Loss-of-Function KCNE2 Variants

True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation?

Jason D. Roberts, Andrew D. Krahn, Michael J. Ackerman, Ram K. Rohatgi, Arthur J. Moss, Babak Nazer, Rafik Tadros, Brenda Gerull, Shubhayan Sanatani, Yanushi D. Wijeyeratne, Alban Elouen Baruteau, Alison R. Muir, Benjamin Pang, Julia Cadrin-Tourigny, Mario Talajic, Lena Rivard, David J. Tester, Taylor Liu, Isaac R. Whitman, Julianne Wojciak & 12 others Susan Conacher, Lorne J. Gula, Peter Leong-Sit, Jaimie Manlucu, Martin S. Green, Robert Hamilton, Jeff S. Healey, Coeli M. Lopes, Elijah R. Behr, Arthur A. Wilde, Michael H. Gollob, Melvin M. Scheinman

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage-gated channel β-subunit, is limited. We sought to further characterize its clinical phenotype. Methods and Results - Individuals with reported pathogenic KCNE2 mutations identified during arrhythmia evaluation were collected from inherited arrhythmia clinics and the Rochester long-QT syndrome (LQTS) registry. Previously reported LQT6 cases were identified through a search of the MEDLINE database. Clinical features were assessed, while reported KCNE2 mutations were evaluated for genotype-phenotype segregation and classified according to the contemporary American College of Medical Genetics guidelines. Twenty-seven probands possessed reported pathogenic KCNE2 mutations, while a MEDLINE search identified 17 additional LQT6 cases providing clinical and genetic data. Sixteen probands had normal resting QTc values and only developed QT prolongation and malignant arrhythmias after exposure to QT-prolonging stressors, 10 had other LQTS pathogenic mutations, and 10 did not have an LQTS phenotype. Although the remaining 8 subjects had an LQTS phenotype, evidence suggested that the KCNE2 variant was not the underlying culprit. The collective frequency of KCNE2 variants implicated in LQT6 in the Exome Aggregation Consortium database was 1.4%, in comparison with a 0.0005% estimated clinical prevalence for LQT6. Conclusions - On the basis of clinical phenotype, the high allelic frequencies of LQT6 mutations in the Exome Aggregation Consortium database, and absence of previous documentation of genotype-phenotype segregation, our findings suggest that many KCNE2 variants, and perhaps all, have been erroneously designated as LQTS-causative mutations. Instead, KCNE2 variants may confer proarrhythmic susceptibility when provoked by additional environmental/acquired or genetic factors, or both.

Original languageEnglish (US)
Article numbere005282
JournalCirculation: Arrhythmia and Electrophysiology
Volume10
Issue number8
DOIs
StatePublished - Aug 1 2017

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Long QT Syndrome
Phenotype
Mutation
Exome
Cardiac Arrhythmias
Databases
MEDLINE
Genotype
Mutation Rate
Documentation
Registries
Guidelines

Keywords

  • exome
  • genetics
  • long QT syndrome
  • mutation
  • prevalence

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Loss-of-Function KCNE2 Variants : True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation? / Roberts, Jason D.; Krahn, Andrew D.; Ackerman, Michael J.; Rohatgi, Ram K.; Moss, Arthur J.; Nazer, Babak; Tadros, Rafik; Gerull, Brenda; Sanatani, Shubhayan; Wijeyeratne, Yanushi D.; Baruteau, Alban Elouen; Muir, Alison R.; Pang, Benjamin; Cadrin-Tourigny, Julia; Talajic, Mario; Rivard, Lena; Tester, David J.; Liu, Taylor; Whitman, Isaac R.; Wojciak, Julianne; Conacher, Susan; Gula, Lorne J.; Leong-Sit, Peter; Manlucu, Jaimie; Green, Martin S.; Hamilton, Robert; Healey, Jeff S.; Lopes, Coeli M.; Behr, Elijah R.; Wilde, Arthur A.; Gollob, Michael H.; Scheinman, Melvin M.

In: Circulation: Arrhythmia and Electrophysiology, Vol. 10, No. 8, e005282, 01.08.2017.

