Clinical impacts of genome-wide noninvasive prenatal testing for rare autosomal trisomy

Xiang, Jiale; Li, Ru; He, Jun; Wang, Xiaohua; Yao, Ling; Song, Nana; Fu, Fang; Zhou, Shihao; Wang, Jie; Gao, Xiaoya; Peng, Jiguang; Wan, Jun-Hui; Hu, Lanping; Liu, Aiju; Guo, Yaya; Peng, Can; Liu, Xiaoxia; Lin, Juncong; Li, Shuai; Sun, Jun; Li, Dong-Zhi; Peng, Zhiyu; Liao, Can

doi:10.1016/j.ajogmf.2022.100790

Cited by 17 publications

(12 citation statements)

References 36 publications

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“…In such cases, we propose that the correct diagnosis (truth) is placental mosaicism, and all the observed data are true and accurate. More recent studies argue that detecting placental mosaicism for RAT is in the best interest for optimal management of a pregnancy 36,37 …”

Section: Discussionmentioning

confidence: 99%

“…More recent studies argue that detecting placental mosaicism for RAT is in the best interest for optimal management of a pregnancy. 36,37 Cell-based NIPT is a promising approach to genetic prenatal diagnosis, although the current inability to recover 5-10 cells in >95% of cases limit its widespread adoption. If sufficient cells could be recovered, it is feasible to perform high-coverage whole genome sequencing (WGS) on trophoblasts 38 raising the possibility of noninvasive trio WGS in the first trimester.…”

Section: Clinical and Analytical Performance With Spike-in Cellsmentioning

confidence: 99%

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Noninvasive single‐cell‐based prenatal genetic testing: A proof of concept clinical study

Bellair,

Amaral,

Ouren

et al. 2024

Prenatal Diagnosis

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ObjectiveTo clinically assess a cell‐based noninvasive prenatal genetic test using sequence‐based copy number analysis of single trophoblasts from maternal blood.MethodsBlood was obtained from 401 (243 + 158) individuals (8–22 weeks) and shipped overnight. Red cells were lysed, and nucleated cells stained for cytokeratin (CK) and CD45 and enriched for positive CK staining. Automated scanning was used to identify and pick single CK+/CD45‐ trophoblasts which were subjected to next‐generation sequencing.ResultsBlood was obtained from 243 pregnancies scheduled for CVS or amniocentesis. Luna results were normal for 160 singletons while 15 cases were abnormal (14 aneuploidy and one monozygotic twin with Williams syndrome deletion). The deletion was confirmed in both fetuses. Placental mosaicism occurred in 7 of 236 (3.0%) Luna cases and in 3 of 188 (1.6%) CVS cases (total 4.6%). No scorable trophoblasts were recovered in 32 of 236 usable samples. Additionally, 158 low‐risk pregnancies not undergoing CVS/amniocentesis showed normal results in 133 cases. Seven had aneuploidy results, and there were three likely pathogenic deletions/duplications, including one15q11‐q13 deletion.ConclusionAlthough the sample size is modest and statistically accurate measures of test performance are not possible, the Luna test detected aneuploidy and deletions/duplications based on concordance with CVS/amniocentesis.

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Section: Discussionmentioning

confidence: 99%

Section: Clinical and Analytical Performance With Spike-in Cellsmentioning

confidence: 99%

Noninvasive single‐cell‐based prenatal genetic testing: A proof of concept clinical study

Bellair,

Amaral,

Ouren

et al. 2024

Prenatal Diagnosis

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“…Owing to the advantage of NIPT in detecting genome-wide chromosomal anomalies (Bianchi and Wilkins-Haug., 2014), more studies have investigated the use of NIPT in detecting rare autosomal trisomies, including trisomy 9 (Lee et al, 2018;Wang et al, 2020;Li et al, 2022). However the positive predictive value of NIPT for rare autosomal trisomies is low (4%-6%) in the general obstetrical population (van der Meij et al, 2019;Van Den Bogaert et al, 2021), and approximately 40% of all rare autosomal trisomy cases culminate in adverse perinatal outcomes (Xiang et al, 2023). Since most of the circulating fetal DNA in maternal plasma is derived primarily from the placental trophoblasts (Flori et al, 2004), and trisomy 9 is usually miscarried in the first trimester (López-Félix et al, 2017), invasive prenatal testing is strongly recommended for all gravidas with positive NIPT results of trisomy 9 to exclude placental or fetal mosaicism.…”

Section: Discussionmentioning

confidence: 99%

“…Due to concerns about the unavoidable risks of invasive prenatal diagnosis methods, she chose NIPT for fetal autosomal aneuploidies screening at 16 +1 weeks of gestation after genetic counseling. Sample preparation, maternal plasma DNA sequencing, and bioinformatics analysis for NIPT were carried out using BGI platform (MGISEQ-2000, Shenzhen, China) as previously described (Xiang et al, 2023). NIPT analysis showed that the Z-scores of other chromosomes were all in the normal range (−3 < Z < 3) except for chromosome 9 (Z = 8.9898) with a cell-free fetal DNA fraction at 11.08% (3.5% is the least reliable cell-free fetal DNA level), suggesting a possibility of trisomy 9 or trisomy 9 mosaicism.…”

Section: Case Report Casementioning

confidence: 99%

Case report: Detection of fetal trisomy 9 mosaicism by multiple genetic testing methods: Report of two cases

Zhu²,

Hu³

et al. 2023

Front. Genet.

