采用ACMG-ClinGen新指南对单中心拷贝数变异的大样本进行回顾性分析

A large-scale retrospective analysis of copy number variations in single center using ACMG-ClinGen latest guidelines

目的通过对单中心拷贝数变异(copy number variations,CNVs)的大样本进行回顾性分析,探讨2019年美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)和临床基因组资源(Clinical Genome Resource,ClinGen)共同提出的《拷贝数变异解读和报告的技术标准指南》对CNVs评级以及临床实验室CNVs解读一致性的影响。方法对本中心2018年8月至2019年12月行单核苷酸多态性微阵列分析、按2011年ACMG指南评估为致病性以及不明临床意义(包括可能致病、临床意义不明和可能良性)的235例CNVs进行重新分析。4名工作人员根据2019年最新指南的解读标准重新进行分类。结果4名工作人员重新进行CNVs临床意义分类的一致性达91%,α检验系数为0.98。对比2011年和2019年版ACMG指南对于CNVs分类的结果显示,原致病性和临床意义不明确的变异解读基本保持一致;原可能致病和可能良性的变异重分析后90%(45/50)被分类为临床意义不明确,差异较为明显。结论最新的CNVs解读和报告标准通过半定量评分系统,结合本中心自建数据库,有助于提高实验室对CNVs结果分析的一致性,也让CNV的解读变得更加规范和透明。

Objective Through a retrospective large sample analysis of copy number variants in single center,we explored the technical standards for the interpretation and reporting of constitutional copy number variants(CNVs)jointly proposed by the American College of Medical Genetics and Genomics(ACMG)and the Clinical Genome Resource(ClinGen)in 2019,analyzing its impact on CNVs ratings and the improvement in the consistency of the classification of CNVs in clinical laboratories.Methods 236 CNVs that assessed as pathogenic,uncertain significant(including likely pathogenic,uncertain and likely benign)by the 2011 ACMG guidelines between August 2018 and December 2019 in our center were re-analyzed.Four working group members of the center reclassified and evaluated 235 CNVs according to 2019 ACMG guidelines.Results The consistency of clinical significance classification of CNVs was 91%and theαtest coefficient was 0.98 among four working group members.Compared with the 2011 and 2019 ACMG technical standards for the CNVs classification,evaluation of pathogenicity and uncertain significant is basically consistent.90%(45/50)of likely pathogenic and likely benign CNVs were Re-evaluated as variants of uncertain significance,and the difference is significant.Conclusion The new version ACMG/ClinGen guidelines for the evaluation of CNVs developed semi-quantitative point-based scoring system and help to improve the consistency in clinical classifications.It can also make the interpretation of CNVs more standardized and transparent.