An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition

Jason D. Roberts; S. Yukiko Asaki; Andrea Mazzanti; J. Martijn Bos; Izabela Tuleta; Alison R. Muir; Lia Crotti; Andrew D. Krahn; Valentina Kutyifa; M. Benjamin Shoemaker; Christopher L. Johnsrude; Takeshi Aiba; Luciana Marcondes; Anwar Baban; Sharmila Udupa; Brynn Dechert; Peter Fischbach; Linda M. Knight; Eric Vittinghoff; Deni Kukavica; Birgit Stallmeyer; John R. Giudicessi; Carla Spazzolini; Keiko Shimamoto; Rafik Tadros; Julia Cadrin-Tourigny; Henry J. Duff; Christopher S. Simpson; Thomas M. Roston; Yanushi D. Wijeyeratne; Imane El Hajjaji; Maisoon D. Yousif; Lorne J. Gula; Peter Leong-Sit; Nikhil Chavali; Andrew P. Landstrom; Gregory M. Marcus; Sven Dittmann; Arthur A.M. Wilde; Elijah R. Behr; Jacob Tfelt-Hansen; Melvin M. Scheinman; Marco V. Perez; Juan Pablo Kaski; Robert M. Gow; Fabrizio Drago; Peter F. Aziz; Dominic J. Abrams; Michael H. Gollob; Jonathan R. Skinner; Wataru Shimizu; Elizabeth S. Kaufman; Dan M. Roden; Wojciech Zareba; Peter J. Schwartz; Eric Schulze-Bahr; Susan P. Etheridge; Silvia G. Priori; Michael J. Ackerman

doi:10.1161/CIRCULATIONAHA.119.043114

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition

Jason D. Roberts, S. Yukiko Asaki, Andrea Mazzanti, J. Martijn Bos, Izabela Tuleta, Alison R. Muir, Lia Crotti, Andrew D. Krahn, Valentina Kutyifa, M. Benjamin Shoemaker, Christopher L. Johnsrude, Takeshi Aiba, Luciana Marcondes, Anwar Baban, Sharmila Udupa, Brynn Dechert, Peter Fischbach, Linda M. Knight, Eric Vittinghoff, Deni KukavicaBirgit Stallmeyer, John R. Giudicessi, Carla Spazzolini, Keiko Shimamoto, Rafik Tadros, Julia Cadrin-Tourigny, Henry J. Duff, Christopher S. Simpson, Thomas M. Roston, Yanushi D. Wijeyeratne, Imane El Hajjaji, Maisoon D. Yousif, Lorne J. Gula, Peter Leong-Sit, Nikhil Chavali, Andrew P. Landstrom, Gregory M. Marcus, Sven Dittmann, Arthur A.M. Wilde, Elijah R. Behr, Jacob Tfelt-Hansen, Melvin M. Scheinman, Marco V. Perez, Juan Pablo Kaski, Robert M. Gow, Fabrizio Drago, Peter F. Aziz, Dominic J. Abrams, Michael H. Gollob, Jonathan R. Skinner, Wataru Shimizu, Elizabeth S. Kaufman, Dan M. Roden, Wojciech Zareba, Peter J. Schwartz, Eric Schulze-Bahr, Susan P. Etheridge, Silvia G. Priori, Michael J. Ackerman

Cardiovascular Medicine

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Original language	English (US)
Pages (from-to)	429-439
Number of pages	11
Journal	Circulation
Volume	141
Issue number	6
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.119.043114
State	Published - Feb 11 2020

Keywords

arrhythmia
genetics
long QT syndrome
penetrance
sudden cardiac death

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology (medical)

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10.1161/CIRCULATIONAHA.119.043114

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Roberts, J. D., Asaki, S. Y., Mazzanti, A., Bos, J. M., Tuleta, I., Muir, A. R., Crotti, L., Krahn, A. D., Kutyifa, V., Shoemaker, M. B., Johnsrude, C. L., Aiba, T., Marcondes, L., Baban, A., Udupa, S., Dechert, B., Fischbach, P., Knight, L. M., Vittinghoff, E., ... Ackerman, M. J. (2020). An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition. Circulation, 141(6), 429-439. https://doi.org/10.1161/CIRCULATIONAHA.119.043114

Roberts, JD, Asaki, SY, Mazzanti, A, Bos, JM, Tuleta, I, Muir, AR, Crotti, L, Krahn, AD, Kutyifa, V, Shoemaker, MB, Johnsrude, CL, Aiba, T, Marcondes, L, Baban, A, Udupa, S, Dechert, B, Fischbach, P, Knight, LM, Vittinghoff, E, Kukavica, D, Stallmeyer, B, Giudicessi, JR, Spazzolini, C, Shimamoto, K, Tadros, R, Cadrin-Tourigny, J, Duff, HJ, Simpson, CS, Roston, TM, Wijeyeratne, YD, El Hajjaji, I, Yousif, MD, Gula, LJ, Leong-Sit, P, Chavali, N, Landstrom, AP, Marcus, GM, Dittmann, S, Wilde, AAM, Behr, ER, Tfelt-Hansen, J, Scheinman, MM, Perez, MV, Kaski, JP, Gow, RM, Drago, F, Aziz, PF, Abrams, DJ, Gollob, MH, Skinner, JR, Shimizu, W, Kaufman, ES, Roden, DM, Zareba, W, Schwartz, PJ, Schulze-Bahr, E, Etheridge, SP, Priori, SG & Ackerman, MJ 2020, 'An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition', Circulation, vol. 141, no. 6, pp. 429-439. https://doi.org/10.1161/CIRCULATIONAHA.119.043114

