A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders
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DOI：
10.1002/humu.22918
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发表时间：
2016-01-01
期刊：
影响因子：
3.9
通讯作者：
Higgins, Joseph J.
中科院分区：
文献类型：
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作者：
Karbassi, Izabela;Maston, Glenn A.;Higgins, Joseph J.
我们开发了一个基于规则的评分系统，将DNA变异分为五类，包括致病、可能致病、不确定意义的变异(VUS)、可能良性和良性。根据从内部和外部收集的预测工具、种群频率、共生情况、分离和功能研究，对338个基因的11,894个变种的16,500多个致病性评估进行了致病性分析。分数是由训练有素的科学家使用量化框架计算出来的，该框架为这五种类型的数据分配了不同的权重。我们对数据集进行了描述性和比较统计，并测试了训练有素的科学家之间的观察者之间的一致性。私人变异定义为在单个家庭中发现的变异(n=5,182)，要么是vus(80.5%；n=4,169)，要么是可能致病的(19.5%；n=1,013)。其余变异(n=6,712)为VUS(38.4%；n=2,577)或可能良性/良性(34.7%；n=2,327)或可能致病/致病(26.9%，n=1,808)。受训科学家对最终变量得分的准确符合率为98.5%[95%可信区间(CI)(98.0，98.9)]，观察者间一致性为97%[95%CI(91.5，99.4)]。不同的分数是稳定的，当定期重新评估时，显示与新数据一致的几率增加。这一精心策划的标准化变种致病性评分系统为临床实验室环境中遇到的DNA变种提供了可靠的致病评分。
We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies collected from internal and external sources. Scores were calculated by trained scientists using a quantitative framework that assigned differential weighting to these five types of data. We performed descriptive and comparative statistics on the dataset and tested interobserver concordance among the trained scientists. Private variants defined as variants found within single families (n=5,182), were either VUS (80.5%; n=4,169) or likely pathogenic (19.5%; n=1,013). The remaining variants (n=6,712) were VUS (38.4%; n=2,577) or likely benign/benign (34.7%; n=2,327) or likely pathogenic/pathogenic (26.9%, n=1,808). Exact agreement between the trained scientists on the final variant score was 98.5% [95% confidence interval (CI) (98.0, 98.9)] with an interobserver consistency of 97% [95% CI (91.5, 99.4)]. Variant scores were stable and showed increasing odds of being in agreement with new data when re-evaluated periodically. This carefully curated, standardized variant pathogenicity scoring system provides reliable pathogenicity scores for DNA variants encountered in a clinical laboratory setting.