Recent advances in next-genetic sequencing technology have facilitated an expansion in the use of exome and genome sequencing in the research and clinical settings. While this has aided in the genetic diagnosis of individuals with atypical clinical presentations, there has been a marked increase in the number of incidentally identified variants of uncertain diagnostic significance in genes identified as clinically actionable by the American College of Medical Genetics guidelines. Approximately 20 of these genes are associated with cardiac diseases, which carry a significant risk of sudden cardiac death. While identification of at-risk individuals is paramount, increased discovery of incidental variants of uncertain diagnostic significance has placed a burden on the clinician tasked with determining the diagnostic significance of these findings. Herein, we describe the scope of this emerging problem using cardiovascular genetics to illustrate the challenges associated with variants of uncertain diagnostic significance interpretation. We review the evidence for diagnostic weight of these variants, discuss the role of clinical genetics providers in patient care, and put forward general recommendations about the interpretation of incidentally identified variants found with clinical genetic testing.

中文翻译：

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解释与心脏通道病和心肌病相关的基因的偶然遗传发现

下一代基因测序技术的最新进展促进了外显子组和基因组测序在研究和临床环境中的应用的扩展。虽然这有助于对具有非典型临床表现的个体进行基因诊断，但在美国医学遗传学会指南确定为临床可操作的基因中，偶然发现的具有不确定诊断意义的变异的数量显着增加。这些基因中大约有 20 个与心脏病相关，这些疾病具有导致心源性猝死的显着风险。虽然识别有风险的个体至关重要，但越来越多地发现具有不确定诊断意义的偶然变异给负责确定这些发现的诊断意义的临床医生带来了负担。在这里，我们使用心血管遗传学描述了这一新兴问题的范围，以说明与不确定诊断意义解释的变体相关的挑战。我们回顾了这些变异的诊断权重的证据，讨论了临床遗传学提供者在患者护理中的作用，并就临床基因检测中偶然发现的变异的解释提出了一般性建议。