Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease.
Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease.
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DOI：
10.1038/s41436-018-0295-y
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发表时间：
2019-05
期刊：
影响因子：
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通讯作者：
Taft RJ
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作者：
Gross AM;Ajay SS;Rajan V;Brown C;Bluske K;Burns NJ;Chawla A;Coffey AJ;Malhotra A;Scocchia A;Thorpe E;Dzidic N;Hovanes K;Sahoo T;Dolzhenko E;Lajoie B;Khouzam A;Chowdhury S;Belmont J;Roller E;Ivakhno S;Tanner S;McEachern J;Hambuch T;Eberle M;Hagelstrom RT;Bentley DR;Perry DL;Taft RJ
目前遗传疾病的诊断测试涉及跨越多种技术的专门测定的连续使用。原则上，基因组测序（GS）可以在一个平台上检测所有基因组致病变异类型。在这里，我们评估拷贝数变异（CNV）调用作为临床认可的GS测试的一部分。我们对17个参考样本进行了CNV的分析验证，比较了基于GS的变异与临床微阵列的变异的灵敏度，并使用正交技术设定了精度范围。我们开发了一种基于GS的CNV呼叫的基于家庭的分析方案，并将其部署在79例罕见和未确诊病例的临床队列中。我们发现，来自GS的CNV调用至少与来自微阵列的CNV调用一样敏感，同时仅产生解释的变体数量的适度增加（每个病例约10个CNV）。我们在分析的前79例病例中发现了15%具有临床意义的CNVs，所有这些病例都通过正交方法得到了证实。该管道还使得能够发现单亲二体性（UPD）和50%镶嵌14三体性。选择CNV的定向分析使得能够实现基因组重排的断点水平解析和从头CNV的定相。在临床测试环境中，通过GS对CNV的稳健鉴定是可能的。
Current diagnostic testing for genetic disorders involves serial use of specialized assays spanning multiple technologies. In principle, genome sequencing (GS) can detect all genomic pathogenic variant types on a single platform. Here we evaluate copy-number variant (CNV) calling as part of a clinically accredited GS test. We performed analytical validation of CNV calling on 17 reference samples, compared the sensitivity of GS-based variants with those from a clinical microarray, and set a bound on precision using orthogonal technologies. We developed a protocol for family-based analysis of GS-based CNV calls, and deployed this across a clinical cohort of 79 rare and undiagnosed cases. We found that CNV calls from GS are at least as sensitive as those from microarrays, while only creating a modest increase in the number of variants interpreted (~10 CNVs per case). We identified clinically significant CNVs in 15% of the first 79 cases analyzed, all of which were confirmed by an orthogonal approach. The pipeline also enabled discovery of a uniparental disomy (UPD) and a 50% mosaic trisomy 14. Directed analysis of select CNVs enabled breakpoint level resolution of genomic rearrangements and phasing of de novo CNVs. Robust identification of CNVs by GS is possible within a clinical testing environment.