Genomic sequencing tests generate less uncertainty and higher diagnostic yield compared to multi-gene panel-based tests: Results of over 1.5 million tests
Genomic sequencing tests generate less uncertainty and higher diagnostic yield compared to multi-gene panel-based tests: Results of over 1.5 million tests
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与基于多基因组的测试相比，基因组测序测试产生的不确定性更少，诊断率更高：超过 150 万次测试的结果
DOI：
10.1101/2022.09.21.22279949
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Niu
中科院分区：
文献类型：
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作者：
H. Rehm;J. Alaimo;S. Aradhya;P. Bayrak;H. Best;R. Brandon;J. Buchan;E. Chao;E. Chen;J. Clifford;A. Cohen;L. Conlin;S. Das;K. W. Davis;D. del Gaudio;F. del Viso;C. Divincenzo;M. Eisenberg;L. Guidugli;M. Hammer;S. M. Harrison;K. Hatchell;L. Havens Dyer;L. Hoang;J. Holt;V. Jobanputra;I. Karbassi;H. Kearney;M. Kelly;J. M. Kelly;M. L. Kluge;T. Komala;P. Kruszka;L. Lau;M. Lebo;C. Marshall;D. McKnight;K. Mcwalter;Y. Meng;N. Nagan;C. Neckelmann;N. Neerman;Niu
基因检测经常识别不确定意义的变异（VUS）。然而，提供者往往准备不足或时间太紧，无法管理这些发现，保险公司担心对临床护理和成本的影响。在这里，我们比较了基于小组和基因组（外显子组和基因组）测试对VUS产生不确定结果的贡献。方法：从2020 - 2021年北美19个临床实验室的150多万次测序测试结果中确定了VUS导致的不确定结果率和诊断率。结果我们发现，与多基因组检测（32.6%; p<0.001）相比，基因组检测（22.5%）由于VUS导致的不确定性检测结果的发生率更低，诊断率更高（17.5% vs 10.3%; p<0.001）。对于面板测试，不确定结果的比率与面板大小相关。使用trios提高了产量（19.5% vs 15.2%; p<0.001），降低了不确定率（18.9% vs 27.6%; p<0.001）。与外显子组相比，使用基因组测序提高了产量（25.1% vs 16.6%; p<0.001），而没有增加不确定结果的比率（22.2% vs 22.6%）。结论基因组测序证明了降低的不确定性和更高的分子诊断产率相比，面板测试。与基因组检测相比，在基于小组的检测中强制性报告所有VUS（其中使用与表型的相关性来限制变异报告），可以最好地解释这种差异。这些结果可能会为未来的基因检测实践提供信息，并提高对基因检测解释所涉及的专业技能的认识。
BACKGROUND Genetic testing frequently identifies variants of uncertain significance (VUSs). Providers, however, are often ill-prepared or too time-constrained to manage these findings, and insurers are concerned about impacts on clinical care and cost. Here we compared the contribution of panel-based and genomic (exome and genome) testing to the generation of inconclusive results due to VUSs. METHODS Rates of inconclusive results due to VUS and diagnostic yield were determined from over 1.5 million sequencing test results from 19 clinical laboratories in North America from 2020 - 2021. RESULTS We found a lower rate of inconclusive test results due to VUSs from genomic tests (22.5%) compared to multi-gene panel tests (32.6%; p<0.001) and a higher diagnostic yield (17.5% vs 10.3%; p<0.001). For panel tests, the rate of inconclusive results correlated with panel size. The use of trios improved yield (19.5% vs 15.2%; p<0.001) and reduced inconclusive rates (18.9% vs 27.6%; p<0.001). The use of genome sequencing compared to exome improved yield (25.1% vs 16.6%; p<0.001) without increasing the rate of inconclusive results (22.2% vs 22.6%). CONCLUSION Genomic sequencing demonstrated reduced uncertainty and higher molecular diagnostic yield compared to panel testing. This difference is best explained by obligatory reporting of all VUSs in panel-based testing compared to genomic testing where correlation with phenotype is used to constrain variant reporting. These results may inform future genetic testing practices and heighten appreciation for the professional skills involved in genomic test interpretation.