Clinical experience with non‐invasive prenatal screening for single‐gene disorders

Mohan, Pooja; Lemoine, Jean; Trotter, Cindy; Rakova, Irina; Billings, Paul R.; Peacock, Sandra; Kao, Charlly; Wang, Y.; Xia, Fan; Eng, Christine M.; Benn, Peter

doi:10.1002/uog.23756

Cited by 38 publications

(43 citation statements)

References 22 publications

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“…NIPT for detection of single gene disorders and corresponding point mutations are most often referred to as NIPS, to distinguish from ‘normal NIPT’. While few authors report on a 100% detection rate for mutations in small proof of principle studies [ 42 ], others are more skeptical. Already in 2009 it was highlighted that NIPT latest then becomes complex when fetus and mother have the same alleles, which are indistinguishable on cffDNA level [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

False-positives and false-negatives in non-invasive prenatal testing (NIPT): what can we learn from a meta-analyses on > 750,000 tests?

Liehr

2022

Mol Cytogenet

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Background Non-invasive prenatal testing (NIPT) has had an incomparable triumph in prenatal diagnostics in the last decade. Over 1400 research articles have been published, predominantly praising the advantages of this test. Methods The present study identified among the 1400 papers 24 original and one review paper, which were suited to re-evaluate the efficacy of > 750,000 published NIPT-results. Special attention was given to false-positive and false-negative result-rates. Those were discussed under different aspects—mainly from a patient-perspective. Results A 27: 1 rate of false-positive compared to false-negative NIPT results was found. Besides, according to all reported, real-positive, chromosomally aberrant NIPT cases, 90% of those would have been aborted spontaneously before birth. These findings are here discussed under aspects like (i) How efficient is NIPT compared to first trimester screening? (ii) What are the differences in expectations towards NIPT from specialists and the public? and (iii) There should also be children born suffering from not by NIPT tested chromosomal aberrations; why are those never reported in all available NIPT studies? Conclusions Even though much research has been published on NIPT, unbiased figures concerning NIPT and first trimester screening efficacy are yet not available. While false positive rates of different NIPT tests maybe halfway accurate, reported false-negative rates are most likely too low. The latter is as NIPT-cases with negative results for tested conditions are yet not in detail followed up for cases with other genetic or teratogenic caused disorders. This promotes an image in public, that NIPT is suited to replace all invasive tests, and also to solve the problem of inborn errors in humans, if not now then in near future. Overall, it is worth discussing the usefulness of NIPT in practical clinical application. Particularly, asking for unbiased figures concerning the efficacy of first trimester-screening compared to NIPT, and for really comprehensive data on false-positive and false-negative NIPT results.

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Section: Discussionmentioning

confidence: 99%

False-positives and false-negatives in non-invasive prenatal testing (NIPT): what can we learn from a meta-analyses on > 750,000 tests?

Liehr

2022

Mol Cytogenet

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“…This test requires genomic DNA from both parents to be tested alongside the cfDNA in order to assist with the interpretation, and it cannot detect variants which are maternally inherited (including those which are also X-linked). A recent review of this service looked at the results for 2208 women, of which 125 (5.7%) were positive [ 112 ]. The authors report no false-positive or -negative results, with a follow-up rate of 53.6%.…”

Section: Commercial Screening For Low-risk Pregnanciesmentioning

confidence: 99%

Non-invasive prenatal diagnosis (NIPD): how analysis of cell-free DNA in maternal plasma has changed prenatal diagnosis for monogenic disorders

