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      Optimizing the Diagnostic Strategy to Identify Genetic Abnormalities in Miscarriage

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          Abstract

          Introduction

          The single most common cause of miscarriage is genetic abnormality.

          Objective

          We conducted a prospective cohort study to compare the performance of conventional karyotyping and chromosomal microarray analysis (CMA) using array comparative genomic hybridization (array-CGH) and single nucleotide polymorphism array (SNP-array) to identify genetic abnormalities in miscarriage specimens.

          Methods

          A total of 63 miscarriage specimens were included. Conventional karyotyping, array-CGH, and SNP-array were performed and the results compared.

          Results

          Genetic abnormalities were detected in 31 cases (49.2%) by at least one testing modality. Single autosomal trisomy was the most common defect (71.0%), followed by polyploidy (16.1%), multiple aneuploidy (9.7%), and monosomy X (3.2%). Mosaicisms were identified in four cases and confirmed by fluorescence in situ hybridization (FISH) using appropriate probes. SNP-array had a higher detection rate of genetic abnormalities than array-CGH (93.5 vs. 77.4%), and conventional karyotyping had the lowest detection rate (76.0%). SNP-array enabled the detection of all types of genetic abnormalities, including polyploidy.

          Conclusions

          Although conventional karyotyping and FISH are still needed, SNP-array represents the first choice for miscarriage because the technique showed excellent performance in the detection of genetic abnormalities and minimized the probability of testing failure as well as time, costs, and labor.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s40291-021-00523-9.

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          Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies.

          David T Miller, Margaret P Adam, Swaroop Aradhya … (2010)
          Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%-20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype ( approximately 3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages. Copyright (c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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            Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis.

            Laura Conlin, Brian D Thiel, Carsten Bönnemann … (2010)
            Mosaic aneuploidy and uniparental disomy (UPD) arise from mitotic or meiotic events. There are differences between these mechanisms in terms of (i) impact on embryonic development; (ii) co-occurrence of mosaic trisomy and UPD and (iii) potential recurrence risks. We used a genome-wide single nucleotide polymorphism (SNP) array to study patients with chromosome aneuploidy mosaicism, UPD and one individual with XX/XY chimerism to gain insight into the developmental mechanism and timing of these events. Sixteen cases of mosaic aneuploidy originated mitotically, and these included four rare trisomies and all of the monosomies, consistent with the influence of selective factors. Five trisomies arose meiotically, and three of the five had UPD in the disomic cells, confirming increased risk for UPD in the case of meiotic non-disjunction. Evidence for the meiotic origin of aneuploidy and UPD was seen in the patterns of recombination visible during analysis with 1-3 crossovers per chromosome. The mechanisms of formation of the UPD included trisomy rescue, with and without concomitant trisomy, monosomy rescue, and mitotic formation of a mosaic segmental UPD. UPD was also identified in an XX/XY chimeric individual, with one cell line having complete maternal UPD consistent with a parthenogenetic origin. Utilization of SNP arrays allows simultaneous evaluation of genomic alterations and insights into aneuploidy and UPD mechanisms. Differentiation of mitotic and meiotic origins for aneuploidy and UPD supports existence of selective factors against full trisomy of some chromosomes in the early embryo and provides data for estimation of recurrence and disease mechanisms.
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              A genomic view of mosaicism and human disease.

              Nancy Spinner, Leslie G Biesecker (2013)
              Genomic technologies, including next-generation sequencing (NGS) and single-nucleotide polymorphism (SNP) microarrays, have provided unprecedented opportunities to assess genomic variation among, and increasingly within, individuals. It has long been known that cancer is a mosaic genetic disorder, but mosaicism is now apparent in a diverse range of other clinical disorders, as indicated by their tissue distributions and inheritance patterns. Recent technical advances have uncovered the causative mosaic variant underlying many of these conditions and have provided insight into the pervasiveness of mosaicism in normal individuals. Here, we discuss the clinical and molecular classes of mosaicism, their detection and the biological insights gained from these studies.
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                Author and article information

                Contributors
                Myungshin Kim:
                ORCID: http://orcid.org/0000-0001-8632-0168
                microkim@catholic.ac.kr
                In Yang Park: ooooobbbbb@catholic.ac.kr
                Journal
                Journal ID (nlm-ta): Mol Diagn Ther
                Journal ID (iso-abbrev): Mol Diagn Ther
                Title: Molecular Diagnosis & Therapy
                Publisher: Springer International Publishing (Cham )
                ISSN (Print): 1177-1062
                ISSN (Electronic): 1179-2000
                Publication date (Electronic): 1 April 2021
                Publication date PMC-release: 1 April 2021
                Publication date (Print): 2021
                Volume: 25
                Issue: 3
                Pages: 351-359
                Affiliations
                [1 ]GRID grid.411947.e, ISNI 0000 0004 0470 4224, Department of Laboratory Medicine, College of Medicine, , The Catholic University of Korea, ; 222 Banpodaero, Seocho-gu, Seoul, 06591 South Korea
                [2 ]GRID grid.411947.e, ISNI 0000 0004 0470 4224, Catholic Genetic Laboratory Center, Seoul St. Mary’s Hospital, College of Medicine, , The Catholic University of Korea, ; 222 Banpodaero, Seocho-gu, Seoul, 06591 South Korea
                [3 ]GRID grid.289247.2, ISNI 0000 0001 2171 7818, Department of Obstetrics and Gynecology, College of Medicine, Kyung Hee University Hospital, , Kyung Hee University, ; 23, Kyung Hee Dae-ro, Dongdaemun-gu, Seoul, 02447 South Korea
                [4 ]GRID grid.411947.e, ISNI 0000 0004 0470 4224, Department of Obstetrics and Gynecology, College of Medicine, , The Catholic University of Korea, ; 222 Banpodaero, Seocho-gu, Seoul, 06591 South Korea
                Author information
                http://orcid.org/0000-0001-8632-0168
                Article
                Publisher ID: 523
                DOI: 10.1007/s40291-021-00523-9
                PMC ID: 8139896
                PubMed ID: 33792848
                SO-VID: face7c1d-cc3c-4fd6-9212-4dca096a5740
                Copyright © © The Author(s) 2021
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Date accepted : 6 March 2021
                Funding
                Funded by: Ministry of Food and Drug Safety (KR)
                Award ID: 18172MFDS182
                Award Recipient :
                Categories
                Subject: Original Research Article
                Custom metadata
                issue-copyright-statement © Springer Nature Switzerland AG 2021

                ScienceOpen disciplines: Molecular medicine
                Data availability:
                ScienceOpen disciplines: Molecular medicine

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