Noninvasive prenatal diagnosis by genome-wide haplotyping of cell-free plasma DNA

Che, Huiwen; Villela, Darine; Dimitriadou, Eftychia; Melotte, Cindy; Brison, Nathalie; Neofytou, Maria; Bogaert, Kris Van Den; Tšuiko, Olga; Devriendt, Koen; Legius, Eric; Esteki, Masoud Zamani; Voet, Thierry; Vermeesch, Joris Robert

doi:10.1038/s41436-019-0748-y

Cited by 29 publications

(17 citation statements)

References 38 publications

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“…Hence, some of the positive cases turned out to be false positive. Although our [25][26][27], several reasons contribute to having false-positive results, including maternal chromosomal abnormality [28,29], confined placental mosaicism [30,31], vanishing twin [32], maternal copy number variations [33], fetal fraction [34], and so on. In addition, a short-term telephone followup to ascertain whether the newborns are normal or not is not entirely reliable and can also contribute to false-positive results.…”

Section: Discussionmentioning

confidence: 98%

Next-generation sequencing: a follow-up of 36,913 singleton pregnancies with noninvasive prenatal testing in central China

Huang

Wang

et al. 2020

J Assist Reprod Genet

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Purpose To evaluate the noninvasive prenatal testing (NIPT) results of 36,913 cases in Jiangxi province of central China and explore its application value in prenatal screening and diagnosis. Methods This retrospective analysis included 36,913 singleton pregnant women who underwent NIPT because of moderate-/high-risk pregnancy or voluntary requirements between January 2017 and December 2019 in our hospital. Chromosomal abnormalities such as trisomies 21, 18, and 13 (T21, T18, T13) and sex chromosome aneuploidies (SCAs) were judged by standard Z-score analysis. Positive NIPT results were confirmed by amniocentesis and karyotyping. Pregnancy outcomes were followed up via telephone interview. Results A total of 1.01% (371/36,913) positive cases were detected by NIPT, comprising 137, 46, 31, and 157 cases of T21, T18, T13, and SCAs, respectively. A total of 116 of T21, 27 of T18, 13 of T13, and 51 of SCAs were confirmed to be true positive; all normal cases that had been followed up were verified to be true negative. The NIPT sensitivity in T21, T18, T13, and SCAs was 100.00% individually, whereas the specificity was 99.94% (36,488/36,509), 99.95% (36,579/36,598), 99.95% (36,594/36,612), and 99.72% (36,472/36,574), respectively. Furthermore, the negative predictive values of T21, T18, T13, and SCAs were all 100%, while the positive predictive values were 84.67%, 58.70%, 41.94%, and 33.33%, respectively. Conclusion NIPT is highly sensitive and has a low false positive rate in testing clinically significant fetal aneuploidies of general reproductive women. However, this technique cannot substitute for amniocentesis and karyotyping, and detailed genetic counseling is also essential for the high-risk group of NIPT.

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Section: Discussionmentioning

confidence: 98%

Next-generation sequencing: a follow-up of 36,913 singleton pregnancies with noninvasive prenatal testing in central China

Huang

Wang

et al. 2020

J Assist Reprod Genet

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“…Additionally, disease-specific or patient-specific assays need to be customized and tested with decent number of patient samples before clinic practise. 10,38 The field is crying for a novel general method for noninvasive prenatal diagnosis of all dominant and recessive monogenic diseases.…”

Section: Discussionmentioning

confidence: 99%

“…However, the cffDNA‐based NIPT for single‐gene diseases could still be challenging for maternally inherited disease due to low cffDNA concentration, DNA fragmentation in maternal plasma and complex inferential statistical analysis. Additionally, disease‐specific or patient‐specific assays need to be customized and tested with decent number of patient samples before clinic practise 10,38 . The field is crying for a novel general method for noninvasive prenatal diagnosis of all dominant and recessive monogenic diseases.…”

