Investigation on combined copy number variation sequencing and cytogenetic karyotyping for prenatal diagnosis

Abstract Background We aimed to evaluate the clinical value of copy number variation-sequencing (CNV-Seq) in combination with cytogenetic karyotyping in prenatal diagnosis. Methods CNV-Seq and cytogenetic karyotyping were performed in parallel for 9452 prenatal samples for comparison of the diagnostic performance of the two methods, and to evaluate the screening performance of maternal age, maternal serum screening, fetal ultrasound scanning and noninvasive prenatal testing (NIPT) for fetal pathogenic copy number variation (CNV). Results Among the 9452 prenatal samples, traditional karyotyping detected 704 cases (7.5%) of abnormal cytogenetic karyotypes, 171 (1.8%) chromosome polymorphism, 20 (0.2%) subtle structural variations, 74 (0.7%) mutual translocation (possibly balanced), 52 (0.6%) without karyotyping results, and 8431 (89.2%) normal cytogenetic karyotypes. Among the 8705 cases with normal karyotype, polymorphism, mutual translocation, or marker chromosome, CNV-Seq detected 63 cases (0.7%) of pathogenic chromosome microdeletion/duplication. Retrospectively, noninvasive prenatal testing (NIPT) had high sensitivity and specificity for the screening of fetal pathogenic CNV, and NIPT combining with maternal age, maternal serum screening or fetal ultrasound scanning, which improved the screening performance. Conclusion The combined application of cytogenetic karyotyping and CNV-Seq significantly improved the detection rate of fetal pathogenic chromosome microdeletion/duplication. NIPT was recommended for the screening of pathogenic chromosome microdeletion/duplication, and NIPT combining with other screening methods further improved the screening performance for pathogenic fetal CNV.

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A Novel Graphic-Aided Algorithm (gNIPT) Improves the Accuracy of Noninvasive Prenatal Testing

BioMed Research International ◽

10.1155/2020/4712657 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Qingwen Zhu ◽

Jing Wang ◽

Xiaoning Xu ◽

Shiying Zhou ◽

Zhengli Liao ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

False Negative ◽

Prenatal Testing ◽

Maternal Blood ◽

Negative Control ◽

Trisomy 13 ◽

Singleton Pregnancy ◽

Noninvasive Prenatal Testing ◽

Number Variation

Noninvasive Prenatal Testing (NIPT) has advanced the detection of fetal chromosomal aneuploidy by analyzing cell-free DNA in peripheral maternal blood. The statistic Z-test that it utilizes, which measures the deviation of each chromosome dosage from its negative control, is now widely accepted in clinical practice. However, when a chromosome has loss and gain regions which offset each other in the z-score calculation, merely using the Z-test for the result tends to be erroneous. To improve the performance of NIPT in this aspect, a novel graphic-aided algorithm (gNIPT) that requires no extra experiment procedures is reported in this study. In addition to the Z-test, this method provides a detailed analysis of each chromosome by dividing each chromosome into multiple 2 Mb size windows, calculating the z-score and copy number variation of each window, and visualizing the z-scores for each chromosome in a line chart. Data from 13537 singleton pregnancy women were analyzed and compared using both the normal NIPT (nNIPT) analysis and the gNIPT method. The gNIPT method had significantly improved the overall positive predictive value (PPV) of nNIPT (88.14% vs. 68.00%, p=0.0041) and the PPV for trisomy 21 (T21) detection (93.02% vs. 71.43%, p=0.0037). There were no significant differences between gNIPT and nNIPT in PPV for trisomy 18 (T18) detection (88.89% vs. 63.64%, p=0.1974) and in PPV for trisomy 13 (T13) detection (57.14% vs. 50.00%, p=0.8004). One false-negative T18 case in nNIPT was detected by gNIPT, which demonstrates the potency of gNIPT in discerning chromosomes that have variation in multiple regions with an offsetting effect in z-score calculation. The gNIPT was also able to detect copy number variation (CNV) in chromosomes, and one case with pathogenic CNV was detected during the study. With no additional test requirement, gNIPT presents a reasonable solution in improving the accuracy of normal NIPT.

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Copy number variation profile in noninvasive prenatal testing (NIPT) can identify co-existing maternal malignancies: Case reports and a literature review

Taiwanese Journal of Obstetrics and Gynecology ◽

10.1016/j.tjog.2018.10.032 ◽

2018 ◽

Vol 57 (6) ◽

pp. 871-877 ◽

Cited By ~ 1

Author(s):

Xing Ji ◽

Fang Chen ◽

Yafeng Zhou ◽

Jia Li ◽

Yuying Yuan ◽

...

