Medical Scientist Training Program, Mayo Clinic, Rochester, Minnesota.
Department of Cardiovascular Medicine, Clinician-Investigator Training Program, Mayo Clinic, Rochester, Minnesota.
Heart Rhythm. 2020 Jun;17(6):937-944. doi: 10.1016/j.hrthm.2020.02.003. Epub 2020 Feb 10.
KCNE1 loss-of-function variants cause type 5 long QT syndrome (LQT5). However, most alleged LQT5-causative KCNE1 variants were identified before the true rate of background genetic variation was appreciated fully.
The purpose of this study was to reassess the clinical and electrophysiological (EP) phenotypes associated with KCNE1 variants detected in a single-center LQTS cohort.
Retrospective analysis of 1026 LQTS patients was used to identify those individuals with isolated KCNE1 ultra-rare variants (minor allele frequency [MAF] <0.0004 in the Genome Aggregation Database [gnomAD]). After classification according to American College of Medical Genetics (ACMG) guidelines, variants of uncertain significance (VUS) were characterized in vitro using whole-cell patch-clamp technique. Lastly, the clinical phenotype observed in ACMG pathogenic/likely pathogenic (P/LP) KCNE1-positive individuals was assessed.
Overall, 6 KCNE1 variants were identified in 38 of 1026 LQTS patients (3.7%). Based on existing data, 2 KCNE1 variants (p.Asp76Asn-KCNE1 and p.Arg98Trp-KCNE1) were classified as P/LP. Whereas the p.Ser28Leu-KCNE1 VUS conferred a loss-of-function EP phenotype (72% reduction in I current) and was upgraded to an LP variant, the 3 remaining KCNE1 VUS (p.Arg67Cys-KCNE1, p.Arg67His-KCNE1, p.Ser74Leu-KCNE1) were indistinguishable from wild type. Collectively, the phenotype observed in p.Ser28Leu-KCNE1-, p.Asp76Asn-KCNE1-, and p.Arg98Trp-KCNE1-positive individuals (n = 22) was relatively weak (91% asymptomatic; average QTc 444 ± 19 ms; 27% with a maladaptive QTc response during exercise/recovery).
This study indicates that p.Ser28Leu-KCNE1 may be an LQT5-causative substrate analogous to p.Asp76Asn-KCNE1 and p.Arg98Trp-KCNE1. However, the weak phenotype and cumulative gnomAD MAF (42/141,156) associated with these P/LP variants suggest LQT5/KCNE-LQTS may be a more common/weaker form of LQTS than anticipated previously.
KCNE1 功能丧失性变异导致 5 型长 QT 综合征（LQT5）。然而，大多数所谓的导致 LQT5 的 KCNE1 变异在充分了解真实背景遗传变异率之前就已被确定。
本研究旨在重新评估在单中心 LQTS 队列中检测到的 KCNE1 变异相关的临床和电生理（EP）表型。
对 1026 例 LQTS 患者进行回顾性分析，以确定那些携带孤立性 KCNE1 超罕见变异（次要等位基因频率[MAF]＜0.0004 在基因组聚合数据库[gnomAD]中）的个体。根据美国医学遗传学学院（ACMG）指南进行分类后，使用全细胞膜片钳技术对不确定意义的变异（VUS）进行了特征描述。最后，评估了在 ACMG 致病性/可能致病性（P/LP）KCNE1 阳性个体中观察到的临床表型。
总体而言，在 1026 例 LQTS 患者中的 38 例（3.7%）中发现了 6 种 KCNE1 变异。根据现有数据，2 种 KCNE1 变异（p.Asp76Asn-KCNE1 和 p.Arg98Trp-KCNE1）被归类为 P/LP。而 p.Ser28Leu-KCNE1 VUS 表现出丧失功能的 EP 表型（I 电流减少 72%），被升级为 LP 变异，而其余 3 种 KCNE1 VUS（p.Arg67Cys-KCNE1、p.Arg67His-KCNE1 和 p.Ser74Leu-KCNE1）与野生型无法区分。总的来说，p.Ser28Leu-KCNE1-、p.Asp76Asn-KCNE1-和 p.Arg98Trp-KCNE1 阳性个体（n=22）的表型相对较弱（91%无症状；平均 QTc 444±19 ms；27%在运动/恢复期间出现适应性 QTc 反应）。
本研究表明，p.Ser28Leu-KCNE1 可能是类似于 p.Asp76Asn-KCNE1 和 p.Arg98Trp-KCNE1 的 LQT5 致病底物。然而，这些 P/LP 变异与较弱的表型和累积的 gnomAD MAF（42/141,156）相关，表明 LQT5/KCNE-LQTS 可能比之前预期的更为常见/较弱的 LQTS 形式。
