Browsing by Subject "long QT syndrome"

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    ItemOpen Access
    An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.
    (Circulation, 2020-02) Roberts, Jason D; Asaki, S Yukiko; Mazzanti, Andrea; Bos, J Martijn; Tuleta, Izabela; Muir, Alison R; Crotti, Lia; Krahn, Andrew D; Kutyifa, Valentina; Shoemaker, M Benjamin; Johnsrude, Christopher L; Aiba, Takeshi; Marcondes, Luciana; Baban, Anwar; Udupa, Sharmila; Dechert, Brynn; Fischbach, Peter; Knight, Linda M; Vittinghoff, Eric; Kukavica, Deni; Stallmeyer, Birgit; Giudicessi, John R; Spazzolini, Carla; Shimamoto, Keiko; Tadros, Rafik; Cadrin-Tourigny, Julia; Duff, Henry J; Simpson, Christopher S; Roston, Thomas M; Wijeyeratne, Yanushi D; El Hajjaji, Imane; Yousif, Maisoon D; Gula, Lorne J; Leong-Sit, Peter; Chavali, Nikhil; Landstrom, Andrew P; Marcus, Gregory M; Dittmann, Sven; Wilde, Arthur AM; Behr, Elijah R; Tfelt-Hansen, Jacob; Scheinman, Melvin M; Perez, Marco V; Kaski, Juan Pablo; Gow, Robert M; Drago, Fabrizio; Aziz, Peter F; Abrams, Dominic J; Gollob, Michael H; Skinner, Jonathan R; Shimizu, Wataru; Kaufman, Elizabeth S; Roden, Dan M; Zareba, Wojciech; Schwartz, Peter J; Schulze-Bahr, Eric; Etheridge, Susan P; Priori, Silvia G; Ackerman, Michael J
    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.
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    Genotype Predicts Outcomes in Fetuses and Neonates With Severe Congenital Long QT Syndrome.
    (JACC. Clinical electrophysiology, 2020-11) Moore, Jeremy P; Gallotti, Roberto G; Shannon, Kevin M; Bos, J Martijn; Sadeghi, Elham; Strasburger, Janette F; Wakai, Ronald T; Horigome, Hitoshi; Clur, Sally-Ann; Hill, Allison C; Shah, Maully J; Behere, Shashank; Sarquella-Brugada, Georgia; Czosek, Richard; Etheridge, Susan P; Fischbach, Peter; Kannankeril, Prince J; Motonaga, Kara; Landstrom, Andrew P; Williams, Matthew; Patel, Akash; Dagradi, Federica; Tan, Reina B; Stephenson, Elizabeth; Krishna, Mani Ram; Miyake, Christina Y; Lee, Michelle E; Sanatani, Shubhayan; Balaji, Seshadri; Young, Ming-Lon; Siddiqui, Saad; Schwartz, Peter J; Shivkumar, Kalyanam; Ackerman, Michael J

    Objectives

    This study sought to determine the relationship between long QT syndrome (LQTS) subtype (LTQ1, LTQ2, LTQ3) and postnatal cardiac events (CEs).

    Background

    LQTS presenting with 2:1 atrioventricular block or torsades de pointes in the fetus and/or neonate has been associated with risk for major CEs, but overall outcomes and predictors remain unknown.

    Methods

    A retrospective study involving 25 international centers evaluated the course of fetuses/newborns diagnosed with congenital LQTS and either 2:1 atrioventricular block or torsades de pointes. The primary outcomes were age at first CE after dismissal from the newborn hospitalization and death and/or cardiac transplantation during follow-up. CE was defined as aborted cardiac arrest, appropriate shock from implantable cardioverter-defibrillator, or sudden cardiac death.

    Results

    A total of 84 fetuses and/or neonates were identified with LQTS (12 as LQT1, 35 as LQT2, 37 as LQT3). Median gestational age at delivery was 37 weeks (interquartile range: 35 to 39 weeks) and age at hospital discharge was 3 weeks (interquartile range: 2 to 5 weeks). Fetal demise occurred in 2 and pre-discharge death in 1. Over a median of 5.2 years, there were 1 LQT1, 3 LQT2, and 23 LQT3 CEs (13 aborted cardiac arrests, 5 sudden cardiac deaths, and 9 appropriate shocks). One patient with LQT1 and 11 patients with LQT3 died or received cardiac transplant during follow-up. The only multivariate predictor of post-discharge CEs was LQT3 status (LQT3 vs. LQT2: hazard ratio: 8.4; 95% confidence interval: 2.6 to 38.9; p < 0.001), and LQT3, relative to LQT2, genotype predicted death and/or cardiac transplant (p < 0.001).

    Conclusions

    In this large multicenter study, fetuses and/or neonates with LQT3 but not those with LQT1 or LQT2 presenting with severe arrhythmias were at high risk of not only frequent, but lethal CEs.
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    TBX5-encoded T-box transcription factor 5 variant T223M is associated with long QT syndrome and pediatric sudden cardiac death.
    (American journal of medical genetics. Part A, 2021-03) Markunas, Alexandra M; Manivannan, Perathu KR; Ezekian, Jordan E; Agarwal, Agnim; Eisner, William; Alsina, Katherina; Allen, Hugh D; Wray, Gregory A; Kim, Jeffrey J; Wehrens, Xander HT; Landstrom, Andrew P
    Long QT syndrome (LQTS) is a genetic disease resulting in a prolonged QT interval on a resting electrocardiogram, predisposing affected individuals to polymorphic ventricular tachycardia and sudden death. Although a number of genes have been implicated in this disease, nearly one in four individuals exhibiting the LQTS phenotype are genotype-negative. Whole-exome sequencing identified a missense T223M variant in TBX5 that cosegregates with prolonged QT interval in a family with otherwise genotype-negative LQTS and sudden death. The TBX5-T223M variant was absent among large ostensibly healthy populations (gnomAD) and predicted to be pathogenic by in silico modeling based on Panther, PolyPhen-2, Provean, SIFT, SNAP2, and PredictSNP prediction tools. The variant was located in a highly conserved region of TBX5 predicted to be part of the DNA-binding interface. A luciferase assay identified a 57.5% reduction in the ability of TBX5-T223M to drive expression at the atrial natriuretic factor promotor compared to wildtype TBX5 in vitro. We conclude that the variant is pathogenic in this family, and we put TBX5 forward as a disease susceptibility allele for genotype-negative LQTS. The identification of this familial variant may serve as a basis for the identification of previously unknown mechanisms of LQTS with broader implications for cardiac electrophysiology.