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Low-pass genome sequencing: a validated method in clinical cytogenetics.
Human Genetics ( IF 5.3 ) Pub Date : 2020-05-25 , DOI: 10.1007/s00439-020-02185-9
Matthew Hoi Kin Chau 1, 2, 3 , Huilin Wang 4 , Yunli Lai 5, 6 , Yanyan Zhang 1, 2 , Fuben Xu 5, 6 , Yanqing Tang 5, 6 , Yanfang Wang 4 , Zihan Chen 2 , Tak Yeung Leung 1, 2, 7 , Jacqueline Pui Wah Chung 1 , Yvonne K Kwok 1, 2 , Shuk Ching Chong 3, 7, 8 , Kwong Wai Choy 1, 2, 3, 7 , Yuanfang Zhu 4 , Likuan Xiong 4 , Weihong Wei 5, 6 , Zirui Dong 1, 2, 3
Affiliation  

Clinically significant copy-number variants (CNVs) known to cause human diseases are routinely detected by chromosomal microarray analysis (CMA). Recently, genome sequencing (GS) has been introduced for CNV analysis; however, sequencing depth (determined by sequencing read-length and read-amount) is a variable parameter across different laboratories. Variating sequencing depths affect the CNV detection resolution and also make it difficult for cross-laboratory referencing or comparison. In this study, by using data from 50 samples with high read-depth GS (30×) and the reported clinically significant CNVs, we first demonstrated the optimal read-amount and the most cost-effective read-length for CNV analysis to be 15 million reads and single-end 50 bp (equivalent to a read-depth of 0.25-fold), respectively. In addition, we showed that CNVs at mosaic levels as low as 30% are readily detected, furthermore, CNVs larger than 2.5 Mb are also detectable at mosaic levels as low as 20%. Herein, by conducting a retrospective back-to-back comparison study of low-pass GS versus routine CMA for 532 prenatal, miscarriage, and postnatal cases, the overall diagnostic yield was 22.4% (119/532) for CMA and 23.1% (123/532) for low-pass GS. Thus, the overall relative improvement of the diagnostic yield by low-pass GS versus CMA was ~ 3.4% (4/119). Identification of cryptic and clinically significant CNVs among prenatal, miscarriage, and postnatal cases demonstrated that CNV detection at higher resolutions is warranted for clinical diagnosis regardless of referral indications. Overall, our study supports low-pass GS as the first-tier genetic test for molecular cytogenetic testing.



中文翻译:

低通基因组测序:临床细胞遗传学中一种经过验证的方法。

通常通过染色体微阵列分析(CMA)检测已知引起人类疾病的临床上重要的拷贝数变异(CNV)。最近,已经引入了基因组测序(GS)来进行CNV分析。但是,测序深度(由测序读取长度和读取量决定)是跨不同实验室的可变参数。变化的测序深度会影响CNV检测的分辨率,也使跨实验室参考或比较变得困难。在这项研究中,通过使用50个具有较高读取深度GS(30x)的样品和报告的临床上显着的CNV的数据,我们首先证明了CNV分析的最佳读取量和最具成本效益的读取长度为15百万次读取和单端50 bp(相当于0.25倍的读取深度)。此外,我们表明,很容易检测到镶嵌水平低至30%的CNV,此外,在镶嵌水平低至20%时也可检测到大于2.5 Mb的CNV。本文通过对532例产前,流产和产后病例进行低通GS与常规CMA的回顾性背对背比较研究,CMA的总诊断率为22.4%(119/532),总诊断率为23.1%(123) / 532)用于低通GS。因此,与CMA相比,低通GS的诊断产率总体相对改善为〜3.4%(4/119)。在产前,流产和产后病例中鉴定出隐匿性和临床上显着的CNV,表明无论采用何种指征,都需要以较高的分辨率进行CNV检测以进行临床诊断。总的来说,我们的研究支持低通GS作为分子细胞遗传学测试的第一级遗传测试。

更新日期:2020-05-25
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