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:10.1097/01.ogx.0000516407.08742.9c

Cited by 19 publications

(40 citation statements)

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“…SNP Microarray. SNP-based whole-genome chromosomal microarray analysis (CMA) was performed using the HumanCytoSNP-12 microarray (Illumina, San Diego, CA) at Invitae as previously described (26).…”

Section: Histopathological Reviewmentioning

confidence: 99%

Comprehensive analysis of 204 sporadic hydatidiform moles: revisiting risk factors and their correlations with the molar genotypes

et al. 2020

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Hydatidiform mole (HM) is an aberrant human pregnancy characterized by excessive trophoblastic proliferation and abnormal embryonic development. HM have two morphological types, complete (CHM) and partial (PHM), and non-recurrent ones have three genotypic types, androgenetic monospermic, androgenetic dispermic, and triploid dispermic. Most available studies on risk factors predisposing to different types of HM and their malignant transformation mainly suffer from the lack of comprehensive genotypic analysis of large cohorts of molar tissues combined with accurate postmolar hCG follow-up. Moreover, 10-20% of patients with one HM have at least one non-molar miscarriage, which is higher than the frequency of two pregnancy losses in the general population (2-5%) suggesting a common genetic susceptibility to HM and miscarriages. However, the underlying causes of the miscarriages in these patients are unknown. Here, we comprehensively analyzed 204 HM, mostly from patients referred to the Quebec Registry of Trophoblastic Diseases and for which postmolar hCG monitoring are available, and 30 of their non-molar miscarriages. We revisited the risk of maternal age and neoplastic transformation across the different HM genotypic categories and investigated the presence of chromosomal abnormalities in their non-molar miscarriages. We confirm that androgenetic CHM are more prone to gestational trophoblastic neoplasia (GTN) than triploid dispermic PHM, and androgenetic dispermic CHM are more prone to high risk GTN and choriocarcinoma (CC) than androgenetic monospermic CHM. We also confirm the association between increased maternal age and androgenetic CHM and their malignancies. Most importantly, we demonstrate for the first time that patients with an HM and miscarriages are at higher risk for aneuploid miscarriages [83.3%, 95% confidence interval (CI) 0.653-0.944] than women with sporadic (51.5%, 95% CI 50.3-52.7%, p-value = 0.0003828) or recurrent miscarriages (43.8%, 95% CI 40.7-47.0%, p-value = 0.00002). Our data suggest common genetic female germline defects predisposing to HM and aneuploid non-molar miscarriages in some patients.

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Section: Histopathological Reviewmentioning

confidence: 99%

Comprehensive analysis of 204 sporadic hydatidiform moles: revisiting risk factors and their correlations with the molar genotypes

et al. 2020

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“…A recent systematic review by Wang et al (2020) found nine CNVs associated to miscarriage, and one of those, del7q11.23, has also been found in our series. A second microdeletion, del1q21.1, has been identified in the previous studies (Levy et al, 2014;Sahoo et al, 2017), but it is not a so-well-established cause of miscarriage. Finally, we wish to point out that our routine offer to women with early pregnancy loss had a wide acceptance since uptake was 82% (459/559) during the study period.…”

Section: Discussionmentioning

confidence: 88%

“…Furthermore, it has been shown that identifying the cause of the loss help reduce the feelings of self-blame (Nikcevic et al, 1999) and has a major impact on the couple's future reproductive plans (Borrell and Stergiotou, 2013). Although it is not recommended by the clinical guidelines, the fact that there are large series reporting the use of arrays in POC of non-recurrent early pregnancy losses supports this rationale (Levy et al, 2014;Wang et al, 2014Wang et al, , 2017Wou et al, 2016;Sahoo et al, 2017;Qu et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

