Reducing misdiagnosis caused by maternal cell contamination in genetic testing for early pregnancy loss

Voložonoka, Ludmila; Gailīte, Linda; Perminov, Dmitrijs; Kornejeva, Liene; Fodina, Violeta; Kempa, Inga; Miskova, Anna

doi:10.1080/19396368.2020.1827081

Cited by 5 publications

(7 citation statements)

References 50 publications

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“…In recent years, maternal cell contamination rate has reduced, possibly due to techniques such as careful sorting of the villi and washing with normal saline before submitting samples for examination, have been widely practiced. In 2020, Volozonoka et al reported a maternal cell contamination rate of approximately 30% in all POC samples, which is consistent with our study findings 7 …”

Section: Discussionsupporting

confidence: 92%

“…If the villous tissue was visually confirmed on submission, the probability of maternal cell contamination is theoretically low. Volozonoka et al have reported that POC samples showing clear presence of chorionic villi did not contain any signs of maternal genome 7 . However, maternal cell contamination was also seen in some of our cases with visually confirmed chorionic villi, wherein washing of the samples was possibly not sufficient.…”

Section: Discussionmentioning

confidence: 51%

“…In 2020, Volozonoka et al reported a maternal cell contamination rate of approximately 30% in all POC samples, which is consistent with our study findings. 7 The risks and causes of maternal cell contamination are unknown. A previous report suggested that submitting a small amount of tissue for chromosome analysis may be one of the reasons.…”

Section: Discussionmentioning

confidence: 99%

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Maternal cell contamination in embryonic chromosome analysis of missed abortions

Ouchi

Takeshita

Kasano

et al. 2022

J of Obstet and Gynaecol

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Aim: The fetal sample used for embryonic chromosome analysis is often contaminated with maternal cells, making it difficult to evaluate the fetal chromosomes. We examined on the rate of maternal cell contamination and its relationship with maternal information in the embryonic chromosome analysis of missed abortions using the Giemsabanding method. Methods: Chromosome analysis was performed in 200 cases of delayed miscarriages in first trimester between July 1, 2000 and May 31, 2019. Chorionic villi were collected and were analyzed using the Giemsa banding method. Among the 20 cells for which chromosomal examination was performed, cells wherein 46,XX chromosomes were found together with normal male karyotype or abnormal chromosomes were defined as maternal cell contamination. Results: Of the 200 cases analyzed, 136 had abnormal chromosomes. The normal female karyotype (n = 52) was four times more prevalent than the normal male karyotype (n = 12). Maternal cell contamination was seen in 15.4% of the abnormal chromosome cases and 8.3% of the normal male karyotype cases. There was no significant difference in the gestational age between the contaminated and noncontaminated groups at the time of miscarriage diagnosis. However, miscarriage before fetal heartbeat confirmation was significantly associated with higher maternal cell contamination. Conclusion: We found maternal cell contamination in 15% of all the cases. Moreover, in many cases of the normal female karyotype, it was suspected that only maternal chromosomes were cultured. When performing embryonic chromosome analysis in recurrent miscarriages, we should pay attention to maternal cell contamination and interpret the results accordingly.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 51%

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Maternal cell contamination in embryonic chromosome analysis of missed abortions

Ouchi

Takeshita

Kasano

et al. 2022

J of Obstet and Gynaecol

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“…PGT-M with STR haplotyping was performed according to previously validated protocols [9] , [18] . The patient gave birth to a healthy boy who did not demonstrate any clinical symptoms linked to XLHED.…”

Section: Discussionmentioning

confidence: 99%

“…An in vitro fertilisation cycle was performed according to standard controlled ovarian hyperstimulation protocols. Preimplantation genetic testing for aneuploidies (PGT-A) and monogenic diseases (PGT-M) was carried out as described elsewhere [9] , [18] . Selection of EDA -linked short tandem repeats (STR) flanking the EDA gene 2.5 Mb upstream and downstream was performed using the UCSC Genome Browser.…”

Section: Methodsmentioning

confidence: 99%

A novel EDA variant causing X-linked hypohidrotic ectodermal dysplasia: Case report

Alksere

Kornejeva

Grinfelde

et al. 2021

Molecular Genetics and Metabolism Reports

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Hereditary ectodermal dysplasias are a complex group of inherited disorders characterised by abnormalities in two or more ectodermal derivatives (skin, nails, sweat glands, etc. ). There are two main types of these disorders – hidrotic and hypohidrotic/anhidrotic ectodermal dysplasias. Hypohidrotic ectodermal dysplasia (HED) or Christ-Siemens-Touraine syndrome (OMIM: 305100 ) occurs in 1 out of 5000–10,000 births [19] and has an X-linked recessive inheritance pattern (X-linked hypohydrotic ectodermal dysplasia – XLHED) [2] . The main cause of XLHED is a broad range of pathogenic variants in the EDA gene (HGNC:3157, Xq12-13) which encodes the transmembrane protein ectodysplasin-A [4] . We report here the case of a patient with a novel inherited allelic variant in the EDA gene – NM_001399.5:c.337C>T (p.Gln113*) – in the heterozygous state. Targeted family member screening was conducted and other carriers of this EDA gene pathogenic variant were identified and phenotypically characterised. The patient subsequently underwent in vitro fertilisation with preimplantation genetic testing for monogenic diseases (PGT-M).