Research output: Contribution to journalArticle

Roberts, JD, Krahn, AD, Ackerman, MJ, Rohatgi, RK, Moss, AJ, Nazer, B, Tadros, R, Gerull, B, Sanatani, S, Wijeyeratne, YD, Baruteau, AE, Muir, AR, Pang, B, Cadrin-Tourigny, J, Talajic, M, Rivard, L, Tester, DJ, Liu, T, Whitman, IR, Wojciak, J, Conacher, S, Gula, LJ, Leong-Sit, P, Manlucu, J, Green, MS, Hamilton, R, Healey, JS, Lopes, CM, Behr, ER, Wilde, AA, Gollob, MH & Scheinman, MM 2017, 'Loss-of-Function KCNE2 Variants: True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation?', Circulation: Arrhythmia and Electrophysiology, vol. 10, no. 8, e005282. https://doi.org/10.1161/CIRCEP.117.005282
Roberts, Jason D. ; Krahn, Andrew D. ; Ackerman, Michael J. ; Rohatgi, Ram K. ; Moss, Arthur J. ; Nazer, Babak ; Tadros, Rafik ; Gerull, Brenda ; Sanatani, Shubhayan ; Wijeyeratne, Yanushi D. ; Baruteau, Alban Elouen ; Muir, Alison R. ; Pang, Benjamin ; Cadrin-Tourigny, Julia ; Talajic, Mario ; Rivard, Lena ; Tester, David J. ; Liu, Taylor ; Whitman, Isaac R. ; Wojciak, Julianne ; Conacher, Susan ; Gula, Lorne J. ; Leong-Sit, Peter ; Manlucu, Jaimie ; Green, Martin S. ; Hamilton, Robert ; Healey, Jeff S. ; Lopes, Coeli M. ; Behr, Elijah R. ; Wilde, Arthur A. ; Gollob, Michael H. ; Scheinman, Melvin M. / Loss-of-Function KCNE2 Variants : True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation?. In: Circulation: Arrhythmia and Electrophysiology. 2017 ; Vol. 10, No. 8.
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title = "Loss-of-Function KCNE2 Variants: True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation?",
abstract = "Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage-gated channel β-subunit, is limited. We sought to further characterize its clinical phenotype. Methods and Results - Individuals with reported pathogenic KCNE2 mutations identified during arrhythmia evaluation were collected from inherited arrhythmia clinics and the Rochester long-QT syndrome (LQTS) registry. Previously reported LQT6 cases were identified through a search of the MEDLINE database. Clinical features were assessed, while reported KCNE2 mutations were evaluated for genotype-phenotype segregation and classified according to the contemporary American College of Medical Genetics guidelines. Twenty-seven probands possessed reported pathogenic KCNE2 mutations, while a MEDLINE search identified 17 additional LQT6 cases providing clinical and genetic data. Sixteen probands had normal resting QTc values and only developed QT prolongation and malignant arrhythmias after exposure to QT-prolonging stressors, 10 had other LQTS pathogenic mutations, and 10 did not have an LQTS phenotype. Although the remaining 8 subjects had an LQTS phenotype, evidence suggested that the KCNE2 variant was not the underlying culprit. The collective frequency of KCNE2 variants implicated in LQT6 in the Exome Aggregation Consortium database was 1.4{\%}, in comparison with a 0.0005{\%} estimated clinical prevalence for LQT6. Conclusions - On the basis of clinical phenotype, the high allelic frequencies of LQT6 mutations in the Exome Aggregation Consortium database, and absence of previous documentation of genotype-phenotype segregation, our findings suggest that many KCNE2 variants, and perhaps all, have been erroneously designated as LQTS-causative mutations. Instead, KCNE2 variants may confer proarrhythmic susceptibility when provoked by additional environmental/acquired or genetic factors, or both.",
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author = "Roberts, {Jason D.} and Krahn, {Andrew D.} and Ackerman, {Michael J.} and Rohatgi, {Ram K.} and Moss, {Arthur J.} and Babak Nazer and Rafik Tadros and Brenda Gerull and Shubhayan Sanatani and Wijeyeratne, {Yanushi D.} and Baruteau, {Alban Elouen} and Muir, {Alison R.} and Benjamin Pang and Julia Cadrin-Tourigny and Mario Talajic and Lena Rivard and Tester, {David J.} and Taylor Liu and Whitman, {Isaac R.} and Julianne Wojciak and Susan Conacher and Gula, {Lorne J.} and Peter Leong-Sit and Jaimie Manlucu and Green, {Martin S.} and Robert Hamilton and Healey, {Jeff S.} and Lopes, {Coeli M.} and Behr, {Elijah R.} and Wilde, {Arthur A.} and Gollob, {Michael H.} and Scheinman, {Melvin M.}",
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T1 - Loss-of-Function KCNE2 Variants

T2 - True Monogenic Culprits of Long-QT Syndrome or Proarrhythmic Variants Requiring Secondary Provocation?

AU - Roberts, Jason D.

AU - Krahn, Andrew D.

