A phenotype-enhanced variant classification framework to decrease the burden of missense variants of uncertain significance in type 1 long QT syndrome,Heart Rhythm

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A phenotype-enhanced variant classification framework to decrease the burden of missense variants of uncertain significance in type 1 long QT syndrome
Heart Rhythm ( IF 5.5 ) Pub Date : 2021-11-17 , DOI: 10.1016/j.hrthm.2021.11.017
Sahej Bains ₁ , Steven M Dotzler ₁ , Christian Krijger ₂ , John R Giudicessi ₃ , Dan Ye ₄ , Hennie Bikker ₅ , Ram K Rohatgi ₆ , David J Tester ₇ , J Martijn Bos ₇ , Arthur A M Wilde ₈ , Michael J Ackerman ₇

Affiliation

Medical Scientist Training Program, Mayo Clinic, Rochester, Minnesota; Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota.
Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, Minnesota.
Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota.
Department of Human Genetics, University of Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands.
Department of Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), Mayo Clinic, Rochester, Minnesota.
Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota; Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, Minnesota; Department of Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), Mayo Clinic, Rochester, Minnesota.
Department of Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Cardiology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background

Pathogenic/likely pathogenic (P/LP) variants in the KCNQ1-encoded Kv7.1 potassium channel cause type 1 long QT syndrome (LQT1). Despite the revamped 2015 American College of Medical Genetics (ACMG) variant interpretation guidelines, the burden of KCNQ1 variants of uncertain significance (VUS) in patients with LQTS remains ∼30%.

Objective

The purpose of this study was to determine whether a phenotype-enhanced (PE) variant classification approach could reduce the VUS burden in LQTS genetic testing.

Methods

Retrospective analysis was performed on 79 KCNQ1 missense variants in 356 patients from Mayo Clinic and an independent cohort of 42 variants in 225 patients from Amsterdam University Medical Center (UMC). Each variant was classified initially using the ACMG guidelines and then readjudicated using a PE-ACMG framework that incorporated the LQTS clinical diagnostic Schwartz score plus 4 “LQT1-defining features”: broad-based/slow upstroke T waves, syncope/seizure during exertion, swimming-associated events, and a maladaptive LQT1 treadmill stress test.

Results

According to the ACMG guidelines, Mayo Clinic variants were classified as follows: 17 of 79 P variants (22%), 34 of 79 LP variants (43%), and 28 of 79 VUS (35%). Similarly, for Amsterdam UMC, the variant distribution was 9 of 42 P variants (22%), 14 of 42 LP variants (33%), and 19 of 42 variants VUS (45%). After PE-ACMG readjudication, the total VUS burden decreased significantly from 28 (35%) to 13 (16%) (P = .0007) for Mayo Clinic and from 19 (45%) to 12 (29%) (P = .02) for Amsterdam UMC.

Conclusion

Phenotype-guided variant adjudication decreased significantly the VUS burden of LQT1 case–derived KCNQ1 missense variants in 2 independent cohorts. This study demonstrates the value of incorporating LQT1-specific phenotype/clinical data to aid in the interpretation of KCNQ1 missense variants identified during genetic testing for LQTS.

中文翻译：

一种表型增强的变异分类框架，可减少 1 型长 QT 综合征中意义不确定的错义变异的负担

背景

KCNQ1编码的Kv7.1 钾通道中的致病性/可能致病性 (P/LP) 变异导致 1 型长 QT 综合征 (LQT1)。尽管修订了 2015 年美国医学遗传学会 (ACMG) 变异解释指南，但LQTS 患者中意义不确定的KCNQ1变异 (VUS) 的负担仍然约为 30%。

客观的

本研究的目的是确定表型增强 (PE) 变异分类方法是否可以减少 LQTS 基因检测中的 VUS 负担。

方法

对来自 Mayo Clinic 的 356 名患者的 79 个KCNQ1错义变异以及来自阿姆斯特丹大学医学中心 (UMC) 的 225 名患者的 42 个变异的独立队列进行了回顾性分析。每个变体最初使用 ACMG 指南进行分类，然后使用 PE-ACMG 框架重新判断，该框架结合了 LQTS 临床诊断 Schwartz 评分和 4 个“LQT1 定义特征”：广泛/缓慢上行 T 波、劳累时晕厥/癫痫发作、游泳相关事件和适应不良的 LQT1 跑步机压力测试。

结果

根据 ACMG 指南，Mayo Clinic 变体分类如下：79 个 P 变体中的 17 个（22%）、79 个 LP 变体中的 34 个（43%）和 79 个 VUS 中的 28 个（35%）。同样，对于阿姆斯特丹 UMC，变异分布为 42 个 P 变异中的 9 个 (22%)、42 个 LP 变异中的 14 个 (33%) 和 42 个 VUS 变异中的 19 个 (45%)。在 PE-ACMG 重新裁定后，Mayo Clinic 的总 VUS 负担从 28 (35%) 显着降低到 13 (16%) ( P = .0007)，从 19 (45%) 显着降低到 12 (29%) ( P = . 02) 为阿姆斯特丹联电。