Evaluating the performance of a clinical genome sequencing program for diagnosis of rare genetic disease, seen through the lens of craniosynostosis.
Evaluating the performance of a clinical genome sequencing program for diagnosis of rare genetic disease, seen through the lens of craniosynostosis.
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DOI：
10.1038/s41436-021-01297-5
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Wilkie AOM
中科院分区：
文献类型：
--
作者：
Hyder Z;Calpena E;Pei Y;Tooze RS;Brittain H;Twigg SRF;Cilliers D;Morton JEV;McCann E;Weber A;Wilson LC;Douglas AGL;McGowan R;Need A;Bond A;Tavares ALT;Thomas ERA;Genomics England Research Consortium;Hill SL;Deans ZC;Boardman-Pretty F;Caulfield M;Scott RH;Wilkie AOM
用于诊断罕见遗传病的基因组测序(GS)正被引入临床，但数据的复杂性给开发具有高诊断灵敏度的管道提出了挑战。我们评估了英国基因组学100,000基因组计划(100kGP)基于面板的管道的性能，使用颅骨融合症作为测试疾病。一个专门的研究小组仔细检查了114名患有颅缝早闭的先证者及其亲属(314个样本)的GS数据，这些数据没有经过常规基因测试，并将诊断结果与100kGP做出的诊断进行了比较。100kGP鉴定出16个可能的致病/致病变异。研究小组还确定了另外18个可能的致病/致病变异，表明100kGP板对颅缝融合症的诊断敏感性仅为47%。可以增加诊断的措施是改进现有的小组基因(+18%的灵敏度)，审查更新的小组(+12%)，对从头开始的小变异的综合分析(+29%)和拷贝数/结构变异(+9%)。英国国民健康保险制度最近部分纳入这些措施的建议应达到85%的总体敏感度(+38%)。GS在29.8%以前未诊断的颅缝早闭患者中发现了可能的致病/致病变异。这证明了研究分析的价值和不断改进算法的重要性，以最大限度地发挥临床GS的潜力。
Genome sequencing (GS) for diagnosis of rare genetic disease is being introduced into the clinic, but the complexity of the data poses challenges for developing pipelines with high diagnostic sensitivity. We evaluated the performance of the Genomics England 100,000 Genomes Project (100kGP) panel-based pipelines, using craniosynostosis as a test disease. GS data from 114 probands with craniosynostosis and their relatives (314 samples), negative on routine genetic testing, were scrutinised by a specialized research team, and diagnoses compared with those made by 100kGP. Sixteen likely pathogenic/pathogenic variants were identified by 100kGP. Eighteen additional likely pathogenic/pathogenic variants were identified by the research team, indicating that for craniosynostosis, 100kGP panels had a diagnostic sensitivity of only 47%. Measures that could have augmented diagnoses were improved calling of existing panel genes (+18% sensitivity), review of updated panels (+12%), comprehensive analysis of de novo small variants (+29%) and copy number/structural variants (+9%). Recent NHS England recommendations that partially incorporate these measures should achieve 85% overall sensitivity (+38%). GS identified likely pathogenic/pathogenic variants in 29.8% of previously undiagnosed patients with craniosynostosis. This demonstrates the value of research analysis and the importance of continually improving algorithms to maximise the potential of clinical GS.
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作者：
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通讯作者：
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作者：
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通讯作者：
Wilkie AO