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title = "An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition",

abstract = "Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.",

keywords = "arrhythmia, genetics, long QT syndrome, penetrance, sudden cardiac death",

author = "Roberts, {Jason D.} and Asaki, {S. Yukiko} and Andrea Mazzanti and Bos, {J. Martijn} and Izabela Tuleta and Muir, {Alison R.} and Lia Crotti and Krahn, {Andrew D.} and Valentina Kutyifa and Shoemaker, {M. Benjamin} and Johnsrude, {Christopher L.} and Takeshi Aiba and Luciana Marcondes and Anwar Baban and Sharmila Udupa and Brynn Dechert and Peter Fischbach and Knight, {Linda M.} and Eric Vittinghoff and Deni Kukavica and Birgit Stallmeyer and Giudicessi, {John R.} and Carla Spazzolini and Keiko Shimamoto and Rafik Tadros and Julia Cadrin-Tourigny and Duff, {Henry J.} and Simpson, {Christopher S.} and Roston, {Thomas M.} and Wijeyeratne, {Yanushi D.} and {El Hajjaji}, Imane and Yousif, {Maisoon D.} and Gula, {Lorne J.} and Peter Leong-Sit and Nikhil Chavali and Landstrom, {Andrew P.} and Marcus, {Gregory M.} and Sven Dittmann and Wilde, {Arthur A.M.} and Behr, {Elijah R.} and Jacob Tfelt-Hansen and Scheinman, {Melvin M.} and Perez, {Marco V.} and Kaski, {Juan Pablo} and Gow, {Robert M.} and Fabrizio Drago and Aziz, {Peter F.} and Abrams, {Dominic J.} and Gollob, {Michael H.} and Skinner, {Jonathan R.} and Wataru Shimizu and Kaufman, {Elizabeth S.} and Roden, {Dan M.} and Wojciech Zareba and Schwartz, {Peter J.} and Eric Schulze-Bahr and Etheridge, {Susan P.} and Priori, {Silvia G.} and Ackerman, {Michael J.}",

year = "2020",

month = feb,

day = "11",

doi = "10.1161/CIRCULATIONAHA.119.043114",

language = "English (US)",

volume = "141",

pages = "429--439",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "6",

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TY - JOUR

T1 - An International Multicenter Evaluation of Type 5 Long QT Syndrome

T2 - A Low Penetrant Primary Arrhythmic Condition

AU - Roberts, Jason D.

AU - Asaki, S. Yukiko

AU - Mazzanti, Andrea

AU - Bos, J. Martijn

AU - Tuleta, Izabela

AU - Muir, Alison R.

AU - Crotti, Lia

AU - Krahn, Andrew D.

AU - Kutyifa, Valentina

AU - Shoemaker, M. Benjamin

AU - Johnsrude, Christopher L.

AU - Aiba, Takeshi

AU - Marcondes, Luciana

AU - Baban, Anwar

AU - Udupa, Sharmila

AU - Dechert, Brynn

AU - Fischbach, Peter

AU - Knight, Linda M.

AU - Vittinghoff, Eric

AU - Kukavica, Deni

AU - Stallmeyer, Birgit

AU - Giudicessi, John R.

AU - Spazzolini, Carla

AU - Shimamoto, Keiko

AU - Tadros, Rafik

AU - Cadrin-Tourigny, Julia

AU - Duff, Henry J.

AU - Simpson, Christopher S.

AU - Roston, Thomas M.

AU - Wijeyeratne, Yanushi D.

AU - El Hajjaji, Imane

AU - Yousif, Maisoon D.

AU - Gula, Lorne J.

AU - Leong-Sit, Peter

AU - Chavali, Nikhil

AU - Landstrom, Andrew P.

AU - Marcus, Gregory M.

AU - Dittmann, Sven

AU - Wilde, Arthur A.M.

AU - Behr, Elijah R.

AU - Tfelt-Hansen, Jacob

AU - Scheinman, Melvin M.

AU - Perez, Marco V.

AU - Kaski, Juan Pablo

AU - Gow, Robert M.

AU - Drago, Fabrizio

AU - Aziz, Peter F.

AU - Abrams, Dominic J.

AU - Gollob, Michael H.

AU - Skinner, Jonathan R.

AU - Shimizu, Wataru

AU - Kaufman, Elizabeth S.

AU - Roden, Dan M.

AU - Zareba, Wojciech

AU - Schwartz, Peter J.

AU - Schulze-Bahr, Eric

AU - Etheridge, Susan P.

AU - Priori, Silvia G.

AU - Ackerman, Michael J.

PY - 2020/2/11

Y1 - 2020/2/11

N2 - Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

AB - Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

KW - arrhythmia

KW - genetics

KW - long QT syndrome

KW - penetrance

KW - sudden cardiac death

UR - http://www.scopus.com/inward/record.url?scp=85081142352&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85081142352&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.119.043114

DO - 10.1161/CIRCULATIONAHA.119.043114

M3 - Article

C2 - 31941373

AN - SCOPUS:85081142352

SN - 0009-7322

VL - 141

SP - 429

EP - 439

JO - Circulation

JF - Circulation

IS - 6

ER -

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition

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