhythm, Vol. 7, No. 12, 01.12.2010, p. 1872-1882.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death

AU - Burashnikov, Elena

AU - Pfeiffer, Ryan

AU - Barajas-Martinez, Hctor

AU - Delpn, Eva

AU - Hu, Dan

AU - Desai, Mayurika

AU - Borggrefe, Martin

AU - Hissaguerre, Michel

AU - Kanter, Ronald

AU - Pollevick, Guido D.

AU - Guerchicoff, Alejandra

AU - Laio, Ruben

AU - Marieb, Mark

AU - Nademanee, Koonlawee

AU - Nam, Gi Byoung

AU - Robles, Roberto

AU - Schimpf, Rainer

AU - Stapleton, Dwight D.

AU - Viskin, Sami

AU - Winters, Stephen

AU - Wolpert, Christian

AU - Zimmern, Samuel

AU - Veltmann, Christian

AU - Antzelevitch, Charles

PY - 2010/12/1

Y1 - 2010/12/1

N2 - Background L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death. Objective The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Cav1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing. Methods/Results Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, β2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval. Conclusion The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Ca v genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.

AB - Background L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death. Objective The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Cav1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing. Methods/Results Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, β2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval. Conclusion The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Ca v genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.

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