Is prenatal cytogenetic diagnosis with genomic array indicated in pregnancies at risk for a molecular or metabolic disorder?

Srebniak, Malgorzata I.; Govaerts, L.; Diderich, Karin E. M.; Joosten, Marieke; Vries, Femke A.T. de; Galjaard, Robert-Jan H; Opstal, Diane Van

doi:10.1038/gim.2015.95

Cited by 6 publications

(4 citation statements)

References 10 publications

(11 reference statements)

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“…In many laboratories/clinics, only stand‐alone RAD or NIPT is offered when a fetus does not show any structural anomaly on ultrasound. Our results are in line with previous reports that showed a 1%–2% risk for a pathogenic submicroscopic chromosome aberration in uncomplicated pregnancies (Fiorentino et al., ; Van Opstal et al., ; Wapner et al., ) and in fetuses not at increased risk for a chromosome aberration (e.g., molecular and biochemical referrals) (Srebniak et al., ). Moreover, when all fetuses without ultrasound anomalies in our cohort were tested with microarray in 2013, 33% of all aberrations found were not detectable by RAD.…”

Section: Discussionsupporting

confidence: 93%

“…Sufficient experience and data have been gathered (de Wit et al., ; Hillman et al., ; Hillman et al., ; Lee et al., ; Srebniak et al., ; Strassberg, Fruhman, & Van den Veyver, ; Wapner et al., ) for a genomic array testing to be recommended in both postnatal and prenatal settings in cases of congenital anomalies. Although it is not a common practice, it has been said before that it may be performed in all other cases when referred for invasive testing (American College of Obstetricians and Gynecologists Committee on Genetics, ; Miller et al., ; Srebniak et al., ). Routine whole‐genome array testing with a resolution of 0.15 Mb allowing the detection of unbalanced microscopic and submicroscopic chromosome aberrations was introduced in our laboratory in 2010 (Srebniak et al., ).…”

Section: Methodsmentioning

confidence: 99%

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The influence of SNP-based chromosomal microarray and NIPT on the diagnostic yield in 10,000 fetuses with and without fetal ultrasound anomalies

et al. 2017

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Prenatal diagnostics has been impacted by technological changes in the past decade, which have affected the diagnostic yield. The aim of this study was to evaluate the impact of SNP array and noninvasive prenatal testing (NIPT) on the diagnostic yield and the number of invasive tests in our center. The frequency of pathogenic fetal unbalanced chromosome aberrations was studied in 10,005 cases referred for prenatal testing in 2009-2015. Chromosomal SNP microarray analysis replaced karyotyping in all invasively tested pregnancies and since 2014 a choice between NIPT and diagnostic testing with microarray was offered to women with an increased risk for common aneuploidy. The introduction of microarray led to an additional yield of submicroscopic pathogenic chromosome aberrations: 3.6% in fetuses with ultrasound anomalies and 1.9% in fetuses without ultrasound anomalies. The introduction of NIPT led to a decrease of invasive tests and of diagnostic yield. Moreover, a diagnostic delay in about 1:350 cases was observed. Since 20%-33% of pathogenic fetal chromosome aberrations are different from the common aneuploidies and triploidy, whole-genome analysis should be offered after invasive sampling. Because NIPT (as a second screening) has led to a decreased diagnostic yield, it should be accompanied by an appropriate pretest counseling.

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Section: Discussionsupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

The influence of SNP-based chromosomal microarray and NIPT on the diagnostic yield in 10,000 fetuses with and without fetal ultrasound anomalies

et al. 2017

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“…These were considered to be cases of potential low-level fetal mosaicism instead of pseudomosaicism because of the initial detection of the chromosome aberration with NIPT showing that at least the CTB of CV was affected. 9,29 Cytogenetic follow-up investigations in two of three cases, however, make the diagnosis of CPM more likely, which is supported by the clinical outcome of all three cases and confirms previous studies reporting on an association between CPM and an increased risk of adverse pregnancy outcomes. [30][31][32] TFM can, however, never be excluded based on the analysis of AF cells and a few fetal tissues like cord blood or buccal cells.…”

Section: Discussionsupporting

confidence: 86%

Limited additional value of karyotyping cultured amniotic fluid cell colonies in addition to microarray on uncultured cells for confirmation of abnormal non‐invasive prenatal testing results

