Low-pass genome sequencing versus chromosomal microarray analysis: implementation in prenatal diagnosis

Huilin Wang, Zirui Dong, Rui Zhang, Matthew Hoi Kin Chau, Zhenjun Yang, Kathy Yin Ching Tsang, Hoi Kin Wong, Baoheng Gui, Zhuo Meng, Kelin Xiao, Xiaofan Zhu, Yanfang Wang, Shaoyun Chen, Tak Yeung Leung, Sau Wai Cheung, Yvonne K. Kwok, Cynthia C. Morton, Yuanfang Zhu, Kwong Wai Choy

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Emerging studies suggest that low-pass genome sequencing (GS) provides additional diagnostic yield of clinically significant copy-number variants (CNVs) compared with chromosomal microarray analysis (CMA). However, a prospective back-to-back comparison evaluating accuracy, efficacy, and incremental yield of low-pass GS compared with CMA is warranted.

A total of 1023 women undergoing prenatal diagnosis were enrolled. Each sample was subjected to low-pass GS and CMA for CNV analysis in parallel. CNVs were classified according to guidelines of the American College of Medical Genetics and Genomics.

Low-pass GS not only identified all 124 numerical disorders or pathogenic or likely pathogenic (P/LP) CNVs detected by CMA in 121 cases (11.8%, 121/1023), but also defined 17 additional and clinically relevant P/LP CNVs in 17 cases (1.7%, 17/1023). In addition, low-pass GS significantly reduced the technical repeat rate from 4.6% (47/1023) for CMA to 0.5% (5/1023) and required less DNA (50 ng) as input.

In the context of prenatal diagnosis, low-pass GS identified additional and clinically significant information with enhanced resolution and increased sensitivity of detecting mosaicism as compared with the CMA platform used. This study provides strong evidence for applying low-pass GS as an alternative prenatal diagnostic test.
Original languageEnglish
JournalGenetics in Medicine
Early online date26 Aug 2019
Publication statusE-pub ahead of print - 26 Aug 2019


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