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

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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Expanded noninvasive prenatal testing for fetal aneuploidy and copy number variations and parental willingness for invasive diagnosis in a cohort of 18,516 cases

BMC Medical Genomics ◽

10.1186/s12920-021-00955-6 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Yunsheng Ge ◽

Jia Li ◽

Jianlong Zhuang ◽

Jian Zhang ◽

Yanru Huang ◽

...

Keyword(s):

Prenatal Diagnosis ◽

High Risk ◽

Pregnant Women ◽

Copy Number ◽

Prenatal Testing ◽

Copy Number Variations ◽

Trisomy 13 ◽

Noninvasive Prenatal Testing ◽

Predictive Values ◽

Parental Willingness

Abstract Background Noninvasive prenatal testing (NIPT) has been wildly used to screen for common aneuplodies. In recent years, the test has been expanded to detect rare autosomal aneuploidies (RATs) and copy number variations (CNVs). This study was performed to investigate the performance of expanded noninvasive prenatal testing (expanded NIPT) in screening for common trisomies, sex chromosomal aneuploidies (SCAs), rare autosomal aneuploidies (RATs), and copy number variations (CNVs) and parental willingness for invasive prenatal diagnosis in a Chinese prenatal diagnosis center. Methods A total of 24,702 pregnant women were retrospectively analyzed at the Women and Children’s Hospital from January 2013 to April 2019, among which expanded NIPT had been successfully conducted in 24,702 pregnant women. The high-risk expanded NIPT results were validated by karyotype analysis and chromosomal microarray analysis. All the tested pregnant women were followed up for pregnancy outcomes. Results Of the 24,702 cases, successful follow-up was conducted in 98.77% (401/446) of cases with common trisomies and SCAs, 91.95% (80/87) of RAT and CNV cases, and 76.25% (18,429/24,169) of cases with low-risk screening results. The sensitivity of expanded NIPT was 100% (95% confidence interval[CI], 97.38–100%), 96.67%(95%CI, 82.78–99.92%), and 100%(95%CI, 66.37–100.00%), and the specificity was 99.92%(95%CI, 99.87–99.96%), 99.96%(95%CI, 99.91–99.98%), and 99.88% (95%CI, 99.82–99.93%) for the detection of trisomies 21, 18, and 13, respectively. Expanded NIPT detected 45,X, 47,XXX, 47,XXY, XYY syndrome, RATs, and CNVs with positive predictive values of 25.49%, 75%, 94.12%, 76.19%, 6.45%, and 50%, respectively. The women carrying fetuses with Trisomy 21/Trisomy 18/Trisomy 13 underwent invasive prenatal diagnosis and terminated their pregnancies at higher rates than those at high risk for SCAs, RATs, and CNVs. Conclusions Our study demonstrates that the expanded NIPT detects fetal trisomies 21, 18, and 13 with high sensitivity and specificity. The accuracy of detecting SCAs, RATs, and CNVs is still relatively poor and needs to be improved. With a high-risk expanded NIPT result, the women at high risk for common trisomies are more likely to undergo invasive prenatal diagnosis procedures and terminate their pregnancies than those with unusual chromosome abnormalities.

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8p23.1 duplication syndrome differentiated from copy number variation of the defensin cluster at prenatal diagnosis in four new families

Molecular Cytogenetics ◽

10.1186/1755-8166-3-3 ◽

2010 ◽

Vol 3 (1) ◽

pp. 3 ◽

Cited By ~ 18

Author(s):

John CK Barber ◽

Dave Bunyan ◽

Merryl Curtis ◽

Denise Robinson ◽

Susanne Morlot ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Copy Number Variation ◽

Copy Number ◽

Number Variation ◽

Duplication Syndrome

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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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A case of prenatal diagnosis of 18p deletion syndrome following noninvasive prenatal testing

Molecular Cytogenetics ◽

10.1186/s13039-019-0464-y ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 2

Author(s):

Ganye Zhao ◽

Peng Dai ◽

Shanshan Gao ◽

Xuechao Zhao ◽

Conghui Wang ◽

...

Keyword(s):

Prenatal Diagnosis ◽

De Novo ◽

Prenatal Testing ◽

Nuchal Translucency ◽

Deletion Syndrome ◽

Chromosome 18 ◽

Partial Monosomy ◽

Noninvasive Prenatal Testing ◽

First Case ◽

Case Presentations

Abstract Background Chromosome 18p deletion syndrome is a disease caused by the complete or partial deletion of the short arm of chromosome 18, there were few cases reported about the prenatal diagnosis of 18p deletion syndrome. Noninvasive prenatal testing (NIPT) is widely used in the screening of common fetal chromosome aneuploidy. However, the segmental deletions and duplications should also be concerned. Except that some cases had increased nuchal translucency or holoprosencephaly, most of the fetal phenotype of 18p deletion syndrome may not be evident during the pregnancy, 18p deletion syndrome was always accidentally discovered during the prenatal examination. Case presentations In our case, we found a pure partial monosomy 18p deletion during the confirmation of the result of NIPT by copy number variation sequencing (CNV-Seq). The result of NIPT suggested that there was a partial or complete deletion of X chromosome. The amniotic fluid karyotype was normal, but result of CNV-Seq indicated a 7.56 Mb deletion on the short arm of chromosome 18 but not in the couple, which means the deletion was de novo deletion. Finally, the parents chose to terminate the pregnancy. Conclusions To our knowledge, this is the first case of prenatal diagnosis of 18p deletion syndrome following NIPT.NIPT combined with ultrasound may be a relatively efficient method to screen chromosome microdeletions especially for the 18p deletion syndrome.