Donze,

Srebniak,

Diderich

et al. 2023

Prenatal Diagnosis

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ObjectivesNon‐invasive prenatal testing (NIPT) allows the detection of placental chromosome aberrations. To verify whether the fetus also has the chromosome aberration, diagnostic follow‐up testing is required. The aim of this retrospective study was to assess the added value of analyzing amniotic fluid (AF) cell cultures in addition to uncultured AF cells for the detection of fetal mosaicism.MethodNIPT was performed as part of the Dutch TRIDENT study. Cytogenetic studies in uncultured AF were performed using single nucleotide polymorphism (SNP)‐array. Cultured AF cell colonies (in situ method) were investigated with fluorescent in situ hybridization and/or karyotyping. Clinical outcome data were collected in cases with discordant results.ResultsBetween April 2014 and December 2021, 368 amniocenteses were performed after a chromosomal aberration was detected with NIPT. Excluding 134 cases of common aneuploidies (confirmed by quantitative fluorescence polymerase chain reaction), 29 cases with investigation of uncultured cells only and 1 case without informed consent, 204 cases were eligible for this study. In 196 (96%) cases, the results in uncultured and cultured cells were concordant normal, abnormal or mosaic. Five cases (2%) showed mosaicism in cultured AF cells, whereas uncultured AF cells were normal. Two (1%) of these, one mosaic trisomy 13 and one mosaic trisomy 16, were considered true fetal mosaics.ConclusionThe added value of investigating AF cell cultures in addition to uncultured cells is limited to two of 204 (1%) cases in which true fetal mosaicsm would otherwise be missed. The clinical relevance of one (trisomy 13) remained unknown and the other case also showed ultrasound anomalies, which determined pregnancy management. This seems to justify limiting prenatal cytogenetic confirmatory testing to SNP arrays on uncultured AF cells, considerably shortening the reporting time.

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“…Third, we suspect that the low diagnostic yield of CMA observed in the study of Egloff et al might actually reflect the diagnostic improvement of CMA itself. We think that the incidence (1.8%) of submicroscopic pathogenic CNVs in their cohort might be attributed to accidental findings, similar to the incidence (1–2%) in cases with advanced maternal age and in cases in which chorionic villus sampling or amniocentesis was performed for other reasons (including parental anxiety or molecular and biochemical referrals). According to Lee et al , there is a 0.52% baseline risk of submicroscopic genomic imbalance, even in women with an uneventful prenatal examination.…”

mentioning

confidence: 64%

Diagnostic value of chromosomal microarray in fetuses with increased nuchal translucency

2019

Ultrasound in Obstet & Gyne

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We read with interest the paper of Egloff et al. in which they determined the frequency and nature of copy number variants (CNVs) identified by chromosomal microarray analysis (CMA) in prenatal samples from fetuses with isolated nuchal translucency thickness (NT) ≥ 3.5 mm 1 . This is the largest multicenter study of its kind to date, comprising a total of 599 euploid fetuses that underwent CMA testing. The authors reported a 2.7% prevalence of pathogenic CNVs, including a 1.8% prevalence of cryptic pathogenic CNVs. The authors concluded that the benefit of CMA in the etiological diagnosis of fetuses with isolated increased NT is obvious. However, we feel this report raises some questions that need to be addressed.First, what was the diagnostic criterion for 'isolated' increased NT? Did all the patients referred for NT measurement undergo an in-depth first-trimester ultrasound examination, or was an early in-depth scan performed only in patients with increased NT? Since a detailed first-trimester ultrasound scan requires additional examination time and specialized personnel, usually it is not offered routinely to the general population; instead, it is performed in selective cases, such as those with increased NT or unexpected findings. In a recent study by Tekesin, major sonographic findings could be detected in 51.8% of fetuses with NT ≥ 3.5 mm using an early anomaly scan 2 . Similarly, Kenkhuis et al. concluded that an early scan performed at 12-13 weeks' gestation by a competent sonographer can detect about half of the prenatally detectable structural anomalies and 100% of those expected to be detected at this stage 3 . In the study of Egloff et al. 1 , information on ultrasound findings after the first trimester is not available. In cases in which anomalies were detected at follow-up mid-trimester ultrasound examination, were these still designated as having isolated increased NT in their retrospective study?Second, the authors attributed the low incremental diagnostic yield of CMA observed in their study to the inclusion of only fetuses with apparently strictly isolated increased NT. In comparison, an additional 7% of cryptic CNVs were detected in a study in which increased NT was associated with at least one other ultrasound finding 4 . Indeed, the authors had the opportunity to demonstrate this difference by reporting the rate of cryptic CNVs detected in their cases with non-isolated increased NT. However, these cases were excluded from their study. Furthermore, information on pregnancy outcome in their cohort was also unavailable. Consequently, it remains unanswered what percentage of cases with increased NT had abnormal mid-trimester ultrasound findings and whether the incidence of cryptic CNVs differed significantly between cases with isolated increased NT and those with abnormal mid-trimester ultrasound.Third, we suspect that the low diagnostic yield of CMA observed in the study of Egloff et al. might actually reflect the diagnostic improvement of CMA itself. We think that the incidence (1.8%) of submic...

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Is prenatal cytogenetic diagnosis with genomic array indicated in pregnancies at risk for a molecular or metabolic disorder?

Cited by 6 publications

References 10 publications

The influence of SNP-based chromosomal microarray and NIPT on the diagnostic yield in 10,000 fetuses with and without fetal ultrasound anomalies

The influence of SNP-based chromosomal microarray and NIPT on the diagnostic yield in 10,000 fetuses with and without fetal ultrasound anomalies

Limited additional value of karyotyping cultured amniotic fluid cell colonies in addition to microarray on uncultured cells for confirmation of abnormal non‐invasive prenatal testing results

Diagnostic value of chromosomal microarray in fetuses with increased nuchal translucency

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