Division of Pediatric Cardiology, Department of Pediatrics (M.B.R., I.M.L., A.P.L.), Duke University School of Medicine, Durham, NC.
Department of Cell Biology (A.P.L.), Duke University School of Medicine, Durham, NC.
Circ Genom Precis Med. 2022 Jun;15(3):e003491. doi: 10.1161/CIRCGEN.121.003491. Epub 2022 May 11.
Accurately determining variant pathogenicity is critical in the diagnosis of cardiac channelopathies; however, it remains unknown how variant pathogenicity status changes over time. Our aim is to use a comprehensive analysis of ClinVar to understand the mutability of variant evaluation in channelopathy-associated genes to inform clinical decision-making around variant calling.
We identified 10 genes () strongly associated with cardiac channelopathies, as well as 3 comparison gene sets (disputed long QT syndrome, sudden unexpected death in epilepsy, and all ClinVar). We comprehensively analyzed variant pathogenicity calls over time using the ClinVar database with Rstudio. Analyses focused on the frequency and directionality of clinically meaningful changes in disease association, defined as a change from one of the following three categories to another: likely benign/benign, conflicting evidence of pathogenicity/variant of uncertain significance, and likely pathogenic/pathogenic.
In total, among channelopathy-associated genes, there were 9975 variants in ClinVar and 8.4% had a clinically meaningful change in disease association at least once over the past 10 years, as opposed to 4.9% of all ClinVar variants. The 3 channelopathy-associated genes with the most variants undergoing a clinically significant change were (20.9%) (11.2%), and (10.1%). Ten of the 12 included genes had variant evaluations that trended toward diagnostic uncertainty over time. Specifically, channelopathy-associated gene variants with either pathogenic/likely pathogenic or benign/likely benign assignments were 5.6× and 2×, respectively, as likely to be reevaluated to conflicting/variant of uncertain significance compared to the converse.
Over the past 10 years, 8.4% of variants in channelopathy-associated genes have changed pathogenicity status with a decline in overall diagnostic certainty. Ongoing clinical and genetic variant follow-up is needed to account for presence of clinically meaningful change in variant pathogenicity assignment over time.
准确确定变异的致病性对于心脏通道病的诊断至关重要；然而，目前尚不清楚变异的致病性状态随时间如何变化。我们的目的是使用 ClinVar 的综合分析来了解通道病相关基因中变异评估的可变性，以告知围绕变异调用的临床决策。
我们确定了 10 个（）与心脏通道病强烈相关的基因，以及 3 个比较基因集（有争议的长 QT 综合征、癫痫猝死和所有 ClinVar）。我们使用 Rstudio 全面分析了 ClinVar 数据库中随时间变化的变异致病性调用。分析重点是疾病相关性的临床有意义的变化的频率和方向性，定义为以下三个类别之一到另一个类别的变化：可能良性/良性、致病性/不确定意义的变异的矛盾证据，以及可能的致病性/致病性。
在总共的 ClinVar 中，通道病相关基因中有 9975 个变异，其中 8.4%在过去 10 年内至少有一次疾病相关性的临床有意义变化，而所有 ClinVar 变异的 4.9%。在经历临床显著变化的 3 个通道病相关基因中，（20.9%）（11.2%）和 （10.1%）的变异最多。12 个纳入基因中有 10 个的变异评估随着时间的推移趋于诊断不确定性。具体来说，与相反的情况相比，致病性/可能致病性或良性/可能良性分配的通道病相关基因变异更有可能被重新评估为矛盾/变异的不确定意义，分别为 5.6 倍和 2 倍。
在过去的 10 年中，8.4%的通道病相关基因的变异已经改变了致病性状态，整体诊断确定性下降。需要进行持续的临床和遗传变异随访，以说明变异致病性赋值随时间的临床意义变化。
