Diagnostic yield of chromosomal microarray analysis in fetuses with isolated increased nuchal translucency: a French  multicenter study

Egloff, M.; Hervé, Bérénice; Quibel, T.; Jaillard, Sylvie; Bouar, G. Le; Uguen, Kévin; Saliou, Anne-Hélène; Valduga, Mylène; Perdriolle, E.; Coutton, Charles; Coston, Anne-Laure; Coussement, A.; Anselem, O.; Missirian, Chantal; Bretelle, Florence; Prieur, Fabienne; Fanget, C.; Muti, Christine; Jacquemot, M.-C.; Bénéteau, Claire; Vaillant, C. Le; Vekemans, Michel; Salomon, Laurent; Vialard, François; Malan, Valérie

doi:10.1002/uog.18928

Cited by 51 publications

(60 citation statements)

References 35 publications

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“…This rate is higher than that observed by Lichtenbelt et al . (11%) or in the French multicenter study (12%); while the respective rate varies in large series including high‐risk fetuses, from 11% in the study of Khalil et al ,. to 21% in a study from the FMF.…”

Section: Discussioncontrasting

confidence: 61%

“…A strength of this study is that genetic testing was performed consistently during the study, using a protocol for increased NT that was set up in our center in 2002 and was updated in 2013 to replace karyotyping with CMA. In addition, the incidence of common trisomies in this study (30%) was higher than that described previously, probably due to the advanced maternal age of this population, thus minimizing the reported proportion of atypical anomalies that were missed by cfDNA testing.…”

Section: Discussioncontrasting

confidence: 59%

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Should cell‐free DNA testing be used in pregnancy with increased fetal nuchal translucency?

Miranda

Miño

Borobio

et al. 2020

Ultrasound in Obstet & Gyne

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CONTRIBUTIONWhat are the novel findings of this work? With the introduction of fetal cell-free DNA (cfDNA) as a screening test for fetal aneuploidy, the utility of the components of first-trimester combined screening, such as nuchal translucency (NT) measurement, has been challenged. We found that conventional cfDNA testing would miss 12-19% of genetic anomalies in fetuses with NT > 99 th centile, thus questioning its suitability as a screening test in patients with increased NT. What are the clinical implications of this work?All pregnant women should be offered an 11-13-week ultrasound scan for NT and early anatomy assessment, irrespective of the applied aneuploidy screening method. If the 11-13-week scan is performed with no prior cfDNA testing, then the finding of an increased NT > 99 th centile should discourage the use of cfDNA testing. ABSTRACTObjective To assess the frequency of atypical chromosomal and submicroscopic anomalies, as well as fetal structural abnormalities, observed on first-trimester ultrasound scan in fetuses with nuchal translucency (NT) thickness > 99 th centile, in order to evaluate the suitability of using standard cell-free DNA (cfDNA) testing as the sole screening test in these pregnancies. MethodsThis was a retrospective cohort study of 226 fetuses with NT > 99 th centile at 11-14 weeks' gestation, setting in which greater than 95% of pregnant women receive first-trimester combined screening. All patients underwent genetic testing by means of quantitative fluorescence polymerase chain reaction and chromosomal microarray analysis, mainly in chorionic villus samples. We assessed the theoretical yield of two cfDNA testing models, targeted cfDNA (chromosomes 21, 18 and 13) and extended cfDNA (chromosomes 21, 18, 13 and sex chromosomes), and compared it with that of cytogenetic testing and ultrasound assessment in the first and second or third trimesters. ResultsIn the 226 fetuses analyzed, cytogenetic testing revealed 84 (37%) anomalies, including 68 typical aneuploidies (involving chromosomes 13, 18 or 21), six sex chromosome aneuploidies (four cases of monosomy X and two of trisomy X), three clinically relevant atypical chromosomal anomalies (one trisomy 22, one trisomy 21 mosaicism and one unbalanced translocation), five submicroscopic pathogenic variants and two cases with Noonan syndrome. Targeted and extended cfDNA testing would miss at least 12% (10/84) and 19% (16/84), respectively, of genetic anomalies, accounting for 4.4% and 7.1% of the fetuses with an increased NT, respectively. Finally, of the 142 fetuses with no identified genetic anomaly, a major fetal malformation was observed in 15 (10.6%) fetuses at the early anomaly scan, and in 19 (13.4%) in the second or third trimester.Conclusions cfDNA does not appear to be the appropriate genetic test in fetuses with NT > 99 th centile, given that it would miss 12-19% of genetic anomalies in this group. Additionally, first-trimester ultrasound

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Section: Discussioncontrasting

confidence: 61%

Section: Discussioncontrasting

confidence: 59%

Should cell‐free DNA testing be used in pregnancy with increased fetal nuchal translucency?

