Comprehensive gene panels provide advantages over clinical exome sequencing for Mendelian diseases.
Comprehensive gene panels provide advantages over clinical exome sequencing for Mendelian diseases.
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DOI：
10.1186/s13059-015-0693-2
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发表时间：
2015-06-26
期刊：
影响因子：
12.3
通讯作者：
Saudi Mendeliome Group
中科院分区：
文献类型：
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作者：
Saudi Mendeliome Group
为了了解孟德尔突变对疑似遗传起源的未诊断疾病负担的贡献，我们开发了下一代基于测序的多重检测，其中包括约3000个已知的孟德尔基因。我们称之为孟德尔基因组的这项检测包括基于临床主题的13个基因组，涵盖了儿科和成人临床遗传医学的范围。我们探讨了这些面板与临床全外显子组测序（WES）的比较。我们测试了2357名疑似遗传诊断的患者，几乎来自每个医学专业。在1018例患者中发现了一种可能的致病突变，总体临床敏感性为43%，与WES相比更为有利。此外，临床级WES的成本很高（通常超过4500美元），而在我们的面板上运行样品的成本约为75-150美元，具体取决于面板。在“阴性”病例中，WES随后发现11%在已知疾病基因中具有可能的因果突变（主要在我们的测定设计后鉴定的基因中），如从178个代表性样品推断的。尽管我们的研究人群富含血缘关系，但245例（24%）已解决的病例为常染色体显性，35例（4%）为X连锁，表明我们的测定也适用于远交人群。尽管遗漏了大量病例，但目前版本的孟德尔基因组测定法可以解释大部分疑似遗传性疾病，并提供了优于临床WES的显著实用优势。本文的在线版本（doi：10.1186/s13059-015-0693-2）包含补充材料，可供授权用户使用。
To understand the contribution of Mendelian mutations to the burden of undiagnosed diseases that are suspected to be genetic in origin, we developed a next-generation sequencing-based multiplexing assay that encompasses the ~3000 known Mendelian genes. This assay, which we term the Mendeliome, comprises 13 gene panels based on clinical themes, covering the spectrum of pediatric and adult clinical genetic medicine. We explore how these panels compare with clinical whole exome sequencing (WES). We tested 2357 patients referred with suspected genetic diagnoses from virtually every medical specialty. A likely causal mutation was identified in 1018 patients, with an overall clinical sensitivity of 43 %, comparing favorably with WES. Furthermore, the cost of clinical-grade WES is high (typically more than 4500 US dollars), whereas the cost of running a sample on one of our panels is around 75–150 US dollars, depending on the panel. Of the “negative” cases, 11 % were subsequently found by WES to harbor a likely causal mutation in a known disease gene (largely in genes identified after the design of our assay), as inferred from a representative sample of 178. Although our study population is enriched for consanguinity, 245 (24 %) of solved cases were autosomal dominant and 35 (4 %) were X-linked, suggesting that our assay is also applicable to outbred populations. Despite missing a significant number of cases, the current version of the Mendeliome assay can account for a large proportion of suspected genetic disorders, and provides significant practical advantages over clinical WES. The online version of this article (doi:10.1186/s13059-015-0693-2) contains supplementary material, which is available to authorized users.
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DOI：
10.1038/nrg3493
发表时间：
2013-06
期刊：
Nature reviews. Genetics
影响因子：
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作者：
通讯作者：
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影响因子：
8.8
作者：
Al-Qattan, Sarah M.;Wakil, Salma M.;Alkuraya, Fowzan S.
通讯作者：
Alkuraya, Fowzan S.
影响因子：
1.2
作者：
Khan, Arif O.;Aldahmesh, Mohammed A.;Alkuraya, Fowzan S.
通讯作者：
Alkuraya, Fowzan S.
影响因子：
8
作者：
Abdul-Karim, Ruqayyah;Berkman, Benjamin E.;Hull, Sara Chandros
通讯作者：
Hull, Sara Chandros
DOI：
10.1038/nrg3463
发表时间：
2013-04
期刊：
Nature reviews. Genetics
影响因子：
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作者：
通讯作者：
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