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

BMC Pregnancy and Childbirth ◽

10.1186/s12884-021-03918-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jinman Zhang ◽

Xinhua Tang ◽

Jilin Hu ◽

Guilin He ◽

Jian Wang ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Prenatal Testing ◽

Maternal Serum ◽

Ultrasound Scanning ◽

Maternal Serum Screening ◽

Fetal Ultrasound ◽

Noninvasive Prenatal Testing ◽

Screening Performance ◽

Number Variation

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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HandyCNV: Standardized Summary, Annotation, Comparison, and Visualization of Copy Number Variant, Copy Number Variation Region, and Runs of Homozygosity

Frontiers in Genetics ◽

10.3389/fgene.2021.731355 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jinghang Zhou ◽

Liyuan Liu ◽

Thomas J. Lopdell ◽

Dorian J. Garrick ◽

Yuangang Shi

Keyword(s):

Copy Number ◽

Copy Number Variants ◽

Copy Number Variant ◽

R Package ◽

Copy Number Variation Region ◽

Runs Of Homozygosity ◽

Number Variation ◽

Genomic Studies ◽

Computing Platforms ◽

Analysis System

Detection of CNVs (copy number variants) and ROH (runs of homozygosity) from SNP (single nucleotide polymorphism) genotyping data is often required in genomic studies. The post-analysis of CNV and ROH generally involves many steps, potentially across multiple computing platforms, which requires the researchers to be familiar with many different tools. In order to get around this problem and improve research efficiency, we present an R package that integrates the summarization, annotation, map conversion, comparison and visualization functions involved in studies of CNV and ROH. This one-stop post-analysis system is standardized, comprehensive, reproducible, timesaving, and user-friendly for researchers in humans and most diploid livestock species.

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Copy number variant detection with low-coverage whole-genome sequencing is a viable replacement for the traditional array-CGH

10.1101/2020.09.07.20183665 ◽

2020 ◽

Author(s):

Marcel Kucharik ◽

Jaroslav Budis ◽

Michaela Hyblova ◽

Gabriel Minarik ◽

Tomas Szemes

Keyword(s):

In Silico ◽

Copy Number ◽

Normal Population ◽

Genetic Disorders ◽

Prenatal Testing ◽

In Silico Analysis ◽

Copy Number Variant ◽

Detection Algorithm ◽

Copy Number Variations ◽

Cnv Detection

Copy number variations (CNVs) are a type of structural variant involving alterations in the number of copies of specific regions of DNA, which can either be deleted or duplicated. CNVs contribute substantially to normal population variability; however, abnormal CNVs cause numerous genetic disorders. Nowadays, several methods for CNV detection are used, from the conventional cytogenetic analysis through microarray-based methods (aCGH) to next-generation sequencing (NGS). We present GenomeScreen - NGS based CNV detection method based on a previously described CNV detection algorithm used for non-invasive prenatal testing (NIPT). We determined theoretical limits of its accuracy and confirmed it with extensive in-silico study and already genotyped samples. Theoretically, at least 6M uniquely mapped reads are required to detect CNV with a length of 100 kilobases (kb) or more with high confidence (Z-score > 7). In practice, the in-silico analysis showed the requirement at least 8M to obtain >99% accuracy (for 100 kb deviations). We compared GenomeScreen with one of the currently used aCGH methods in diagnostic laboratories, which has a 200 kb mean resolution. GenomeScreen and aCGH both detected 59 deviations, GenomeScreen furthermore detected 134 other (usually) smaller variations. Furthermore, the overall cost per sample is about 2-3x lower in the case of GenomeScreen.

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Trends in Invasive Prenatal Diagnosis: Effect of Sequential Screening and Noninvasive Prenatal Testing

Fetal Diagnosis and Therapy ◽

10.1159/000441028 ◽

2015 ◽

Vol 39 (4) ◽

pp. 292-296 ◽

Cited By ~ 10

Author(s):

Adeeb Khalifeh ◽

Stuart Weiner ◽

Vincenzo Berghella ◽

Alan Donnenfeld

Keyword(s):

Prenatal Diagnosis ◽

Chorionic Villus ◽

Prenatal Testing ◽

Chorionic Villus Sampling ◽

Invasive Procedures ◽

Noninvasive Prenatal Testing ◽

Sequential Screening ◽

Period 2 ◽

Prenatal Diagnostic ◽

The Impact

Objective: To examine trends in the incidence and method of invasive prenatal diagnosis due to the impact of sequential screening and noninvasive prenatal testing. Methods: This is a retrospective review of all pregnancies that have undergone invasive prenatal diagnostic testing between June 2002 and June 2014, divided in 3 periods: period 1 from June 2002 to October 2006, period 2 from November 2006 to December 2011, and period 3 from January 2012 to June 2014. The main outcome measures were trends in the incidence and method of each procedure. Results: There were 88,135 deliveries and 6,080 invasive procedures during the study period. In period 1, 2,755 (8.8%) procedures were carried out, in period 2 2,820 (7.3%), and in period 3 505 (2.5%; p < 0.01). In period 1, there were 1,990 (6.3%) cases of amniocentesis, 1,646 (4.3%) in period 2, and 254 (1.2%) in period 3 (p < 0.01). In addition, in 765 (2.5%) cases, chorionic villus sampling (CVS) was performed in period 1, compared to 1,174 (3.0%) cases in period 2 and 251 (1.3%) cases in period 3 (p < 0.01). Advanced maternal age as the sole indication for invasive procedures decreased significantly over time, while the indication of abnormal serum screening and abnormal ultrasound findings increased (p < 0.01). Conclusion: There was a significant decline in the incidence of invasive prenatal testing over the 12 years of the study. The decrease in amniocentesis was more marked than that in CVS.

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