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

doi:10.1161/CIRCULATIONAHA.119.043114

Clinical Trial

. 2020 Feb 11;141(6):429-439.

doi: 10.1161/CIRCULATIONAHA.119.043114. Epub 2020 Jan 16.

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

Jason D Roberts¹, S Yukiko Asaki², Andrea Mazzanti^{3

4}, J Martijn Bos, Izabela Tuleta^{4

5}, Alison R Muir⁶, Lia Crotti^{4

7

8

9}, Andrew D Krahn¹⁰, Valentina Kutyifa¹¹, M Benjamin Shoemaker^{12

13}, Christopher L Johnsrude¹⁴, Takeshi Aiba¹⁵, Luciana Marcondes¹⁶, Anwar Baban^{4

17}, Sharmila Udupa¹⁸, Brynn Dechert¹⁹, Peter Fischbach²⁰, Linda M Knight²⁰, Eric Vittinghoff²¹, Deni Kukavica^{3

4}, Birgit Stallmeyer^{4

22}, John R Giudicessi¹², Carla Spazzolini^{4

7}, Keiko Shimamoto¹⁵, Rafik Tadros²³, Julia Cadrin-Tourigny²³, Henry J Duff²⁴, Christopher S Simpson²⁵, Thomas M Roston¹⁰, Yanushi D Wijeyeratne^{4

26}, Imane El Hajjaji¹, Maisoon D Yousif¹, Lorne J Gula¹, Peter Leong-Sit¹, Nikhil Chavali¹³, Andrew P Landstrom²⁷, Gregory M Marcus²⁸, Sven Dittmann^{4

22}, Arthur A M Wilde^{4

28}, Elijah R Behr^{4

26}, Jacob Tfelt-Hansen^{4

29}, Melvin M Scheinman³⁰, Marco V Perez³¹, Juan Pablo Kaski^{4

32}, Robert M Gow¹⁸, Fabrizio Drago^{4

17}, Peter F Aziz³³, Dominic J Abrams³⁴, Michael H Gollob³⁵, Jonathan R Skinner¹⁶, Wataru Shimizu^{15

36}, Elizabeth S Kaufman³⁷, Dan M Roden^{13

38

39}, Wojciech Zareba¹¹, Peter J Schwartz^{4

7}, Eric Schulze-Bahr^{4

22}, Susan P Etheridge², Silvia G Priori^{3

4}, Michael J Ackerman¹²

Affiliations

¹ Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada (J.D.R., I.E.H., M.D.Y., L.J.G., P.L.-S.).
² Department of Pediatrics, University of Utah, and Primary Children's Hospital, Salt Lake City (S.Y.A., S.P.E.).
³ Molecular Cardiology, Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico and Department of Molecular Medicine, University of Pavia, Italy (A.M., D.K., S.G.P.).
⁴ European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (A.M., I.T., L.C., A.B., D.K., B.S., C.S., Y.D.W., S.D., A.A.M.W., E.R.B., J.T.-H., J.P.K., F.D., P.J.S., E.S.-B., S.G.P.).
⁵ Department of Cardiology I (I.T.), University Hospital Muenster, Germany.
⁶ Northern Ireland Inherited Cardiac Conditions Service, Belfast City Hospital, United Kingdom (A.R.M.).
⁷ Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.C., C.S., P.J.S.).
⁸ Department of Medicine and Surgery, University of Milano-Bicocca, Italy (L.C.).
⁹ Istituto Auxologico Italiano, IRCCS, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Milan, Italy (L.C.).
¹⁰ Heart Rhythm Services, Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, Canada (A.D.K., T.M.R.).
¹¹ Clinical Cardiovascular Research Center, University of Rochester Medical Center, NY (V.K., W.Z.).
¹² Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN (M.B., J.R.G., M.J.A.).
¹³ Departments of Medicine (M.B.S., N.C., D.M.R.), Vanderbilt University Medical Center, Nashville, TN.
¹⁴ Division of Pediatric Cardiology, Department of Pediatrics, University of Louisville, KY (C.L.J.).
¹⁵ Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan (T.A., K.S., W.S.).
¹⁶ Cardiac Inherited Disease Group New Zealand, Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland (L.M., J.R.S.).
¹⁷ Pediatric Cardiology and Cardiac Arrhythmias Complex Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy (A.B., F.D.).
¹⁸ Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Canada (S.U., R.M.G.).
¹⁹ Division of Cardiology, Department of Pediatrics, University of Michigan Children's Hospital, University of Michigan, Ann Arbor (B.D.).
²⁰ Children's Healthcare of Atlanta, Sibley Heart Center Cardiology, GA (P.F., L.M.K.).
²¹ Department of Epidemiology and Biostatistics (E.V.), University of California San Francisco.
²² Institute for Genetics of Heart Disease (B.S., S.D., E.S.-B.), University Hospital Muenster, Germany.
²³ Cardiovascular Genetics Center, Montreal Heart Institute, Université de Montréal, Quebec, Canada (R.T., J., C.-T.).
²⁴ Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Canada (H.J.D.).
²⁵ Division of Cardiology, Queen's University, Kingston, Ontario, Canada (C.S.S.).
²⁶ Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St. George's University of London, and St. George's University Hospitals NHS Foundation Trust, United Kingdom (Y.D.W., E.R.B.).
²⁷ Department of Pediatrics, Division of Pediatric Cardiology, and Department of Cell Biology, Duke University School of Medicine, Durham, NC (A.P.L.).
²⁸ Amsterdam University Medical Centre, location AMC, Heart Center, Department of Clinical and Experimental Cardiology, The Netherlands (G.M.M., A.A.M.W.).
²⁹ The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Denmark (J.T.-H.).
³⁰ Department of Medicine, Division of Cardiology, Section of Cardiac Electrophysiology M.M.S.), University of California San Francisco.
³¹ Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (M.V.P.).
³² Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital and UCL Institute of Cardiovascular Science, London, United Kingdom (J.P.K.).
³³ Department of Pediatric Cardiology, Cleveland Clinic, OH (P.F.A.).
³⁴ Inherited Cardiac Arrhythmia Program, Boston Children's Hospital, Harvard Medical School, MA (D.J.A.).
³⁵ Department of Physiology and Department of Medicine, Toronto General Hospital, University of Toronto, Ontario, Canada (M.H.G.).
³⁶ Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan (W.S.).
³⁷ The Heart and Vascular Research Center, Metro-Health Campus, Case Western Reserve University, Cleveland, OH (E.S.K.).
³⁸ Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, TN.
³⁹ Biomedical Informatics (D.M.R.), Vanderbilt University Medical Center, Nashville, TN.