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A pilot investigation of low-pass genome sequencing identifying site-specific variation in chromosomal mosaicisms by a multiple site sampling approach in first-trimester miscarriages

Chau

Zhang

et al. 2023

Human Reproduction

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STUDY QUESTION Can multiple-site low-pass genome sequencing (GS) of products of conception (POCs) improve the detection of genetic abnormalities, especially heterogeneously distributed mosaicism and homogeneously distributed mosaicism in first-trimester miscarriage? SUMMARY ANSWER Multiple-site sampling combined with low-pass GS significantly increased genetic diagnostic yield (77.0%, 127/165) of first-trimester miscarriages, with mosaicisms accounting for 17.0% (28/165), especially heterogeneously distributed mosaicisms (75%, 21/28) that are currently underappreciated. WHAT IS KNOWN ALREADY Aneuploidies are well known to cause first-trimester miscarriage, which are detectable by conventional karyotyping and next-generation sequencing (NGS) on a single-site sampling basis. However, there are limited studies demonstrating the implications of mosaic genetic abnormalities in first-trimester miscarriages, especially when genetic heterogeneity is present in POCs. STUDY DESIGN, SIZE, DURATION This is a cross-sectional cohort study carried out at a university-affiliated public hospital. One hundred seventy-four patients diagnosed with first-trimester miscarriage from December 2018 to November 2021 were offered ultrasound-guided manual vacuum aspiration (USG-MVA) treatment. Products of conception were subjected to multiple-site low-pass GS for the detection of chromosomal imbalances. PARTICIPANTS/MATERIALS, SETTING, METHODS For each POC, multiple sites of villi (three sites on average) were biopsied for low-pass GS. Samples with maternal cell contamination (MCC) and polyploidy were excluded based on the quantitative fluorescence polymerase chain reaction (QF-PCR) results. The spectrum of chromosomal abnormalities, including mosaicism (heterogeneously distributed and homogeneously distributed) and constitutional abnormalities was investigated. Chromosomal microarray analysis and additional DNA fingerprinting were used for validation and MCC exclusion. A cross-platform comparison between conventional karyotyping and our multiple-site approach was also performed. MAIN RESULTS AND THE ROLE OF CHANCE One hundred sixty-five POCs (corresponding to 490 DNA samples) were subjected to low-pass GS. Genetic abnormalities were detected in 77.0% (127/165) of POCs by our novel approach. Specifically, 17.0% (28/165) of cases had either heterogeneously distributed mosaicism (12.7%, 21/165) or homogeneously distributed mosaicism (6.1%, 10/165) (three cases had both types of mosaicism). The remaining 60.0% (99/165) of cases had constitutional abnormalities. In addition, in the 71 cases with karyotyping performed in parallel, 26.8% (19/71) of the results could be revised by our approach. LIMITATIONS, REASONS FOR CAUTION Lack of a normal gestational week-matched cohort might hinder the establishment of a causative link between mosaicisms and first-trimester miscarriage. WIDER IMPLICATIONS OF THE FINDINGS Low-pass GS with multiple-site sampling increased the detection of chromosomal mosaicisms in first-trimester miscarriage POCs. This innovative multiple-site low-pass GS approach enabled the novel discovery of heterogeneously distributed mosaicism, which was prevalent in first-trimester miscarriage POCs and frequently observed in preimplantation embryos, but is currently unappreciated by conventional single-site cytogenetic investigations. STUDY FUNDING/COMPETING INTEREST(S) This work was supported partly by Research Grant Council Collaborative Research Fund (C4062-21GF to K.W.C), Science and Technology Projects in Guangzhou (202102010005 to K.W.C), Guangdong-Hong Kong Technology Cooperation Funding Scheme (TCFS), Innovation and Technology Fund (GHP/117/19GD to K.W.C), HKOG Direct Grant (2019.050 to J.P.W.C), and Hong Kong Health and Medical Research Fund (05160406 to J.P.W.C). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER N/A.

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Reducing misdiagnosis caused by maternal cell contamination in genetic testing for early pregnancy loss

Cited by 5 publications

References 50 publications

Maternal cell contamination in embryonic chromosome analysis of missed abortions

Maternal cell contamination in embryonic chromosome analysis of missed abortions

A novel EDA variant causing X-linked hypohidrotic ectodermal dysplasia: Case report

A pilot investigation of low-pass genome sequencing identifying site-specific variation in chromosomal mosaicisms by a multiple site sampling approach in first-trimester miscarriages

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