Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance
Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance
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DOI：
10.1161/circgen.119.002510
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发表时间：
2019-05-01
影响因子：
7.4
通讯作者：
Ackerman, Michael J.
中科院分区：
文献类型：
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作者：
Giudicessi, John R.;Lieve, Krystien V. V.;Ackerman, Michael J.
背景技术背景：在临床确诊的儿茶酚胺能多形性室性心动过速患者中发现的许多罕见的、潜在致病的RYR 2变异体被模糊地归类为意义不确定的变异体（VUS）。我们的目的是确定一个表型增强的变异分类方法，可以减少负担RYR 2 VUS遇到临床genetictesting.METHODS：这项回顾性研究进行了84 RYR 2阳性的个人从马约诊所（罗切斯特，MN）和验证149 RYR 2阳性的个人从阿姆斯特丹大学医学中心（阿姆斯特丹，荷兰）。使用新开发的诊断记分卡，测定所有RYR 2阳性个体的儿茶酚胺能多形性室性心动过速的预试验临床概率。每个RYR 2变异，然后重新调整使用表型增强的美国医学遗传学学院的方法，采用新的标准，反映了与每个人RYR 2 variant.RESULTS相关的表型强度：总体而言，72个不同的RYR 2变异被确定之间的84马约诊所（39独特）和149阿姆斯特丹大学医学中心（30独特）的情况下。两个队列中均存在三种变体。美国医学遗传学学会指南将所有RYR 2变体的47%归类为VUS。在马约诊所的队列中，使用美国医学遗传学学会改良的表型增强标准进行再判定，VUS率显著下降（20/42 [48%] vs 3/42 [7%]; P
BACKGROUND: Many rare, potentially pathogenic, RYR2 variants identified in individuals with clinically definite catecholaminergic polymorphic ventricular tachycardia are classified ambiguously as variants of uncertain significance (VUS). We aimed to determine if a phenotype-enhanced variant classification approach could reduce the burden of RYR2 VUS encountered during clinical genetic testing.METHODS: This retrospective study was conducted in 84 RYR2-positive individuals from the Mayo Clinic (Rochester, MN) and validated in 149 RYR2-positive individuals from Amsterdam University Medical Center (Amsterdam, NL). Using a newly developed diagnostic scorecard, the pretest clinical probability of catecholaminergic polymorphic ventricular tachycardia was determined for all RYR2-positive individuals. Each RYR2 variant was then readjudicated using a phenotype-enhanced American College of Medical Genetics approach that incorporates new criteria that reflect the phenotypic strength associated with each individual RYR2 variant.RESULTS: Overall, 72 distinct RYR2 variants were identified among the 84 Mayo Clinic (39 unique) and 149 Amsterdam University Medical Center (30 unique) cases. Three variants were present in both cohorts. American College of Medical Genetics guidelines classified 47% of all RYR2 variants as VUS. In the Mayo Clinic cohort, readjudication using amended phenotype-enhanced American College of Medical Genetics standards dropped the VUS rate significantly (20/42 [48%] versus 3/42 [7%]; P