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

• Published in: Circulation (New York, N.Y.) Vol. 141; no. 6; pp. 429 - 439
• Main Authors: 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 A. M., 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.
• Format: Journal Article
• Language: English
• Published: United States by the American College of Cardiology Foundation and the American Heart Association, Inc 11-02-2020
• Subjects: Adolescent; Adult; Death, Sudden, Cardiac; Electric Countershock; Electrocardiography; Female; Heart Arrest - genetics; Heart Arrest - mortality; Heart Arrest - physiopathology; Heart Arrest - therapy; Humans; Long QT Syndrome - genetics; Long QT Syndrome - mortality; Long QT Syndrome - physiopathology; Long QT Syndrome - therapy; Male; Middle Aged; Penetrance; Potassium Channels, Voltage-Gated - genetics; Registries; genetics; sudden cardiac death; long QT syndrome; arrhythmia; penetrance
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.119.043114

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
variants implicated in LQT5 was sought through an international multicenter collaboration.
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.
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.
A total of 32 distinct
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,
<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];
=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],
=0.590). The cumulative prevalence of the 32
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%).
The present study suggests that putative/confirmed loss-of-function
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.