High‐resolution chromosomal microarrays in prenatal diagnosis significantly increase diagnostic power

Oneda, Beatrice; Baldinger, Rosa; Reissmann, Regina; Reshetnikova, Irina; Krejci, Pavel; Masood, Rahim; Ochsenbein‐Kölble, Nicole; Bartholdi, Deborah; Steindl, Katharina; Morotti, Denise; Faranda, Marzia; Baumer, Alessandra; Asadollahi, Reza; Joset, Pascal; Niedrist, Dunja; Breymann, Christian; Hebisch, Gundula; Hüsler, M; Mueller, R. H.; Prentl, Elke; Wisser, Josef; Zimmermann, Roland; Rauch, Anita

doi:10.1002/pd.4342

Cited by 43 publications

(44 citation statements)

References 25 publications

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“…This detection rate is lower than the one reported in the literature [Callaway et al, 2013;Oneda et al, 2014;Grande et al, 2015]. The detection rate of clinically relevant CNVs is 6.5% in cases with fetal malformations detected upon ultrasound examination [Shaffer et al, 2012b].…”

Section: Discussioncontrasting

confidence: 49%

A French Approach to Test Fetuses with Ultrasound Abnormalities Using a Customized Microarray as First-Tier Genetic Test

Malan

Lapierre²,

Egloff³

et al. 2015

Cytogenet Genome Res

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Cytogenetic microarray analysis is now the first-tier genetic test used in a postnatal clinical setting to explore genomic imbalances in individuals with developmental disability and/or birth defects. However, in a prenatal setting, this technique is not widely implemented, largely because the clinical impact of some copy number variants (CNVs) remains difficult to assess. This limitation is especially true in France where termination of pregnancy for medical reasons may be performed at any stage of gestation. During a period of 15 months, we investigated 382 fetuses presenting with ultrasound anomalies, using a customized microarray designed to avoid the detection of CNVs raising challenges for genetic counseling. After excluding common aneuploidies, 20/374 (5.3%) fetuses had a pathogenic CNV, among which 12/374 (3.2%) could have been detected by karyotyping, whereas 8/374 (2.1%) were cryptic. Within these 374 cases, 300 were ongoing pregnancies at the time of array comparative genomic hybridization (aCGH) testing. For these pregnancies, we detected 18/300 (6%) pathogenic CNVs, among which 6/300 (2%) were cryptic. Using this approach, only 2/300 (0.6%) of the detected CNVs raised difficulties for genetic counseling. This study confirms the added value of this strategy in a prenatal clinical setting to minimize ethical issues for genetic counseling while enhancing the detection of genomic imbalances.

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Section: Discussioncontrasting

confidence: 49%

A French Approach to Test Fetuses with Ultrasound Abnormalities Using a Customized Microarray as First-Tier Genetic Test

Malan

Lapierre²,

Egloff³

et al. 2015

Cytogenet Genome Res

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“…Two further cohorts, including 65 and 45 nonmalformed FGR fetuses, reported a 2-7% incremental yield [8,9]. The remaining studies had a small FGR subgroup including 3-19 cases and reported detection rates ranging from 0 to 17% in nonmalformed FGR fetuses [11,12,14,21,22] and from 0 to 21% in malformed FGR fetuses [3,11,12]. Funnel plots to assess publication bias are provided in online supplementary Figures 1S and 2S.…”

Section: Resultsmentioning

confidence: 99%

“…Forty-two studies were excluded because they did not include an FGR group, because they included overlapping populations, or because the data required for the analysis could not be extracted. One series without an initial FGR subgroup was finally included because the authors provided us the missing data [12]. Two series from the same group were included as their most recent study included only nonmalformed FGR fetuses, while from the former only malformed FGR fetuses were included [3,9].…”

Section: Resultsmentioning

confidence: 99%

“…The most frequently encountered pathogenic imbalances were five 22q11.2 microduplication syndromes [3,8,9,13], three Xp22.3 [11][12][13] deletion syndromes, and three Williams-Beuren syndromes (7q11.23 microdeletion) [8,11,13]. Three of the 22q11.2 duplicated regions were reciprocal to the DiGeorge/velocardiofacial syndrome recurrent deletions, one was a more distal 22q11.22q11.23 microduplication [13], and in the last no details were given by the authors [9].…”