AU - Ackerman, Michael J.

AU - Rohatgi, Ram K.

AU - Moss, Arthur J.

AU - Nazer, Babak

AU - Tadros, Rafik

AU - Gerull, Brenda

AU - Sanatani, Shubhayan

AU - Wijeyeratne, Yanushi D.

AU - Baruteau, Alban Elouen

AU - Muir, Alison R.

AU - Pang, Benjamin

AU - Cadrin-Tourigny, Julia

AU - Talajic, Mario

AU - Rivard, Lena

AU - Tester, David J.

AU - Liu, Taylor

AU - Whitman, Isaac R.

AU - Wojciak, Julianne

AU - Conacher, Susan

AU - Gula, Lorne J.

AU - Leong-Sit, Peter

AU - Manlucu, Jaimie

AU - Green, Martin S.

AU - Hamilton, Robert

AU - Healey, Jeff S.

AU - Lopes, Coeli M.

AU - Behr, Elijah R.

AU - Wilde, Arthur A.

AU - Gollob, Michael H.

AU - Scheinman, Melvin M.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage-gated channel β-subunit, is limited. We sought to further characterize its clinical phenotype. Methods and Results - Individuals with reported pathogenic KCNE2 mutations identified during arrhythmia evaluation were collected from inherited arrhythmia clinics and the Rochester long-QT syndrome (LQTS) registry. Previously reported LQT6 cases were identified through a search of the MEDLINE database. Clinical features were assessed, while reported KCNE2 mutations were evaluated for genotype-phenotype segregation and classified according to the contemporary American College of Medical Genetics guidelines. Twenty-seven probands possessed reported pathogenic KCNE2 mutations, while a MEDLINE search identified 17 additional LQT6 cases providing clinical and genetic data. Sixteen probands had normal resting QTc values and only developed QT prolongation and malignant arrhythmias after exposure to QT-prolonging stressors, 10 had other LQTS pathogenic mutations, and 10 did not have an LQTS phenotype. Although the remaining 8 subjects had an LQTS phenotype, evidence suggested that the KCNE2 variant was not the underlying culprit. The collective frequency of KCNE2 variants implicated in LQT6 in the Exome Aggregation Consortium database was 1.4%, in comparison with a 0.0005% estimated clinical prevalence for LQT6. Conclusions - On the basis of clinical phenotype, the high allelic frequencies of LQT6 mutations in the Exome Aggregation Consortium database, and absence of previous documentation of genotype-phenotype segregation, our findings suggest that many KCNE2 variants, and perhaps all, have been erroneously designated as LQTS-causative mutations. Instead, KCNE2 variants may confer proarrhythmic susceptibility when provoked by additional environmental/acquired or genetic factors, or both.

AB - Insight into type 6 long-QT syndrome (LQT6), stemming from mutations in the KCNE2-encoded voltage-gated channel β-subunit, is limited. We sought to further characterize its clinical phenotype. Methods and Results - Individuals with reported pathogenic KCNE2 mutations identified during arrhythmia evaluation were collected from inherited arrhythmia clinics and the Rochester long-QT syndrome (LQTS) registry. Previously reported LQT6 cases were identified through a search of the MEDLINE database. Clinical features were assessed, while reported KCNE2 mutations were evaluated for genotype-phenotype segregation and classified according to the contemporary American College of Medical Genetics guidelines. Twenty-seven probands possessed reported pathogenic KCNE2 mutations, while a MEDLINE search identified 17 additional LQT6 cases providing clinical and genetic data. Sixteen probands had normal resting QTc values and only developed QT prolongation and malignant arrhythmias after exposure to QT-prolonging stressors, 10 had other LQTS pathogenic mutations, and 10 did not have an LQTS phenotype. Although the remaining 8 subjects had an LQTS phenotype, evidence suggested that the KCNE2 variant was not the underlying culprit. The collective frequency of KCNE2 variants implicated in LQT6 in the Exome Aggregation Consortium database was 1.4%, in comparison with a 0.0005% estimated clinical prevalence for LQT6. Conclusions - On the basis of clinical phenotype, the high allelic frequencies of LQT6 mutations in the Exome Aggregation Consortium database, and absence of previous documentation of genotype-phenotype segregation, our findings suggest that many KCNE2 variants, and perhaps all, have been erroneously designated as LQTS-causative mutations. Instead, KCNE2 variants may confer proarrhythmic susceptibility when provoked by additional environmental/acquired or genetic factors, or both.

KW - exome

KW - genetics

KW - long QT syndrome

KW - mutation

KW - prevalence

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