An International Multicenter Evaluation of Type 5 Long QT Syndrome
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. 
Published: January 2020

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.