判断 SCN5A Brugada 综合征相关变异的功能测定的多点验证。

IF 6 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Joanne G Ma, Matthew J O'Neill, Ebony Richardson, Kate L Thomson, Jodie Ingles, Ayesha Muhammad, Joseph F Solus, Giovanni Davogustto, Katherine C Anderson, M Benjamin Shoemaker, Andrew B Stergachis, Brendan J Floyd, Kyla Dunn, Victoria N Parikh, Henry Chubb, Mark J Perrin, Dan M Roden, Jamie I Vandenberg, Chai-Ann Ng, Andrew M Glazer
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引用次数: 0

摘要

背景:Brugada 综合征是一种遗传性心律失常,与 SCN5A 中罕见的功能缺失变异有关。解释 SCN5A 错义变异的致病性具有挑战性,ClinVar 中≈79% 的 SCN5A 错义变异目前被归类为意义不确定的变异。自动膜片钳技术实现了离子通道变异的高通量功能研究,并能为变异的重新分类提供证据:体外 SCN5A-Brugada 综合征自动膜片钳测定在范德比尔特大学医学中心和维克多-张心脏研究所(Victor Chang Cardiac Research Institute)产生并进行了独立研究。根据 ClinGen 序列变异解释建议,使用高置信度变异对照(n=49)对该测定进行了校准。根据良性变异检测结果的分布确定了正常和异常功能范围。根据 ClinGen 序列变异解释建议,从实验结果中得出致病几率值。校准后的检测结果被用于研究在 4 个患有 Brugada 综合征和其他与 SCN5A 功能缺失相关的心律失常表型的家族中观察到的意义不确定的 SCN5A 变异:在两个研究地点独立生成的变异通道参数显示出很强的相关性,包括 INa 密度峰值(R2=0.86)。该检测能准确区分良性对照组(24/25 个一致变异)和致病对照组(23/24 个一致变异)。正常功能的致病几率值为 0.042,异常功能的致病几率值为 24.0,与美国医学遗传学和基因组学学会/分子病理学协会良性和致病功能标准(分别为 BS3 和 PS3)的有力证据相对应。对4个临床意义不确定的SCN5A变异应用该检测方法,发现3/4的变异存在功能缺失,从而将其重新分类为可能致病的变异:这一经过验证的高通量测定提供了临床级功能证据,有助于对目前和未来意义不确定的SCN5A-Brugada综合征变异进行分类。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Multisite Validation of a Functional Assay to Adjudicate SCN5A Brugada Syndrome-Associated Variants.

Background: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in SCN5A. Interpreting the pathogenicity of SCN5A missense variants is challenging, and ≈79% of SCN5A missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification.

Methods: An in vitro SCN5A-Brugada syndrome automated patch clamp assay was independently performed at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study SCN5A variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with SCN5A loss-of-function.

Results: Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak INa density (R2=0.86). The assay accurately distinguished benign controls (24/25 concordant variants) from pathogenic controls (23/24 concordant variants). Odds of pathogenicity values were 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical SCN5A variants of uncertain significance revealed loss-of-function for 3/4 variants, enabling reclassification to likely pathogenic.

Conclusions: This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future SCN5A-Brugada syndrome variants of uncertain significance.

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来源期刊
Circulation: Genomic and Precision Medicine
Circulation: Genomic and Precision Medicine Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
9.20
自引率
5.40%
发文量
144
期刊介绍: Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations. Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.
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