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Chromosomal mosaicism remains a perpetual diagnostic and clinical dilemma. In the present study, we detected two prenatal trisomy 9 mosaic syndrome cases by using multiple genetic testing methods. The non-invasive prenatal testing (NIPT) results suggested trisomy 9 in two fetuses. Karyotype analysis of amniocytes showed a high level (42%–50%) of mosaicism, and chromosomal microarray analysis (CMA) of uncultured amniocytes showed no copy number variation (CNV) except for large fragment loss of heterozygosity. Ultrasound findings were unmarkable except for small for gestational age. In Case 1, further umbilical blood puncture confirmed 22.4% and 34% trisomy 9 mosaicism by CMA and fluorescent in situ hybridization (FISH) respectively. After comprehensive consideration of the genetic and ultrasound results, the two gravidas decided to receive elective termination and molecular investigations of multiple tissue samples from the aborted fetus and the placenta. The results confirmed the presence of true fetoplacental mosaicism with levels of trisomy 9 mosaicism from 76% to normal in various tissues. These two cases highlight the necessity of genetic counseling for gravidas whose NIPT results highly suggest the risk of chromosome 9 to ascertain the occurrence of mosaicism. In addition, the comprehensive use of multiple genetic techniques and biological samples is recommended for prenatal diagnosis to avoid false-negative results. It should also be noted that ultrasound results of organs with true trisomy 9 mosaicism can be free of structural abnormalities during pregnancy.

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“…More recent studies argue that detecting placental mosaicism for RAT is in the best interest for optimal management of a pregnancy. 38,39 Such abnormalities carry risks of miscarriage, birth defects, and low birth weight. It has been suggested that such pregnancies should be followed more closely, for example by more frequent ultrasounds.…”

Section: Discussionmentioning

confidence: 99%

Validation study for noninvasive single-cell-based prenatal genetic testing

Bellair,

Amaral,

Ouren

et al. 2023

Preprint

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Objective: To clinically validate a cell-based noninvasive prenatal genetic test using sequence-based copy number analysis of single trophoblasts from maternal blood. Methods: Blood was obtained from 401 individuals (8-22 weeks) and shipped overnight. Red blood cells were lysed, and nucleated cells stained for cytokeratin (CK) and CD45 using fluorescent antibodies and enriched for positive CK staining. Automated microscopic scanning was used to identify and pick single CK+/CD45- trophoblasts which were subjected to whole genome amplification and next-generation sequencing. Results: Blood was obtained from 243 pregnancies scheduled for CVS or amniocentesis. Luna results were normal for 160 singletons while 15 cases were abnormal (14 aneuploidy and one monozygotic twin case with Williams syndrome deletion). These Luna results agreed with CVS/amniocentesis. Placental mosaicism occurred in 7 of 236 (3.0%) Luna cases and in 3 of 188 (1.6%) CVS cases (total 4.6%). No scorable trophoblasts were recovered in 32 of 236 (13.6%) usable samples. Additionally, 158 low-risk pregnancies not undergoing CVS/amniocentesis showed normal results for 133 cases. Seven had aneuploidy results, and there were 3 likely pathogenic deletions or duplications including one15q11-q13 deletion. Conclusion: This noninvasive cell-based prenatal genetic test detected aneuploidy and deletions/duplications with high sensitivity and specificity based on concordance with CVS/amniocentesis. What's already known about this topic? x As a proof of principle for noninvasive genetic prenatal diagnosis, circulating fetal trophoblasts have been isolated from maternal blood and analyzed for detection of aneuploidy and genomic deletions and duplications. x These trophoblasts reflect the genotype of the current placenta(s) but not necessarily the genotype of the fetus because of placental mosaicism. What does this study add? x This study demonstrates the advantages of single cell analysis and the feasibility of launching a test for reliable detection of cytogenetic aneuploidy, deletions, and duplications. x This test has improved detection of deletions and duplications compared to cell-free NIPT, but widespread adoption will require improved recovery of fetal cells from maternal blood and reduced cost through automation and high-throughput.

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Clinical impacts of genome-wide noninvasive prenatal testing for rare autosomal trisomy

Cited by 17 publications

References 36 publications

Noninvasive single‐cell‐based prenatal genetic testing: A proof of concept clinical study

Noninvasive single‐cell‐based prenatal genetic testing: A proof of concept clinical study

Case report: Detection of fetal trisomy 9 mosaicism by multiple genetic testing methods: Report of two cases

Validation study for noninvasive single-cell-based prenatal genetic testing

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