Detection of Clinically Relevant Copy Number Variants with Whole-Exome Sequencing
Detection of Clinically Relevant Copy Number Variants with Whole-Exome Sequencing
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DOI：
10.1002/humu.22387
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发表时间：
2013-10-01
期刊：
影响因子：
3.9
通讯作者：
Hehir-Kwa, Jayne Y.
中科院分区：
文献类型：
--
作者：
de Ligt, Joep;Boone, Philip M.;Hehir-Kwa, Jayne Y.
拷贝数变异(CNV)是一种常见的遗传变异来源，与许多基因组疾病有关。这导致了基因组微阵列作为CNV检测的第一级诊断工具的广泛应用。最近，完整外显子组测序(WES)已被证明在检测临床相关的点突变和小的外显子宽的插入-缺失方面是成功的。我们评估短读WES(固体5500xl)检测10名智障患者DNA中临床相关CNV的有效性，并将这些结果与两个独立的高分辨率微阵列的数据进行比较。通过对WES数据的阅读深度分析，在12个临床相关的CNV中有11个被检测到；所有评估的算法仍然没有检测到杂合性单个外显子缺失。虽然目前WES对小CNV的检测能力比不上高分辨率微阵列平台，但我们发现大多数(88%)包含三个或更多外显子的罕见编码CNV可以被WES成功识别。这些结果表明，WES的CNV检测分辨率与临床常用的中分辨率基因组芯片相当。点突变、INDELS和CNV的联合检测使WES成为一种非常有吸引力的遗传异质性疾病的一级诊断测试。(C)2013年威利期刊公司。
Copy number variation (CNV) is a common source of genetic variation that has been implicated in many genomic disorders. This has resulted in the widespread application of genomic microarrays as a first-tier diagnostic tool for CNV detection. More recently, whole-exome sequencing (WES) has been proven successful for the detection of clinically relevant point mutations and small insertion-deletions exome wide. We evaluate the utility of short-read WES (SOLiD 5500xl) to detect clinically relevant CNVs in DNA from 10 patients with intellectual disability and compare these results to data from two independent high-resolution microarrays. Eleven of the 12 clinically relevant CNVs were detected via read-depth analysis of WES data; a heterozygous single-exon deletion remained undetected by all algorithms evaluated. Although the detection power of WES for small CNVs currently does not match that of high-resolution microarray platforms, we show that the majority (88%) of rare coding CNVs containing three or more exons are successfully identified by WES. These results show that the CNV detection resolution of WES is comparable to that of medium-resolution genomic microarrays commonly used as clinical assays. The combined detection of point mutations, indels, and CNVs makes WES a very attractive first-tier diagnostic test for genetically heterogeneous disorders. (C) 2013 Wiley Periodicals, Inc.