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Circulation. 2020 Jan 16. doi: 10.1161/CIRCULATIONAHA.119.043114. [Epub ahead of print]

An International Multi-Center Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

Author information

1
Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada.
2
Department of Pediatrics, University of Utah, and Primary Childrenâs Hospital, Salt Lake City, UT.
3
Molecular Cardiology, Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico and Department of Molecular Medicine, University of Pavia, Pavia, Italy; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART; http://guardheart.ern-net.eu).
4
Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN.
5
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART; http://guardheart.ern-net.eu); Department of Cardiology I, University Hospital Muenster, Muenster, Germany.
6
Northern Ireland Inherited Cardiac Conditions Service, Belfast City Hospital, Belfast, United Kingdom.
7
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART; http://guardheart.ern-net.eu); Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy; Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy; Istituto Auxologico Italiano, IRCCS, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Milan, Italy.
8
Heart Rhythm Services, Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
9
Clinical Cardiovascular Research Center, University of Rochester Medical Center, Rochester, NY.
10
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.
11
Division of Pediatric Cardiology, Department of Pediatrics, University of Louisville, Louisville, KY.
12
Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
13
Cardiac Inherited Disease Group New Zealand, Paediatric and Congenital Cardiac Services, Starship Childrenâs Hospital, Auckland, New Zealand.
14
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART; http://guardheart.ern-net.eu); Pediatric Cardiology and Cardiac Arrhythmias Complex Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Childrenâs Hospital and Research Institute, Rome 00165, Italy.
15
Childrenâs Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Ottawa, Ontario, Canada.
16
Division of Cardiology, Department of Pediatrics, University of Michigan Childrenâs Hospital, University of Michigan, Ann Arbor, MI.
17
Childrenâs Healthcare of Atlanta, Sibley Heart Center Cardiology, Atlanta, GA.
18
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.
19
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART; http://guardheart.ern-net.eu); Institute for Genetics of Heart Disease, University Hospital Muenster, Muenster, Germany.
20
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART; http://guardheart.ern-net.eu); Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy.
21
Cardiovascular Genetics Center, Montreal Heart Institute, Université de Montréal, Montréal, Canada.
22
Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
23
Division of Cardiology, Queen's University, Kingston, Ontario, Canada.
24
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART; http://guardheart.ern-net.eu); Cardiology Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St. Georgeâs University of London, and St. Georgeâs University Hospitals NHS Foundation Trust, London, United Kingdom.
25
Department of Pediatrics, Division of Pediatric Cardiology, and Department of Cell Biology, Duke University School of Medicine, Durham, NC.
26
Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, CA.
27
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART; http://guardheart.ern-net.eu); Amsterdam University Medical Centre, location AMC, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam, the Netherlands.
28
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART; http://guardheart.ern-net.eu); The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
29
Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA.
30
European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART; http://guardheart.ern-net.eu); Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital and UCL Institute of Cardiovascular Science, London, United Kingdom.
31
Department of Pediatric Cardiology, Cleveland Clinic, Cleveland, OH.
32
Inherited Cardiac Arrhythmia Program, Boston Children's Hospital, Harvard Medical School, MA.
33
Department of Physiology and Department of Medicine, Toronto General Hospital, University of Toronto, Ontario, Canada.
34
Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan; Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.
35
The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH.
36
Departments of Medicine, Pharmacology, and Biomedical Informatics. Vanderbilt University Medical Center. Nashville, TN.

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 multi-center collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (JLNS2, 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 > 460ms 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 JLNS2 patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9 ± 38.6ms) compared to genotype positive family members (441.8 ± 30.9ms, 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% confidence interval [CI]: 2.6-52.2; p=0.001). Event incidence did not differ significantly for JLNS2 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 (gnomAD), 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 JLNS2 patients.

KEYWORDS:

penetrance

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