Section: Discussionmentioning

confidence: 99%

A novel method for noninvasive diagnosis of monogenic diseases from circulating fetal cells

Chang

Zhu

et al. 2020

Prenatal Diagnosis

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Objective: To establish a method for noninvasive fetal cell isolation from maternal blood and prenatal testing of monogenic diseases by a combination of direct sequencing and targeted NGS-based SNP haplotyping from single fetal cells. Method: Peripheral blood of pregnant women in two families (congenital deafness and ichthyosis) was collected. After density-based separation and immunostaining with multiple biomarkers, candidate fetal cells were identified by high-throughput imagine analysis and picked up by automation. Individual fetal cells were subjected to STR-genotyping to identify their origin. Pathogenic mutations were identified by direct Sanger sequencing, and a combination of targeted NGS and SNP haplotyping using a custom panel. All the results were compared with amniotic fluid DNA. Results: Fetal trophoblasts were successfully harvested from maternal blood. STRgenotyping confirmed the fetal origin. Direct sequencing of pathogenic genetic mutations in fetal cells showed consistent results with amniotic fluid samples. For congenital deafness family, NGS-based SNP haplotyping also correctly identified the fetal haplotype. This single cell haplotyping method can be used to diagnose various genetic diseases. Conclusion: We have established a method for noninvasive prenatal testing of monogenic diseases from circulating trophoblast cells. This cell-based NIPT can be further applied to the prenatal diagnosis of various monogenic diseases.

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“…Proof-of-principle studies have demonstrated that micro-fluidics-based linked-read sequence technology can be used to deduce parental haplotypes directly without the need for reference samples [18,19], although the cost analysis for this currently makes it prohibitive for routine clinical use. An alternative is the use of grandparental samples for haplotype phasing [20,21]. While complexity and costs could prohibit this being developed for autosomal recessive conditions, it is more suitable for dominant disorders such as Rb, where only one set of grandparents would be required.…”

Section: Discussionmentioning

confidence: 99%

Non-Invasive Prenatal Diagnosis of Retinoblastoma Inheritance by Combined Targeted Sequencing Strategies

Gerrish

Bowns

Mashayamombe-Wolfgarten

et al. 2020

JCM

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Retinoblastoma, the most common childhood eye cancer, presents in two forms: heritable or sporadic. Heritable retinoblastoma is caused by a germline mutation in the RB1 gene. Early diagnosis of children at risk of inheriting an RB1 mutation is crucial to achieve optimal clinical outcome. Currently, the majority of genetic testing is performed on newborns, which has multiple disadvantages for both families and the healthcare system. We have developed a non-invasive prenatal diagnosis (NIPD) service for retinoblastoma, available from 8 weeks’ gestation, which uses a combination of massively parallel sequencing (MPS) techniques, dependent on the inheritance model. Detection of paternal or suspected de novo RB1 variants is achieved through amplicon-based MPS. NIPD of a fetus at risk of maternal inheritance is performed using capture-based targeted sequencing and relative haplotype dosage analysis. In addition, we show proof of principle of how capture-based sequencing can be used for de novo variants unsuitable for amplicon-based testing. In total, we report the NIPD of 15 pregnancies, results of which show 100% concordance with all postnatal testing performed at the time of publication (n = 12) with remaining pregnancies ongoing. NIPD of retinoblastoma therefore offers a viable alternative to newborn genetic testing.

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Noninvasive prenatal diagnosis by genome-wide haplotyping of cell-free plasma DNA

Cited by 29 publications

References 38 publications

Next-generation sequencing: a follow-up of 36,913 singleton pregnancies with noninvasive prenatal testing in central China

Next-generation sequencing: a follow-up of 36,913 singleton pregnancies with noninvasive prenatal testing in central China

A novel method for noninvasive diagnosis of monogenic diseases from circulating fetal cells

Non-Invasive Prenatal Diagnosis of Retinoblastoma Inheritance by Combined Targeted Sequencing Strategies

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