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An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.
Circulation ( IF 37.8 ) Pub Date : 2020-01-16 , DOI: 10.1161/circulationaha.119.043114
Jason D Roberts 1 , S Yukiko Asaki 2 , Andrea Mazzanti 3, 4 , J Martijn Bos , Izabela Tuleta 4, 5 , Alison R Muir 6 , Lia Crotti 4, 7, 8, 9 , Andrew D Krahn 10 , Valentina Kutyifa 11 , M Benjamin Shoemaker 12, 13 , Christopher L Johnsrude 14 , Takeshi Aiba 15 , Luciana Marcondes 16 , Anwar Baban 4, 17 , Sharmila Udupa 18 , Brynn Dechert 19 , Peter Fischbach 20 , Linda M Knight 20 , Eric Vittinghoff 21 , Deni Kukavica 3, 4 , Birgit Stallmeyer 4, 22 , John R Giudicessi 12 , Carla Spazzolini 4, 7 , Keiko Shimamoto 15 , Rafik Tadros 23 , Julia Cadrin-Tourigny 23 , Henry J Duff 24 , Christopher S Simpson 25 , Thomas M Roston 10 , Yanushi D Wijeyeratne 4, 26 , Imane El Hajjaji 1 , Maisoon D Yousif 1 , Lorne J Gula 1 , Peter Leong-Sit 1 , Nikhil Chavali 13 , Andrew P Landstrom 27 , Gregory M Marcus 28 , Sven Dittmann 4, 22 , Arthur A M Wilde 4, 28 , Elijah R Behr 4, 26 , Jacob Tfelt-Hansen 4, 29 , Melvin M Scheinman 30 , Marco V Perez 31 , Juan Pablo Kaski 4, 32 , Robert M Gow 18 , Fabrizio Drago 4, 17 , Peter F Aziz 33 , Dominic J Abrams 34 , Michael H Gollob 35 , Jonathan R Skinner 16 , Wataru Shimizu 15, 36 , Elizabeth S Kaufman 37 , Dan M Roden 13, 38, 39 , Wojciech Zareba 11 , Peter J Schwartz 4, 7 , Eric Schulze-Bahr 4, 22 , Susan P Etheridge 2 , Silvia G Priori 3, 4 , Michael J Ackerman 12
Affiliation  

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.

中文翻译:

5型长QT综合征的国际多中心评估:低渗透原发性心律失常。

背景:对5型长QT综合征(LQT5)的了解仅限于病例报告和小型家庭系列。通过国际多中心合作,寻求对与LQT5牵连的罕见KCNE1变异相关的临床表型和遗传学特征的加深了解。(N = 19)来自9个国家/地区的22个遗传性心律不齐诊所和4个注册中心。KCNE1评估变体的ECG渗透率(定义为呈现ECG时QTc> 460 ms)和基因型-表型分离。多变量Cox回归用于比较临床和遗传变量与明确的心律失常事件(包括适当的植入式心脏复律除颤器电击,流产的心脏骤停和心脏猝死)的复合主要结果之间的关联。结果:总共32种不同的KCNE1罕见在89位先证者和140位基因型阳性家族成员中推测LQT5,另外19名2型Jervell和Lange-Nielsen综合征患者中发现了这些变异。在假定的LQT5患者中,先证者的平均QTc在先证者中(476.9±38.6 ms)明显长于基因型阳性家庭成员(441.8±30.9 ms),P<0.001)。杂合基因型阳性家庭成员的ECG渗透率为20.7%(29/140)。16.9%(15/89)的杂合先证者经历了明确的心律不齐事件,而家庭成员为1.4%(2/140)(调整后的危险比[HR] 11.6 [95%CI,2.6-52.2];P = 0.001)。相对于总体杂合队列,2型Jervell和Lange-Nielsen综合征患者的事件发生率无显着差异(10.5%[2/19]; HR 1.7 [95%CI,0.3-10.8],P = 0.590)。32 KCNE1的累积患病率Genome Aggregation Database是一个人类基因组和基因组测序数据的人类数据库,目前已有140 000多人的变体,比所有LQT5合并的预期患病率高238倍(0.238%vs 0.001%)。研究表明,推定的/确认的功能丧失的KCNE1变异体倾向于QT延长,但是,观察到的低ECG渗透率表明它们并未在大多数个体中临床表现,与2型Jervell和Lange-尼尔森综合症患者。
更新日期:2020-02-11
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