Miranda

Miño

Borobio

et al. 2020

Ultrasound in Obstet & Gyne

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show abstract

“…Lund et al reported one of the highest diagnostic rates (28.8%, 38/132) of chromosomal aneuploidies and the highest detection rate (12.8%, 12/94) of pathogenic CNVs detected by CMA in fetuses with an NT ≥3.5 mm [17]. A French multicenter retrospective study reported one of the largest populations of increased NT and found that 16 (2.7%) pathogenic CNVs could be detected by CMA [16]. Pan et al in China found that 5.7% of pathogenic CNVs could be detected by CMA [21].…”

Section: Discussionmentioning

confidence: 99%

“…Especially in cases with structural anomalies found during prenatal imaging examinations, CMA can detect another 5.6% pathogenic copy number variants (CNVs) in isolated defects and 9.1% pathogenic CNVs in multiple defects [14]. Recent studies have concluded different detection rates for pathogenic CNVs in cases with increased NT (0-15%) [15][16][17]. Some microdeletion/microduplication syndromes, including 22q11.2 deletion syndrome, have been found to be associated with enlarged NT thickness [18,19].…”

Section: Introductionmentioning

confidence: 99%

Prenatal Diagnostic Value of Chromosomal Microarray in Fetuses with Nuchal Translucency Greater than 2.5 mm

Zhang

Wang

et al. 2019

BioMed Research International

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Objective. To assess the clinical value of prenatal diagnosis using quantitative fluorescent polymerase chain reaction (QF-PCR) and chromosomal microarray analysis (CMA) for the examination of genomic imbalances in prenatal amniotic fluid samples from fetuses with a nuchal translucency (NT) greater than or equal to 2.5 mm. Materials and Methods. A total of 494 amniotic fluid samples and 5 chorionic villus samples were included in this study, with a fetal NT ≥ 2.5 mm at 11–13+6 weeks of gestation from November 2015 to December 2018. All cases were examined with QF-PCR, and those with normal QF-PCR results were then analyzed by CMA. Results. Of the 499 cases, common aneuploidies were detected by QF-PCR in 61 (12.2%) cases. One case of triploidy, one case of trisomy 21 mosaicism, and two cases of X/XX mosaicism were further confirmed by fluorescence in situ hybridization (FISH). Among the 434 cases with normal QF-PCR results, microarray detected additional pathogenic copy number variants (CNVs) in 4.8% (21/434) of cases. Six cases would have been expected to be detectable by conventional karyotyping because of large deletions/duplications (>10 Mb), leaving fifteen (3.5%, 15/428) cases with pathogenic CNVs only detectable by CMA. Pathogenic CNVs, especially those <10 Mb, were centralized in cases with an NT < 4.5 mm, including 5 pathogenic CNVs in cases with an NT of 2.5–3.5 mm and 7 pathogenic CNVs in cases with an NT of 3.5–4.5 mm. Conclusions. It is rational to use a diagnostic strategy in which CMA is preceded by a less-expensive, rapid method, namely, QF-PCR, to detect common aneuploidies. CMA allows for the detection of a number of pathogenic chromosomal aberrations in fetuses with an NT ≥ 2.5 mm.

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“…An increased NT (≥3.5 mm, or >99th percentile) is correlated not only with chromosomal aneuploidies, but also with important defects of the heart and arteries, skeletal dysplasia to a considerable extent, as well as some genetic syndromes. In addition, when these defects occur, there is an increased risk of miscarriage, intrauterine fetal death, or delayed development [1,2].…”

Section: Introductionmentioning

confidence: 99%

Clinical application of chromosomal microarray for pathogenic genomic imbalance in fetuses with increased nuchal translucency but normal karyotype

Lee¹,

Go²,

Na³

et al. 2020

J Genet Med

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Purpose: To evaluate the additive value of prenatal chromosomal microarray analysis (CMA) in assessing increased nuchal translucency (NT) (≥3.5 mm) with normal karyotype and the possibility of detecting clinically significant genomic imbalance, based on specific indications. Materials and Methods: Invasive samples from 494 pregnancies with NT ≥3.5 mm, obtained from the Research Center of Fertility & Genetics of Hamchoon Women's Clinic between January 2019 and February 2020, were included in this study and CMA was performed in addition to a standard karyotype. Results: In total, 494 cases were subjected to both karyotype and CMA analyses. Among these, 199 cases of aneuploidy were excluded. CMA was performed on the remaining 295 cases (59.7%), which showed normal (231/295, 78.3%) or non-significant copy number variation (CNV), such as benign CNV or variants of uncertain clinical significance likely benign (53/295, 18.0%). Clinically significant CNVs were detected in 11 cases (11/295, 3.7%). Conclusion: Prenatal CMA resulted in a 3% to 4% higher CNV diagnosis rate in fetuses exhibiting increased NT (≥3.5 mm) without other ultrasound detected anomalies and normal karyotype. Therefore, we suggest using high resolution, non-targeting CMA to provide valuable additional information for prenatal diagnosis. Further, we recommend that a genetics specialist should be consulted to interpret the information appropriately and provide counseling and follow-up services after prenatal CMA.

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Diagnostic yield of chromosomal microarray analysis in fetuses with isolated increased nuchal translucency: a French multicenter study

Abstract: Our study demonstrates the benefit of CMA in the etiological diagnosis of fetuses with isolated increased NT. It is worth noting that most (69%) of the detected pathogenic CNVs were cryptic. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Cited by 51 publications

References 35 publications

Should cell‐free DNA testing be used in pregnancy with increased fetal nuchal translucency?

Should cell‐free DNA testing be used in pregnancy with increased fetal nuchal translucency?

Prenatal Diagnostic Value of Chromosomal Microarray in Fetuses with Nuchal Translucency Greater than 2.5 mm

Clinical application of chromosomal microarray for pathogenic genomic imbalance in fetuses with increased nuchal translucency but normal karyotype

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