Comprehensive genetic analysis of pregnancy loss by chromosomal microarrays: outcomes, benefits, and challenges

Sahoo, Trilochan; Dzidic, Natasa; Strecker, Michelle N.; Commander, Sara; Travis, Mary K.; Doherty, Charles; Tyson, R. Weslie; Mendoza, Arturo; Stephenson, Mary D.; Dise, Craig A.; Benito, Carlos; Ziadie, Mandolin; Hovanes, Karine

doi:10.1038/gim.2016.69

Cited by 146 publications

(121 citation statements)

References 34 publications

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“…The overall detection rate of clinically significant chromosomal abnormalities was 55.1% (295/535), and the rate of VOUS was 2.8%, which is in accordance with previous studies (6,7,9,15). We also compared the frequency and distribution of chromosomal abnormalities between patients with SA and RM.…”

Section: Discussionsupporting

confidence: 89%

Clinical application of SNP array analysis in first‐trimester pregnancy loss: a prospective study

Wang¹,

Cheng

Meng³

et al. 2016

Clinical Genetics

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Chromosomal microarray analysis (CMA) has been used routinely in pediatric and prenatal genetic diagnosis in clinical practice, but it has rarely been applied to miscarriage analysis. In this study, we conducted a prospective study to evaluate the feasibility of CMA for genetic diagnosis of first-trimester miscarriage specimens. We successfully analyzed 551 fresh miscarriage specimens using single-nucleotide polymorphism (SNP) array. Among the specimens, 2.9% (16/551) had significant maternal cell contamination and were excluded from the study. Clinically significant chromosomal abnormalities were identified in 295 (55.1%) cases, including 214 (40%) with aneuploidy, 40 (7.5%) with polyploidy, 19 (3.6%) with partial aneuploidy, 12 (2.2%) with pathogenic microdeletion/microduplication, and 10 (1.9%) with uniparental isodisomy (isoUPD). Variants of uncertain significance were obtained in 15 cases (2.8%). Notably, isoUPD involving a single chromosome (chromosome 22) and two recurrent copy number variations, 22q11.2 microdeletion and 7q11.23 microdeletion, were identified as probably to be associated with miscarriage. The frequency and distribution of genetic aberrations in the spontaneous abortion group was not significantly different from those in the recurrent miscarriage group. Our study suggests SNP array is a reliable, robust, and high-resolution technology for genetic diagnosis of miscarriage in clinical practice.

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Section: Discussionsupporting

confidence: 89%

Clinical application of SNP array analysis in first‐trimester pregnancy loss: a prospective study

Wang¹,

Cheng

Meng³

et al. 2016

Clinical Genetics

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“…Our success rate is similar to the 92.4% rate obtained in the recent study of Sahoo et al [2017] using mostly SNP-array analysis in fresh tissue samples, but lower than the 99.9% rate reported by Levy et al [2014], although in this case 22% of the samples were not valid due to maternal cell contamination. The reason for our high success rate is that CV samples were obtained before evacuation and were processed within a few hours, thus minimizing microbiological contamination and allowing a high success in STC karyotype achievement.…”

Section: Success Rate Abnormality Rate and Overall Frequenciessupporting

confidence: 65%

“…CMA has a much higher ability to detect subtle genomic changes than conventional cytogenetics, but it is unable to detect balanced structural rearrangements, some polyploidies [Robberecht et al, 2009;Dhillon et al, 2014], and presents difficulties to detect low-level mosaicisms. More recently, SNP-based CMA has increased the diagnostic power, adding the detection of uniparental disomy [Levy et al, 2014;Sahoo et al, 2017]. However, the involvement and relevance of small chromosome imbalances as well as uniparental disomy of individual chromosomes in early pregnancy losses still needs to be established, and variants of unknown significance can be detected [Dhillon et al, 2014], which could lead to anxiety in the parents and hinder the subsequent genetic counseling.…”

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confidence: 99%

Overview of Chromosome Abnormalities in First Trimester Miscarriages: A Series of 1,011 Consecutive Chorionic Villi Sample Karyotypes

