Non-invasive prenatal diagnosis and screening for monogenic disorders

Scotchman, Elizabeth; Shaw, Joe J.; Paternoster, B.; Chandler, Natalie; Chitty, Lyn S.

doi:10.1016/j.ejogrb.2020.08.001

Cited by 52 publications

(42 citation statements)

References 67 publications

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“…Discussion cfDNA is becoming a crucial tool for diagnosis and management in various clinical disorders. In the eld the noninvasive prenatal testing, cfDNA has been applied fetal gender determination, RHD genotyping, and detecting of chromosomal aneuploidies, chromosomal aneuploidies, and increasing number of monogenic disorders [5][6][7][8][9][10][11][12][13] . NIPS is becoming a routine clinical management screening more and more genetic disorders [19] .…”

Section: Clinical Outcome Follow-upmentioning

confidence: 99%

“…In recent years, cfDNA was used to screen for sex chromosome aneuploidy and chromosome copy number variants (CNVs) [9,10] . Studies have demonstrated the utility of NIPS in fetal sex determination, fetal Rhesus D genotyping in D-negative mothers, and in some monogenic disorders [11][12][13] . Achondroplasia is of the rst monogenic disorders that can be noninvasively prenatal diagnosed thought cfDNA, because genetic absence of de novo mutation from the maternal and the high prevalence of FGFR3 single point hot spot mutations makes the detection easier to get high speci city and high coverage.…”

Section: Introductionmentioning

confidence: 99%

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Non-Invasive Prenatal Detecting of Achondroplasia In Earlier Stage of Pregnancy By Droplet-Digital PCR

Wang

et al. 2021

Preprint

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Background: Achondroplasia (ACH) is generally detected by abnormal prenatal ultrasound findings in the late stage of pregnancy and then confirmed by molecular genetic testing of fetal genomic DNA obtained invasively. Most ACH cases appear to be de novo mutations with FGFR3 gene, so it is a challenge to screen ACH fetus out in the early stage of pregnancy.Objective: The aim of this study was to validate the possibility of detect fetus ACH along with non-invasive prenatal screening(NIPS) routinely in the early stage of pregnancy.Methods: 5927 cases of pregnant women undergoing NIPS were enrolled in this study. An additional 5ml of blood was collected together with NIPS blood sampling. Cell free DNA was extracted for the detecting of fetus ACH. Droplet-digital PCR(ddPCR) method based on the amplification of the two possible mutant alleles (c. 1138G>A and c. 1138G>C) of FGFR3 gene was performed to screen fetus ACH. Prenatal ultrasound and amniocentesis were then performed to confirm the positive screening result of ACH cases. The mutation sites of fetus were identified via Sanger sequencing by using amniotic fluid cells. For the screen negative cases of pregnant women, we followed up the results of prenatal diagnosis or the general conditions of the newborns.Results: One pregnant woman with fetus ACH were screened out at 22 weeks by Non-invasive prenatal detecting. Later prenatal ultrasound confirmed fetal skeletal dysplasia. Sanger sequencing confirmed de novo FGFR3 1138G>A mutant of the fetus. No ACH fetus or newborns were found in the rest detected negative cases of enrolled pregnant women.Conclusion: ddPCR technology could effectively identify de novo mutation like ACH of fetus noninvasively. We prospect the clinical application of ddPCR can expand the range of prenatal screen in the future.

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Section: Clinical Outcome Follow-upmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Non-Invasive Prenatal Detecting of Achondroplasia In Earlier Stage of Pregnancy By Droplet-Digital PCR

Wang

et al. 2021

Preprint

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“…The application of high-resolution assays in prenatal management significantly improves the detection rate for genomic alterations causing aberrant phenotypes (for review: [44,45]). On the other hand, the ascertainment of an increasing amount of genetic data is accompanied by a growing number of incidental findings, comprising both obviously pathogenic variants as well as variants of unknown clinical significance.…”

Section: Detection Of Upd In the Era Of Prenatal High-resolution Testingmentioning

confidence: 99%

Prenatal Detection of Uniparental Disomies (UPD): Intended and Incidental Finding in the Era of Next Generation Genomics

Eggermann

2020

Genes

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Prenatal detection of uniparental disomy (UPD) is a methodological challenge, and a positive testing result requires comprehensive considerations on the clinical consequences as well as ethical issues. Whereas prenatal testing for UPD in families which are prone to UPD formation (e.g., in case of chromosomal variants, imprinting disorders) is often embedded in genetic counselling, the incidental identification of UPD is often more difficult to manage. With the increasing application of high-resolution test systems enabling the identification of UPD, an increase in pregnancies with incidental detection of UPD can be expected. This paper will cover the current knowledge on uniparental disomies, their clinical consequences with focus on prenatal testing, genetic aspects and predispositions, genetic counselling, as well as methods (conventional tests and high-throughput assays).

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“…The cffDNA can be first detected in maternal blood as early as 5 weeks of gestation, but the amount of cffDNA at that time is still too low to be tested [ 9 ]. In fact, cffDNA usually reaches levels sufficient for prenatal diagnosis of monogenic disorders at around gestation week 6–7 [ 10 ]. The discovery of cffDNA in the maternal peripheral blood in combination with the development of next-generation sequencing (NGS) technology has allowed for a wider application of NIPD in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Noninvasive fetal genotyping of single nucleotide variants and linkage analysis for prenatal diagnosis of monogenic disorders

Zhou

Jiang³

et al. 2022

Hum Genomics

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Background High-cost, time-consuming and complex processes of several current approaches limit the use of noninvasive prenatal diagnosis (NIPD) for monogenic disorders in clinical application. Thus, a more cost-effective and easily implementable approach is required. Methods We established a low-cost and convenient test to noninvasively deduce fetal genotypes of the mutation and single nucleotide polymorphisms (SNPs) loci by means of targeted amplification combined with deep sequencing of maternal genomic and plasma DNA. The sequential probability ratio test was performed to detect the allelic imbalance in maternal plasma. This method can be employed to directly examine familial pathogenic mutations in the fetal genome, as well as infer the inheritance of parental haplotypes through a group of selected SNPs linked to the pathogenic mutation. Results The fetal mutations in 17 families with different types of monogenic disorders including hemophilia A, von Willebrand disease type 3, Duchenne muscular dystrophy, hyper-IgM type 1, glutaric acidemia type I, Nagashima-type palmoplantar keratosis, and familial exudative vitreoretinopathy were identified in the study. The mutations included various forms: point mutations, gene inversion, deletions/insertions and duplication. The results of 12 families were verified by sequencing of amniotic fluid samples, the accuracy of the approach in fetal genotyping at the mutation and SNPs loci was 98.85% (172/174 loci), and the no-call rate was 28.98% (71/245 loci). The overall accuracy was 12/12 (100%). Moreover, the approach was successfully applied in plasma samples with a fetal fraction as low as 2.3%. Conclusions We have shown in this study that the approach is a cost-effective, less time consuming and accurate method for NIPD of monogenic disorders.

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Non-invasive prenatal diagnosis and screening for monogenic disorders

Cited by 52 publications

References 67 publications

Non-Invasive Prenatal Detecting of Achondroplasia In Earlier Stage of Pregnancy By Droplet-Digital PCR

Non-Invasive Prenatal Detecting of Achondroplasia In Earlier Stage of Pregnancy By Droplet-Digital PCR

Prenatal Detection of Uniparental Disomies (UPD): Intended and Incidental Finding in the Era of Next Generation Genomics

Noninvasive fetal genotyping of single nucleotide variants and linkage analysis for prenatal diagnosis of monogenic disorders

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