Low-pass genome sequencing: a validated method in clinical cytogenetics

Chau, Matthew Hoi Kin; Wang, Huilin; Lai, Yunli; Zhang, Yanyan; Xu, Fuben; Tang, Yanqing; Wang, Yanfang; Chen, Zihan; Leung, Tak Yeung; Chung, Jacqueline Pui Wah; Kwok, Yvonne K.; Chong, Shuk Ching; Choy, Kwong Wai; Zhu, Yuanfang; Xiong, Likuan; Wei, Weihong; Dong, Zirui

doi:10.1007/s00439-020-02185-9

Cited by 36 publications

(40 citation statements)

References 33 publications

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“…Additionally, the cost per sample of CNV-seq (USD 300-375) was less than CMA (USD 600-750). This support the replacement of CMA by low-pass genome sequencing for molecular cytogenetic testing [25].…”

Section: Evaluation Of Cnvs By Cnv-seq Vs Cmasupporting

confidence: 54%

Simultaneous Detection of CNVs and SNVs Improves the Diagnostic Yield of Fetuses with Ultrasound Anomalies and Normal Karyotypes

Jiang

Zhou

et al. 2020

Genes

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The routine assessment to determine the genetic etiology for fetal ultrasound anomalies follows a sequential approach, which usually takes about 6–8 weeks turnaround time (TAT). We evaluated the clinical utility of simultaneous detection of copy number variations (CNVs) and single nucleotide variants (SNVs)/small insertion-deletions (indels) in fetuses with a normal karyotype with ultrasound anomalies. We performed CNV detection by chromosomal microarray analysis (CMA) or low pass CNV-sequencing (CNV-seq), and in parallel SNVs/indels detection by trio-based clinical exome sequencing (CES) or whole exome sequencing (WES). Eight-three singleton pregnancies with a normal fetal karyotype were enrolled in this prospective observational study. Pathogenic or likely pathogenic variations were identified in 30 cases (CNVs in 3 cases, SNVs/indels in 27 cases), indicating an overall molecular diagnostic rate of 36.1% (30/83). Two cases had both a CNV of uncertain significance (VOUS) and likely pathogenic SNV, and one case carried both a VOUS CNV and an SNV. We demonstrated that simultaneous analysis of CNVs and SNVs/indels can improve the diagnostic yield of prenatal diagnosis with shortened reporting time, namely, 2–3 weeks. Due to the relatively long TAT for sequential procedure for prenatal genetic diagnosis, as well as recent sequencing technology advancements, it is clinically necessary to consider the simultaneous evaluation of CNVs and SNVs/indels to enhance the diagnostic yield and timely TAT, especially for cases in the late second trimester or third trimester.

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Section: Evaluation Of Cnvs By Cnv-seq Vs Cmasupporting

confidence: 54%

Simultaneous Detection of CNVs and SNVs Improves the Diagnostic Yield of Fetuses with Ultrasound Anomalies and Normal Karyotypes

Jiang

Zhou

et al. 2020

Genes

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“…In addition, previous prenatal CMA findings indicated that 84.0% of known pathogenic CNVs are less than 5 Mb [ 31 ], which were unlikely to be detectable even by expanded NIPS. For the segmental chromosomal abnormalities, fetuses would commonly present with ultrasound anomalies, which warrants an invasive test for comprehensive genetic evaluation via CMA or genome sequencing (low-pass or high read-depth) [ 22 , 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

Performance of Cell-Free DNA Screening for Fetal Common Aneuploidies and Sex Chromosomal Abnormalities: A Prospective Study from a Less Developed Autonomous Region in Mainland China

Lai

Zhu

et al. 2021

Genes

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To evaluate the performance of noninvasive prenatal screening (NIPS) in the detection of common aneuploidies in a population-based study, a total of 86,262 single pregnancies referred for NIPS were prospectively recruited. Among 86,193 pregnancies with reportable results, follow-up was successfully conducted in 1160 fetuses reported with a high-risk result by NIPS and 82,511 cases (95.7%) with a low-risk result. The screen-positive rate (SPR) of common aneuploidies and sex chromosome abnormalities (SCAs) provided by NIPS were 0.7% (586/83,671) and 0.6% (505/83,671), respectively. The positive predictive values (PPVs) for Trisomy 21, Trisomy 18, Trisomy 13 and SCAs were calculated as 89.7%, 84.0%, 52.6% and 38.0%, respectively. In addition, less rare chromosomal abnormalities, including copy number variants (CNVs), were detected, compared with those reported by NIPS with higher read-depth. Among these rare abnormalities, only 23.2% (13/56) were confirmed by prenatal diagnosis. In total, four common trisomy cases were found to be false negative, resulting in a rate of 0.48/10,000 (4/83,671). In summary, this study conducted in an underdeveloped region with limited support for the new technology development and lack of cost-effective prenatal testing demonstrates the importance of implementing routine aneuploidy screening in the public sector for providing early detection and precise prognostic information.

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“…CNV-seq can detect structural abnormalities larger than 100 kb and mosaicism as low as 5% [7,8]. More and more studies have supported a higher sensitivity for low-pass GS in identifying low-level mosaicisms of both numerical disorders and submicroscopic rearrangements compared with routine CMA [5,9,10]. However, there is limited retrospective back-to-back comparison study to evaluate the accuracy and efficacy of CNV-seq compared with CMA has been reported in routine prenatal diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Integrated CNV-seq, karyotyping and SNP-array analyses for effective prenatal diagnosis of chromosomal mosaicism

Chen

et al. 2021

BMC Med Genomics

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Background Emerging studies suggest that low‐coverage massively parallel copy number variation sequencing (CNV-seq) more sensitive than chromosomal microarray analysis (CMA) for detecting low-level mosaicism. However, a retrospective back-to-back comparison evaluating accuracy, efficacy, and incremental yield of CNV-seq compared with CMA is warranted. Methods A total of 72 mosaicism cases identified by karyotyping or CMA were recruited to the study. There were 67 mosaic samples co-analysed by CMA and CNV-seq, comprising 40 with sex chromosome aneuploidy, 22 with autosomal aneuploidy and 5 with large cryptic genomic rearrangements. Results Of the 67 positive mosaic cases, the levels of mosaicism defined by CNV-seq ranged from 6 to 92% compared to the ratio from 3 to 90% by karyotyping and 20% to 72% by CMA. CNV-seq not only identified all 43 chromosomal aneuploidies or large cryptic genomic rearrangements detected by CMA, but also provided a 34.88% (15/43) increased yield compared with CMA. The improved yield of mosaicism detection by CNV-seq was largely due to the ability to detect low level mosaicism below 20%. Conclusion In the context of prenatal diagnosis, CNV-seq identified additional and clinically significant mosaicism with enhanced resolution and increased sensitivity. This study provides strong evidence for applying CNV-seq as an alternative to CMA for detection of aneuploidy and mosaic variants.

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Low-pass genome sequencing: a validated method in clinical cytogenetics

Cited by 36 publications

References 33 publications

Simultaneous Detection of CNVs and SNVs Improves the Diagnostic Yield of Fetuses with Ultrasound Anomalies and Normal Karyotypes

Simultaneous Detection of CNVs and SNVs Improves the Diagnostic Yield of Fetuses with Ultrasound Anomalies and Normal Karyotypes

Performance of Cell-Free DNA Screening for Fetal Common Aneuploidies and Sex Chromosomal Abnormalities: A Prospective Study from a Less Developed Autonomous Region in Mainland China

Integrated CNV-seq, karyotyping and SNP-array analyses for effective prenatal diagnosis of chromosomal mosaicism

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