PMID: 31941373
PMCID: PMC7035205
DOI: 10.1161/CIRCULATIONAHA.119.043114

Clinical Trial

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

Jason D Roberts et al. Circulation. 2020.

. 2020 Feb 11;141(6):429-439.

doi: 10.1161/CIRCULATIONAHA.119.043114. Epub 2020 Jan 16.

Authors

Affiliations

¹ Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada (J.D.R., I.E.H., M.D.Y., L.J.G., P.L.-S.).
² Department of Pediatrics, University of Utah, and Primary Children's Hospital, Salt Lake City (S.Y.A., S.P.E.).
³ Molecular Cardiology, Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico and Department of Molecular Medicine, University of Pavia, Italy (A.M., D.K., S.G.P.).
⁴ European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (A.M., I.T., L.C., A.B., D.K., B.S., C.S., Y.D.W., S.D., A.A.M.W., E.R.B., J.T.-H., J.P.K., F.D., P.J.S., E.S.-B., S.G.P.).
⁵ Department of Cardiology I (I.T.), University Hospital Muenster, Germany.
⁶ Northern Ireland Inherited Cardiac Conditions Service, Belfast City Hospital, United Kingdom (A.R.M.).
⁷ Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (L.C., C.S., P.J.S.).
⁸ Department of Medicine and Surgery, University of Milano-Bicocca, Italy (L.C.).
⁹ Istituto Auxologico Italiano, IRCCS, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Milan, Italy (L.C.).
¹⁰ Heart Rhythm Services, Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, Canada (A.D.K., T.M.R.).
¹¹ Clinical Cardiovascular Research Center, University of Rochester Medical Center, NY (V.K., W.Z.).
¹² Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN (M.B., J.R.G., M.J.A.).
¹³ Departments of Medicine (M.B.S., N.C., D.M.R.), Vanderbilt University Medical Center, Nashville, TN.
¹⁴ Division of Pediatric Cardiology, Department of Pediatrics, University of Louisville, KY (C.L.J.).
¹⁵ Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan (T.A., K.S., W.S.).
¹⁶ Cardiac Inherited Disease Group New Zealand, Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland (L.M., J.R.S.).
¹⁷ Pediatric Cardiology and Cardiac Arrhythmias Complex Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy (A.B., F.D.).
¹⁸ Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Canada (S.U., R.M.G.).
¹⁹ Division of Cardiology, Department of Pediatrics, University of Michigan Children's Hospital, University of Michigan, Ann Arbor (B.D.).
²⁰ Children's Healthcare of Atlanta, Sibley Heart Center Cardiology, GA (P.F., L.M.K.).
²¹ Department of Epidemiology and Biostatistics (E.V.), University of California San Francisco.
²² Institute for Genetics of Heart Disease (B.S., S.D., E.S.-B.), University Hospital Muenster, Germany.
²³ Cardiovascular Genetics Center, Montreal Heart Institute, Université de Montréal, Quebec, Canada (R.T., J., C.-T.).
²⁴ Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Canada (H.J.D.).
²⁵ Division of Cardiology, Queen's University, Kingston, Ontario, Canada (C.S.S.).
²⁶ Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St. George's University of London, and St. George's University Hospitals NHS Foundation Trust, United Kingdom (Y.D.W., E.R.B.).
²⁷ Department of Pediatrics, Division of Pediatric Cardiology, and Department of Cell Biology, Duke University School of Medicine, Durham, NC (A.P.L.).
²⁸ Amsterdam University Medical Centre, location AMC, Heart Center, Department of Clinical and Experimental Cardiology, The Netherlands (G.M.M., A.A.M.W.).
²⁹ The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Denmark (J.T.-H.).
³⁰ Department of Medicine, Division of Cardiology, Section of Cardiac Electrophysiology M.M.S.), University of California San Francisco.
³¹ Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (M.V.P.).
³² Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital and UCL Institute of Cardiovascular Science, London, United Kingdom (J.P.K.).
³³ Department of Pediatric Cardiology, Cleveland Clinic, OH (P.F.A.).
³⁴ Inherited Cardiac Arrhythmia Program, Boston Children's Hospital, Harvard Medical School, MA (D.J.A.).
³⁵ Department of Physiology and Department of Medicine, Toronto General Hospital, University of Toronto, Ontario, Canada (M.H.G.).
³⁶ Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan (W.S.).
³⁷ The Heart and Vascular Research Center, Metro-Health Campus, Case Western Reserve University, Cleveland, OH (E.S.K.).
³⁸ Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, TN.
³⁹ Biomedical Informatics (D.M.R.), Vanderbilt University Medical Center, Nashville, TN.