et al. 2022

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Cell-free fetal DNA (cffDNA) is released into the maternal circulation from trophoblastic cells during pregnancy, is detectable from 4 weeks and is representative of the entire fetal genome. The presence of this cffDNA in the maternal bloodstream has enabled clinical implementation of non-invasive prenatal diagnosis (NIPD) for monogenic disorders. Detection of paternally inherited and de novo mutations is relatively straightforward, and several methods have been developed for clinical use, including quantitative polymerase chain reaction (qPCR), and PCR followed by restriction enzyme digest (PCR-RED) or next-generation sequencing (NGS). A greater challenge has been in the detection of maternally inherited variants owing to the high background of maternal cell-free DNA (cfDNA). Molecular counting techniques have been developed to measure subtle changes in allele frequency. For instance, relative haplotype dosage analysis (RHDO), which uses single nucleotide polymorphisms (SNPs) for phasing of high- and low-risk alleles, is clinically available for several monogenic disorders. A major drawback is that RHDO requires samples from both parents and an affected or unaffected proband, therefore alternative methods, such as proband-free RHDO and relative mutation dosage (RMD), are being investigated. cffDNA was thought to exist only as short fragments (<500 bp); however, long-read sequencing technologies have recently revealed a range of sizes up to ∼23 kb. cffDNA also carries a specific placental epigenetic mark, and so fragmentomics and epigenetics are of interest for targeted enrichment of cffDNA. Cell-based NIPD approaches are also currently under investigation as a means to obtain a pure source of intact fetal genomic DNA.

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“…Conditions screened are autosomal or X-linked dominant in inheritance with reported cases of de novo mutations. 88 These conditions affect quality of life and affected individuals may benefit from medical and/or surgical intervention (mainly impacting skeletal and neurological development). This unique cell-free DNA screening option is able to detect conditions such as Noonan syndrome, achondroplasia, osteogenesis imperfecta, and Rett syndrome.…”

Section: First-trimester Septated Cystic Hygromamentioning

confidence: 99%

“…This unique cell-free DNA screening option is able to detect conditions such as Noonan syndrome, achondroplasia, osteogenesis imperfecta, and Rett syndrome. 88 , 89 First-trimester septated cystic hygroma has been associated with an increased risk of Noonan syndrome in pregnancy. Traditionally, single gene analysis with diagnostic testing has been restricted by insurance coverage and laboratory selection.…”

Section: First-trimester Septated Cystic Hygromamentioning

confidence: 99%

Current Perspectives of Prenatal Cell-free DNA Screening in Clinical Management of First-Trimester Septated Cystic Hygroma

Sherer¹,

Hsieh²,

Hall³

et al. 2022

IJWH

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First-trimester septated cystic hygroma occurs in approximately 1 in 268 pregnancies and has long been associated with a markedly increased risk of fetal aneuploidy and, among euploid fetuses, an increased risk of structural anomalies primarily affecting the cardiac and skeletal systems. Invasive prenatal diagnosis -chorionic villus sampling and/or amniocentesis -encompasses the timehonored clinical tools for the next step in management following prenatal sonographic diagnosis of first-trimester septated cystic hygroma. Currently, prenatal cell-free DNA (cfDNA) screening for fetal aneuploidy with select microdeletions is gradually replacing the considerably less sensitive, and labor-intensive combined first-trimester screening. These new technologies have opened potential new venues in the clinical management of this ominous late first-trimester sonographic diagnosis. Advances in cfDNA technologies are now permitting detection of chromosomal copy number variants (CNV) larger than 7Mb across genome and select serious single-gene disorders (mainly impacting skeletal and neurological development), affecting quality of life and may benefit from medical and/or surgical management. This commentary will address the available non-invasive prenatal screening technologies, which clearly enhance immediate genetic analysis modalities applicable in the presence of the complex sonographic finding of first-trimester septated cystic hygroma.

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Clinical experience with non‐invasive prenatal screening for single‐gene disorders

Abstract: This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as

Cited by 38 publications

References 22 publications

False-positives and false-negatives in non-invasive prenatal testing (NIPT): what can we learn from a meta-analyses on > 750,000 tests?

False-positives and false-negatives in non-invasive prenatal testing (NIPT): what can we learn from a meta-analyses on > 750,000 tests?

Non-invasive prenatal diagnosis (NIPD): how analysis of cell-free DNA in maternal plasma has changed prenatal diagnosis for monogenic disorders

Current Perspectives of Prenatal Cell-free DNA Screening in Clinical Management of First-Trimester Septated Cystic Hygroma

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