Characterizing sensitivity and coverage of clinical WGS as a diagnostic test for genetic disorders.
Characterizing sensitivity and coverage of clinical WGS as a diagnostic test for genetic disorders.
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表征临床WGS的灵敏度和覆盖范围是对遗传疾病的诊断测试。
DOI：
10.1186/s12920-021-00948-5
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发表时间：
2021-04-13
影响因子：
2.7
通讯作者：
Peng Z
中科院分区：
文献类型：
--
作者：
Sun Y;Liu F;Fan C;Wang Y;Song L;Fang Z;Han R;Wang Z;Wang X;Yang Z;Xu Z;Peng J;Shi C;Zhang H;Dong W;Huang H;Li Y;Le Y;Sun J;Peng Z
由于其降低的成本和无可比拟的优势，WGS很可能会导致罕见病和未确诊疾病临床诊断的改变。然而，临床全基因组测序作为遗传性疾病诊断测试的敏感性和覆盖范围尚未得到充分评估。在此，通过使用 MGISEQ-2000 评估其敏感性、PPV、覆盖深度和广度，测量了 NA12878、YH 细胞系和中国三人组中 WGS 的性能。我们还使用 NA12878 比较了 WES 和 WGS 的性能。使用中国三人组的基于家庭的三人组设计来测试灵敏度和PPV。我们进一步开发了系统的 WGS 流程来分析 8 个临床病例。一般来说，SNV/indel 检测的灵敏度和 PPV 随着平均深度的增加而增加，并使用 NA12878 的下采样样本在 40 倍平均深度处达到稳定水平。平均深度为40X时，NA12878纯合子和杂合子SNP的灵敏度分别为≥99.25%和≥99.50%，PPV分别为99.97%和98.96%。纯合和杂合插入缺失表现出较低的敏感性和 PPV。即使平均深度达到 ~ 150X，灵敏度和PPV仍然不是100%。我们还观察到不同工具的 CNV 检测灵敏度存在显着差异，特别是在大小小于 1 kb 的 CNV 中。一般来说，疾病相关基因和 CNV 的覆盖广度随着平均深度的增加而增加。 WGS (~ 40X) 的灵敏度和覆盖范围优于 WES (~ 120X)。在平均深度≥40倍的中国三人组中，后代对SNP和indel检测的敏感性分别为≥99.48%和≥96.36%，PPV分别为99.86%和97.93%。使用我们的 WGS 管道成功检测到 8 个临床病例中的所有 12 个先前验证的变异。当前 40X 平均深度的标准可能足以用于大多数 CNV 的 SNV/indel 检测和识别。建议临床科学家确定特定 WGS 管道的不同类别变异的敏感性和 PPV 范围，这在解释和提供临床报告时非常有用。在线版本包含可在 10.1186/s12920-021-00948-5 获取的补充材料。
Due to its reduced cost and incomparable advantages, WGS is likely to lead to changes in clinical diagnosis of rare and undiagnosed diseases. However, the sensitivity and breadth of coverage of clinical WGS as a diagnostic test for genetic disorders has not been fully evaluated. Here, the performance of WGS in NA12878, the YH cell line, and the Chinese trios were measured by assessing their sensitivity, PPV, depth and breadth of coverage using MGISEQ-2000. We also compared the performance of WES and WGS using NA12878. The sensitivity and PPV were tested using the family-based trio design for the Chinese trios. We further developed a systematic WGS pipeline for the analysis of 8 clinical cases. In general, the sensitivity and PPV for SNV/indel detection increased with mean depth and reached a plateau at an ~ 40X mean depth using down-sampling samples of NA12878. With a mean depth of 40X, the sensitivity of homozygous and heterozygous SNPs of NA12878 was > 99.25% and > 99.50%, respectively, and the PPV was 99.97% and 98.96%. Homozygous and heterozygous indels showed lower sensitivity and PPV. The sensitivity and PPV were still not 100% even with a mean depth of ~ 150X. We also observed a substantial variation in the sensitivity of CNV detection across different tools, especially in CNVs with a size less than 1 kb. In general, the breadth of coverage for disease-associated genes and CNVs increased with mean depth. The sensitivity and coverage of WGS (~ 40X) was better than WES (~ 120X). Among the Chinese trios with an ~ 40X mean depth, the sensitivity among offspring was > 99.48% and > 96.36% for SNP and indel detection, and the PPVs were 99.86% and 97.93%. All 12 previously validated variants in the 8 clinical cases were successfully detected using our WGS pipeline. The current standard of a mean depth of 40X may be sufficient for SNV/indel detection and identification of most CNVs. It would be advisable for clinical scientists to determine the range of sensitivity and PPV for different classes of variants for a particular WGS pipeline, which would be useful when interpreting and delivering clinical reports. The online version contains supplementary material available at 10.1186/s12920-021-00948-5.
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DOI：
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发表时间：
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