Soler

Morales²,

Mademont-Soler³

et al. 2017

Cytogenet Genome Res

128

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In order to contribute to the knowledge of type and frequency of chromosome abnormalities in early pregnancy losses, we analyzed the cytogenetic results from a large series of first trimester miscarriages, using a diagnostic approach with a high success rate and no maternal contamination. A total of 1,119 consecutive chorionic villi samples were obtained before evacuation, and karyotypes were prepared after short-term culture (STC). In 603 samples, a long-term culture (LTC) was also performed. The overall and individual frequencies of the different types of chromosome abnormalities were established, including placental mosaicisms, and their relationship with maternal age and gestational weeks was assessed. An abnormal karyotype was detected in 70.3% of the samples. Single autosomal trisomy was the most frequent abnormality (64.6% of the abnormal cases), followed by triploidy (13.1%) and monosomy X (10.4%). Chromosome rearrangements were found in 5.2%, combined abnormalities in 8.9%, and placental mosaicism in 3.5% of the cases with STC and LTC performed. Individual trisomies behaved differently with respect to maternal age and intrauterine survival. Due to the combination of STC and LTC, our study offers reliable information on the incidence and type of chromosome abnormalities and placental mosaicism in miscarriages and contributes to define the cytogenetic implication in their etiology.

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“…In our cohort, 1.5% (40/2718) of samples were found to have a fully penetrant clinically significant submicroscopic (<10 Mb) CNV, whilst 0.3% (9/2718) were found to have a neurosusceptibility CNVs (nsCNV) >1 Mb in size. Other published cohorts found clinically significant submicroscopic imbalance in 0.6% [6], 0.8% [10], 1.6% [8] of samples, although the Levy study [10] included nsCNV and CNVs of unknown significance in this group. The patient vs patient aCGH strategy provides a significant cost reduction compared with patient vs control testing.…”

Section: Discussionmentioning

confidence: 91%

Efficient and cost-effective genetic analysis of products of conception and fetal tissues using a QF-PCR/array CGH strategy; five years of data

et al. 2017

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BackgroundTraditional testing of miscarriage products involved culture of tissue followed by G-banded chromosome analysis; this approach has a high failure rate, is labour intensive and has a resolution of around 10 Mb. G-banded chromosome analysis has been replaced by molecular techniques in some laboratories; we previously introduced a QF-PCR/MLPA testing strategy in 2007. To improve diagnostic yield and efficiency we have now updated our testing strategy to a more comprehensive QF-PCR assay followed by array CGH. Here we describe the results from the last 5 years of service.MethodsFetal tissue samples and products of conception were tested using QF-PCR which will detect aneuploidy for chromosomes 13, 14, 15, 16, 18, 21, 22, X and Y. Samples that were normal were then tested by aCGH and all imbalance >1Mb and fully penetrant clinically significant imbalance <1Mb was reported.ResultsQF-PCR analysis identified aneuploidy/triploidy in 25.6% of samples. aCGH analysis detected imbalance in a further 9.6% of samples; this included 1.8% with submicroscopic imbalance and 0.5% of uncertain clinical significance. This approach has a failure rate of 1.4%, compared to 30% for G-banded chromosome analysis.ConclusionsThis efficient QF-PCR/aCGH strategy has a lower failure rate and higher diagnostic yield than karyotype or MLPA strategies; both findings are welcome developments for couples with recurrent miscarriage.

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Comprehensive genetic analysis of pregnancy loss by chromosomal microarrays: outcomes, benefits, and challenges

Cited by 146 publications

References 34 publications

Clinical application of SNP array analysis in first‐trimester pregnancy loss: a prospective study

Clinical application of SNP array analysis in first‐trimester pregnancy loss: a prospective study

Overview of Chromosome Abnormalities in First Trimester Miscarriages: A Series of 1,011 Consecutive Chorionic Villi Sample Karyotypes

Efficient and cost-effective genetic analysis of products of conception and fetal tissues using a QF-PCR/array CGH strategy; five years of data

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