Zhang Kuo, Lin Guigao, Han Dongsheng, Han Yanxi, Peng Rongxue, Li Jinming
National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China.
Front Genet. 2022 Mar 10;13:829728. doi: 10.3389/fgene.2022.829728. eCollection 2022.
This study aimed to evaluate inter-laboratory classification concordance for copy number variants (CNVs) with a semiquantitative point-based scoring metric recommended by the American College of Medical Genetics and Genomics (ACMG) and Clinical Genome Resources (ClinGen). A total of 234 CNVs distributed by the National Center of Clinical Laboratories (NCCLs), and 72 CNVs submitted by different laboratories, were distributed to nine clinical laboratories performing routine clinical CNV testing in China and independently classified across laboratories. The overall inter-laboratory complete classification concordance rate of the 234 distributed CNVs increased from 18% (41/234) to 76% (177/234) using the scoring metric compared to the laboratory's previous method. The overall inter-laboratory complete classification concordance rate of the 72 submitted CNVs was 65% (47/72) using the scoring metrics. The 82 variants that initially did not reach complete concordance classification and 1 additional CNV deletion were reviewed; 34 reached complete agreement, and the overall post-review complete concordance rate was 85% (260/306). Additionally, the overall percentage of classification discordance possibly impacting medical management [i.e., pathogenic (P) or likely pathogenic (LP) vs. variant of uncertain significance (VUS)] was 11% (35/306). The causes of initial and final discordance in the classification were identified. The ACMG-ClinGen framework has promoted consistency in interpreting the clinical significance of CNVs. Continuous training among laboratories, further criteria and additional clarification of the standards, sharing classifications and supporting evidence through public database, and ongoing work for dosage sensitive genes/regions curation will be beneficial for harmonization of CNVs classification.
本研究旨在使用美国医学遗传学与基因组学学会（ACMG）和临床基因组资源（ClinGen）推荐的基于半定量评分指标，评估各实验室间对拷贝数变异（CNV）分类的一致性。国家临床检验中心（NCCLs）分发的234个CNV以及不同实验室提交的72个CNV，被分发给中国9家进行常规临床CNV检测的临床实验室，并由各实验室独立进行分类。与实验室之前的方法相比，使用该评分指标，234个分发的CNV的实验室间总体完全分类一致率从18%（41/234）提高到了76%（177/234）。使用该评分指标，72个提交的CNV的实验室间总体完全分类一致率为65%（47/72）。对最初未达到完全一致分类的82个变异和另外1个CNV缺失进行了复查；34个达到了完全一致，复查后的总体完全一致率为85%（260/306）。此外，分类不一致可能影响医疗管理的总体比例[即致病性（P）或可能致病性（LP）与意义未明变异（VUS）相比]为11%（35/306）。确定了分类中初始和最终不一致的原因。ACMG-ClinGen框架促进了CNV临床意义解释的一致性。实验室间持续培训、进一步的标准和对标准的额外澄清、通过公共数据库共享分类和支持证据，以及对剂量敏感基因/区域管理的持续工作，将有利于CNV分类的统一。