Keyword(s):

Literature Review ◽

Copy Number Variation ◽

Copy Number ◽

Case Reports ◽

Prenatal Testing ◽

Noninvasive Prenatal Testing ◽

Number Variation

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Clinical Utility of the Prenatal BACs-on-Beads™ Assay in Invasive Prenatal Diagnosis

Frontiers in Genetics ◽

10.3389/fgene.2021.789625 ◽

2022 ◽

Vol 12 ◽

Author(s):

Yu Jiang ◽

Lili Wu ◽

Yunshen Ge ◽

Jian Zhang ◽

Yanru Huang ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Copy Number Variation ◽

Copy Number ◽

Clinical Utility ◽

Clinical Pathways ◽

Normal Karyotype ◽

Fetal Ultrasound ◽

Prenatal Diagnostic ◽

Diagnostic Center ◽

Number Variation

Background: The prenatal BACs-on-Beads™ (PNBoBs™) assay has been applied worldwide for prenatal diagnosis. However, there are neither guidelines nor consensus on choosing patients, sample types, or clinical pathways for using this technique. Moreover, different perspectives have emerged regarding its clinical value. This study aimed to evaluate its clinical utility in the context of clinical practice located in a prenatal diagnostic center in Xiamen, a city in southeast China.Methods: We tested 2,368 prenatal samples with multiple referral indications using both conventional karyotyping and PNBoBs™. Positive results from PNBoBs™ were verified using current gold-standard approaches.Results: The overall rates for the detection of pathogenic copy number variation (pCNV) by karyotyping and PNBoBs™ were 1.9% (46/2,368) and 2.0% (48/2,368), respectively. The overall detection rate of karyotyping combined with PNBoBs™ for pCNV was 2.3% (54/2,368). A total of 13 cases of copy number variation (CNV)with a normal karyotype were detected by PNBoBs™. Another case with a normal karyotype that was detected as a CNV of sex chromosomes by PNBoBs™ was validated to be maternal cell contamination by short tandem repeat analysis.Conclusion: Karyotyping combined with PNBoBs™ can improve both the yield and efficiency of prenatal diagnosis and is appropriate in the second trimester in all patients without fetal ultrasound anomalies who undergo invasive prenatal diagnosis.

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Prenatal Diagnosis of Microduplication of Fetal Chromosome 17 Following Noninvasive Prenatal Testing

10.21203/rs.3.rs-557915/v1 ◽

2021 ◽

Author(s):

Ye Shi ◽

Fang-xiu Zheng ◽

Jing Wang ◽

Qin Zhou ◽

Ying-ping Chen ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Copy Number ◽

Prenatal Testing ◽

Copy Number Variant ◽

Chromosome 17 ◽

Noninvasive Prenatal Testing ◽

Number Variation ◽

Case Presentations ◽

Chromosome Microarray ◽

Duplication Syndrome

Abstract Background Chromosome 17q12 duplication syndrome is a disease caused by the complete or partial duplication of q12 in the long arm of chromosome 17, there were no cases reported about the prenatal diagnosis of the syndrome. Most of the fetal phenotype of the syndrome may not be evident during the pregnancy, which means the syndrome was only be discovered accidentally or missed during the prenatal examination. Objective Noninvasive prenatal testing (NIPT) is widely used in the screening of common fetal chromosome aneuploidy. However, reports on chromosomal microduplication and microdeletion are rare. The aim of the study was to investigate the application value of NIPT for the detection of chromosomal microduplication. Case presentations: We found two cases of microduplication in the long arm of chromosome 17(17q12), they were first detected by NIPT and then were further diagnosed by copy number variation (CNV) analysis based on chromosome microarray analysis (CMA). The CMA results of prenatal diagnosis showed that the microduplications in 17q12 (one was 1.5Mb, the other was 1.9Mb) were consistent with the NIPT results. The amniotic fluid karyotype analysis showed no abnormalities. Finally, because it was pathogenic copy number variant, both of the parents chose to terminate the pregnancy. Conclusion In the study, two cases of microduplication fragment in the long arm of chromosome 17 were detected by NIPT and were confirmed by CMA. To our knowledge, this is the first report of prenatal diagnosis of chromosome 17q12 duplication syndrome following NIPT. This suggests that NIPT is an effective method to screen chromosome microduplications in prenatal diagnosis, especially for the chromosome 17q12 duplication syndrome.

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