PMID: 31941373
PMCID: PMC7035205
DOI: 10.1161/CIRCULATIONAHA.119.043114

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.

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Figures

**Figure 1:**
ECG Penetrance of Rare *KCNE1* Variants. Penetrance is defined as a QTc > 460ms on their presenting ECG. (N) indicates the number of individuals with the *KCNE1* variant

**Figure 2:**
Arrhythmic Events Among Probands and Genotype Positive Family Members Possessing a Rare *KCNE1* Variant. Outcomes of (A) Syncope, Appropriate ICD Shock, ACA, or SCD and (B) Appropriate ICD Shock, ACA, or SCD. ICD = implantable cardioverter-defibrillator, ACA = aborted cardiac arrest, SCD = sudden cardiac death, ref = reference, HR = hazard ratio, CI = confidence intervals.

**Figure 3:**
Arrhythmic Events Among Males and Females Possessing a Rare *KCNE1* Variant. Outcomes of (A) Syncope, Appropriate ICD Shock, ACA, or SCD and (B) Appropriate ICD Shock, ACA, or SCD. ICD = implantable cardioverter-defibrillator, ACA = aborted cardiac arrest, SCD = sudden cardiac death, ref = reference, HR = hazard ratio, CI = confidence intervals.

**Figure 4:**
Arrhythmic Events Among Type 2 Jervell and Lange-Nielsen Syndrome Patients and *KCNE1* Heterozygotes. Outcomes of (A) Syncope, Appropriate ICD Shock, ACA, or SCD and (B) Appropriate ICD Shock, ACA, or SCD. JLNS2 = Type 2 Jervell and Lange-NieIsen syndrome, ICD = implantable cardioverter-defibrillator, ACA = aborted cardiac arrest, SCD = sudden cardiac death, ref = reference, HR = hazard ratio, CI = confidence intervals.

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Comment in

Time to Rethink the Genetic Architecture of Long QT Syndrome.
Ingles J, Semsarian C. Ingles J, et al. Circulation. 2020 Feb 11;141(6):440-443. doi: 10.1161/CIRCULATIONAHA.119.044760. Epub 2020 Feb 10. Circulation. 2020. PMID: 32078431 No abstract available.

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References

1. Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circ Arrhythm Electrophysiol. 2012;5:868–877. - PMC - PubMed
1. Mazzanti A, Maragna R, Priori S. Genetic causes of sudden cardiac death in the young. Current Opinion in Cardiology. 2017;32:253–261. - PubMed
1. Schwartz PJ, Ackerman MJ, Wilde AAM. Channelopathies as causes of sudden cardiac death. Card Electrophysiol Clin. 2017;9:537–549. - PubMed
1. Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120:1761–1767. - PMC - PubMed
1. Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, Keating MT. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature. 1996;384:80–83. - PubMed

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[1] Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circ Arrhythm Electrophysiol. 2012;5:868–877. - PMC - PubMed

[2] Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circ Arrhythm Electrophysiol. 2012;5:868–877. - PMC - PubMed

[3] Mazzanti A, Maragna R, Priori S. Genetic causes of sudden cardiac death in the young. Current Opinion in Cardiology. 2017;32:253–261. - PubMed

[4] Mazzanti A, Maragna R, Priori S. Genetic causes of sudden cardiac death in the young. Current Opinion in Cardiology. 2017;32:253–261. - PubMed

[5] Schwartz PJ, Ackerman MJ, Wilde AAM. Channelopathies as causes of sudden cardiac death. Card Electrophysiol Clin. 2017;9:537–549. - PubMed

[6] Schwartz PJ, Ackerman MJ, Wilde AAM. Channelopathies as causes of sudden cardiac death. Card Electrophysiol Clin. 2017;9:537–549. - PubMed

[7] Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120:1761–1767. - PMC - PubMed

[8] Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120:1761–1767. - PMC - PubMed

[9] Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, Keating MT. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature. 1996;384:80–83. - PubMed

[10] Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, Keating MT. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature. 1996;384:80–83. - PubMed

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

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

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