A New Stepwise Molecular Work-Up After Chorionic Villi Sampling in Women With an Early Pregnancy Loss

et al. 2021

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Objective: To explore the use of a new molecular work-up based on the stepwise use of Quantitative Fluorescence PCR (QF-PCR) extended to eight chromosomes and single nucleotide polymorphism array (SNP-array) in chorionic villi obtained by chorionic villi sampling (CVS) offered to women experiencing an early pregnancy loss.Methods: During a 3-year period (January 2016–December 2018), CVS was offered to women experiencing an early pregnancy loss before the evacuation of the products of conception (POC) to retrieve chorionic villi, irrespective of the number of previous losses. A new molecular work-up was prospectively assayed encompassing a first QF-PCR round (with the 21, 18, 13, 7, X, and Y chromosomes), a second QF-PCR round (with the 15, 16, and 22 chromosomes), and a high resolution SNP-array in those cases with normal QF-PCR results. A control group in which POC were collected after surgical uterine evacuation was used to be compared with the intervention group.Results: Around 459 women were enrolled in the intervention group (CVS) and 185 in the control group (POC after uterine evacuation). The QF-PCR testing success rates were significantly higher in the intervention group (98.5%: 452/459) as compared to the control group (74%: 109/147; p < 0.001), while the chromosomal anomaly rate at the two QF-PCR rounds was similar between the two groups: 52% (234/452) in the intervention and 42% (46/109) in the control group (p = 0.073). The SNP-array was performed in 202 QF-PCR normal samples of the intervention group and revealed 67 (33%) atypical chromosomal anomalies (>10 Mb), 5 (2.5%) submicroscopic pathogenic copy number variants, and 2 (1%) variant of uncertain significance (VOUS).Conclusion: Eighty-two percent of women experiencing an early pregnancy loss opted for a CVS. The testing success rates were higher in the intervention group (CVS; 98%) as compared to the control group (POC; 74%). The overall yields were 52% by QF-PCR (including three complete hydatiform moles), and 16% by SNP-array, including 15% atypical chromosomal anomalies and 1.1% submicroscopic pathogenic copy number variants.

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“…Clinically significant abnormalities were identified in 53.7% of samples, 94% of which were considered to be the cause of pregnancy loss. (23) Shah et al, analyzed 60 samples simultaneously by cytogenetics, SNP array, and CGH array testing. They found a 33% overall discordance rate in results, due to maternal cell contamination, balanced chromosome rearrangements, polyploidy, and placental mosaicism (detected in 18% of all samples).…”

Section: ❚ Discussionmentioning

confidence: 99%

Genetic analysis of products of conception. Should we abandon classic karyotyping methodology?

Christofolini

Bevilacqua

Mafra

et al. 2021

Einstein (São Paulo)

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Objective: To compare the results obtained by the classic and molecular methodology in the analysis of products of conception, the advantages and disadvantages of each method. Methods: Retrospective non-randomized analysis of results obtained from product of conception samples submitted to genetic evaluation, from 2012 to 2017. The evaluations were performed using cytogenetics and/or chromosomal microarray analysis or arrays. Results: Forty samples were analyzed using classic cytogenetics, of which 10% showed no cell growth, 50% had normal results and 40% had abnormalities. Of the 41 cases sent for array analysis it was not possible to obtain results in 7.3%, 39.5% were normal and 60.5% had abnormalities. There was no statistical difference among the results (p=0.89). Most abnormal results were seen till 9 weeks' gestation. The later abnormal miscarriage was seen at 28 weeks' gestation, with karyotype 46,XX,del(15) (q26.2-qter). The results are corroborated by the international literature. Conclusion: Classic cytogenetics and array techniques showed comparable results on the type of alteration observed. Array analysis is preferable to cell culture in delayed abortions, while cytogenetics is more able to show polyploidies. Both have the same growth failure rates when product of conception tissue is not properly collected.

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Comprehensive Genetic Analysis of Pregnancy Loss by Chromosomal Microarrays: Outcomes, Benefits, and Challenges

Cited by 19 publications

References 0 publications

Comprehensive analysis of 204 sporadic hydatidiform moles: revisiting risk factors and their correlations with the molar genotypes

Comprehensive analysis of 204 sporadic hydatidiform moles: revisiting risk factors and their correlations with the molar genotypes

A New Stepwise Molecular Work-Up After Chorionic Villi Sampling in Women With an Early Pregnancy Loss

Genetic analysis of products of conception. Should we abandon classic karyotyping methodology?

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