Background - Mutation/variant-site specific risk stratification in long-QT syndrome type 1 (LQT1) has been well investigated, but it is still challenging to adapt current enormous genomic information to clinical aspects caused by each mutation/variant. We assessed a novel variant-specific risk stratification in LQT1 patients.Methods - We classified a pathogenicity of 141 KCNQ1 variants among 927 LQT1 patients (536 probands) based on the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines and evaluated whether the ACMG/AMP-based classification was associated with arrhythmic risk in LQT1 patients.Results - Among 141 KCNQ1 variants, 61 (43.3%), 55 (39.0%), and 25 (17.7%) variants were classified into pathogenic (P), likely pathogenic (LP), and variant of unknown significance (VUS), respectively. Multivariable analysis showed that proband (HR = 2.53; 95%CI = 1.94-3.32; p <0.0001), longer QTc (≥500ms) (HR = 1.44; 95%CI = 1.13-1.83; p = 0.004), variants at membrane spanning (MS) (vs. those at N/C terminus) (HR = 1.42; 95%CI = 1.08-1.88; p = 0.01), C-loop (vs. N/C terminus) (HR = 1.52; 95%CI = 1.06-2.16; p = 0.02), and P variants [(vs. LP) (HR = 1.72; 95%CI = 1.32-2.26; p <0.0001), (vs. VUS) (HR = 1.81; 95%CI = 1.15-2.99; p = 0.009)] were significantly associated with syncopal events. The ACMG/AMP-based KCNQ1 evaluation was useful for risk stratification not only in family members but also in probands. A clinical score (0~4) based on proband, QTc (≥500ms), variant location (MS or C-loop) and P variant by ACMG/AMP guidelines allowed identification of patients more likely to have arrhythmic events.Conclusions - Comprehensive evaluation of clinical findings and pathogenicity of KCNQ1 variants based on the ACMG/AMP-based evaluation may stratify arrhythmic risk of congenital long-QT syndrome type 1.

中文翻译：

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使用 ACMG/AMP 指南对 KCNQ1 变异体进行系统评估以及 1 型长 QT 综合征的风险分层。


背景- 1 型长 QT 综合征 (LQT1) 的突变/变异位点特异性风险分层已得到充分研究，但将当前大量基因组信息适应每种突变/变异引起的临床方面仍然具有挑战性。我们评估了 LQT1 患者的一种新的变异特异性风险分层。方法- 我们根据美国医学遗传学和基因组学学会 (ACMG) 和分子病理学协会 (AMP) 指南对 927 名 LQT1 患者（536 名先证者）中的 141 个KCNQ1变异的致病性进行了分类，并评估了基于 ACMG/AMP 的分类是否正确。与 LQT1 患者的心律失常风险相关。结果- 在 141 个KCNQ1变异中，分别有 61 个 (43.3%)、55 个 (39.0%) 和 25 个 (17.7%) 变异被分类为致病性 (P)、可能致病性 (LP) 和意义不明的变异 (VUS) 。多变量分析显示，先证者（HR = 2.53；95%CI = 1.94-3.32；p<0 id=30>KCNQ1评估不仅对家庭成员而且对先证者的风险分层有用。临床评分（0~4）根据 ACMG/AMP 指南，基于先证者、QTc（≥500ms）、变异位置（MS 或 C 环）和 P 变异，可以识别更有可能发生心律失常事件的患者。结论- 综合评估KCNQ1变异的临床表现和致病性。基于 ACMG/AMP 的评估可以对先天性长 QT 综合征 1 型的心律失常风险进行分层。