Section: Discussionmentioning

confidence: 99%

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Chromosomal Microarray Analysis in Fetuses with Growth Restriction and Normal Karyotype: A Systematic Review and Meta-Analysis

Borrell¹,

Grande²,

Pauta³

et al. 2017

Fetal Diagn Ther

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Objective: To perform a systematic review of the literature and a meta-analysis to estimate the incremental yield of chromosomal microarray analysis (CMA) over karyotyping in fetal growth restriction (FGR). Methods: This was a systematic review conducted in accordance with the PRISMA criteria. All articles identified in PubMed, Ovid Medline, and ISI Web of Knowledge (Web of Science) from January 2009 to November 2016 describing pathogenic copy number variants (CNVs) in fetuses with growth restriction were included. Case reports were excluded. Risk differences were pooled to estimate the overall and stratified CMA incremental yield. Results: Ten studies with full data available met the inclusion criteria for analysis. Combined data from these studies revealed a 4% (95% confidence interval [CI] 1-6%) incremental yield of CMA over karyotyping in nonmalformed growth-restricted fetuses, and a 10% (95% CI 6-14%) incremental yield in FGR when associated with fetal malformations. The most frequently found pathogenic CNVs were 22q11.2 duplication, Xp22.3 deletion, and 7q11.23 deletion (Williams-Beuren syndrome), particularly in isolated FGR. Conclusion: The use of genomic CMA provides a 4% incremental yield of detecting pathogenic CNVs in fetuses with isolated growth restriction and normal karyotype.

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“…Indeed, we also observed CNV's representing known and well-documented polymorphisms or inherited benign/low risk variants for which counseling is relatively straightforward, while in our series we did not come across any (un-interpretable) variants of unknown clinical significance. This is in contrast, however, with the multitude of VOUS detected by higher resolution aCGH platforms, with figures ranging from 1-4% [48,50,51], necessitating parental follow-up studies and complicated genetic counseling and perhaps these drawbacks cannot be offset by the slightly higher detection rate.…”

Section: Resultsmentioning

confidence: 44%

Dilemmas in Prenatal Chromosomal Diagnosis Revealed Through a Single Center's 30 Years' Experience and 90,000 Cases

2015

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Introduction: The aim of this article is to provide a perspective of prenatal chromosomal diagnosis (PCD) derived from a single center's evolving experience from ∼90,000 consecutive prenatal cases and to highlight important issues and current dilemmas. Materials and Methods: Prenatal cases in this study (1985-2013) were referred for various indications, and PCD was performed by standard karyotype in 84,255 cases, multiplex ligation-dependent probe amplification (MLPA) panel in 3,010 cases and standalone array comparative genomic hybridization (aCGH) in 3,122 cases. Results: Classic karyotype revealed 1.7 and 7.9% of pathological cases in amniotic fluid and CVS samples, respectively, with common aneuploidies accounting for 59.6 and 64.3% of the total abnormal. Molecular approaches increased the diagnostic yield by 0.6% for MLPA and 1.6% for aCGH, uncovering pathogenic chromosomal abnormalities undetectable by karyotype analysis. Conclusions: Current molecular diagnostic capabilities and the recent introduction of noninvasive prenatal testing (NIPT) point to one current major dilemma in PCD, with serious implications in genetic counseling, relating on the one hand to reaping the benefits from the high detection rate afforded through aCGH but accepting an invasive risk, and on the other hand, offering a lower detection rate practically only for Down syndrome, with minimal invasive risk.

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High‐resolution chromosomal microarrays in prenatal diagnosis significantly increase diagnostic power

Abstract: High-resolution prenatal microarray testing is a reliable technique that increases diagnostic yield by at least 17.3% when compared with conventional karyotyping, without an increase in the frequency of variants of uncertain significance.

Cited by 43 publications

References 25 publications

A French Approach to Test Fetuses with Ultrasound Abnormalities Using a Customized Microarray as First-Tier Genetic Test

A French Approach to Test Fetuses with Ultrasound Abnormalities Using a Customized Microarray as First-Tier Genetic Test

Chromosomal Microarray Analysis in Fetuses with Growth Restriction and Normal Karyotype: A Systematic Review and Meta-Analysis

Dilemmas in Prenatal Chromosomal Diagnosis Revealed Through a Single Center's 30 Years' Experience and 90,000 Cases

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