{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T02:10:59Z","timestamp":1792030259715,"version":"4.4.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T00:00:00Z","timestamp":1764720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,1]]},"abstract":"Abstract<\/jats:title>\n \n STUDY QUESTION<\/jats:title>\n Can comprehensive cytogenetic follow-up of the placenta post-partum uncover possible explanations for discrepancies between non-invasive prenatal testing (NIPT) showing structural chromosomal aberrations and foetal follow-up showing normal results or other chromosomal aberrations?<\/jats:p>\n <\/jats:sec>\n \n SUMMARY ANSWER<\/jats:title>\n In 18\/31 (58%) cases of structural chromosomal aberrations detected with NIPT, where foetal and maternal follow-up was normal or the foetus had another chromosomal aberration, genome-wide examination of term placental chorionic villi confirmed the discrepancy and in 7\/18 (39%) confirmed cases complex foeto-placental mosaicism was found.<\/jats:p>\n <\/jats:sec>\n \n WHAT IS KNOWN ALREADY<\/jats:title>\n Complex chromosomal rearrangements are often seen in single-cell studies of preimplantation embryos, but it is unknown if these persist into the mature placenta. Confined placental mosaicism explains most discordant NIPTs involving a trisomy, but little is known about structural chromosome aberrations.<\/jats:p>\n <\/jats:sec>\n \n STUDY DESIGN, SIZE, DURATION<\/jats:title>\n We performed a retrospective diagnostic test study of cytogenetic follow-up data from post-partum placentas. We included data from pregnancies where (i) NIPT showed a structural aberration, (ii) follow-up of foetus (amniotic fluid and\/or cord blood) and mother (genomic DNA and\/or cfDNA after birth) was normal or the foetus showed another chromosomal aberration, (iii) follow-up was performed in the Erasmus MC, (iv) more than one sample from the post-partum placenta was analysed, and (v) samples were of good quality (not in formaldehyde, sufficient material).<\/jats:p>\n In the period from January 2014 to March 2022, 115\u00a0231 NIPTs were performed in the Erasmus MC; 217 of these showed structural chromosomal aberrations and 123 were followed up in the Erasmus MC (inclusion criteria 3). After exclusion of the foetal (same aberration as with NIPT) and maternal structural chromosome aberrations, 48 placentas were requested to elucidate the discrepancies seen between NIPT (abnormal) and foetal karyotype (normal or differently abnormal; inclusion criteria 1-2). Of these, 31 met criteria 4 and 5 and were included in this study.<\/jats:p>\n <\/jats:sec>\n \n PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n In a diagnostic setting, we performed a cytogenetic analysis of postpartum placentas in order to confirm confined placental mosaicism in 31 cases in which NIPT showed a structural chromosome aberration. Two to four chorionic villus biopsies were taken per placenta, and separated enzymatically into cytotrophoblast (CTB) and mesenchymal core (MC) and analysed using SNP arrays. In our analysis, cases were assessed for copy number variants \u22650.5\u2009Mb and regions of homozygosity \u22653\u2009Mb.<\/jats:p>\n <\/jats:sec>\n \n MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n In 18\/31 cases (58%), we could confirm the structural chromosome aberration detected with NIPT in one or more placental biopsies. In 13\/31 cases (42%), the structural chromosomal aberration detected with NIPT was not confirmed, but in one case an apparently unrelated aberration was found in the CTB of two biopsies. In 11\/18 confirmed cases, the same aberration as detected with NIPT, was confirmed in the placenta. All these cases concerned chromosomally normal foetuses with a chromosome aberration confined to the placenta. In one case, an extra, apparently unrelated, aberration was found in one placental biopsy. In 7\/18 confirmed cases, the aberration detected with NIPT was confirmed in the placenta and showed to be involved in complex mosaicism involving different abnormal cell lines. In four of these seven cases, the foetus was affected with a pathogenic chromosome aberration that was different from the NIPT aberration. In three cases, a related but benign chromosome aberration was present in the foetus.<\/jats:p>\n <\/jats:sec>\n \n LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n As conventional karyotyping, FISH or whole genome sequencing were not performed, we can only hypothesize on the mechanisms behind the origin of the complex foeto-placental mosaicism we see in seven cases, although there is more strong evidence in the literature as well.<\/jats:p>\n <\/jats:sec>\n \n WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n Our results have several implications. First, a genome-wide rather than a targeted approach in foetal follow-up examinations after NIPT showing a structural chromosomal aberration is warranted, as other aberrations may be overlooked in the foetus. Second, counselling of pregnant couples after NIPT showing a structural chromosomal aberration should focus not only on the specific aberration detected by NIPT but also on the possibility that the foetus may harbour another, possibly related, structural aberration. Additionally, a structural chromosomal aberration of apparently uncertain significance may unmask truly pathogenic aberrations in the foetus itself, so all potential foetal cases of structural chromosome aberrations should be followed up. Third, we show how comprehensive examinations of the placenta, specifically the separation of CTB and MC, provides crucial insights into the embryonic origins and mechanisms behind structural chromosomal aberrations. Lastly, our results show that complex chromosomal rearrangements as often seen in single-cell studies of pre-implantation embryos, are not artefacts but a biological phenomenon that can actually persist into the mature placenta and foetus.<\/jats:p>\n <\/jats:sec>\n \n STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n Simon H. Thomsen was funded by a private research donation and the Department of Clinical Medicine, Aarhus University. All authors declare no conflict of interest.<\/jats:p>\n <\/jats:sec>\n \n TRIAL REGISTRATION NUMBER<\/jats:title>\n N\/A.<\/jats:p>\n <\/jats:sec>","DOI":"10.1093\/humrep\/deaf235","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T12:39:45Z","timestamp":1763987985000},"page":"168-177","source":"Crossref","is-referenced-by-count":3,"title":["Studies of post-partum placentas provide insights into the origin of structural chromosomal aberrations"],"prefix":"10.1093","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5523-8954","authenticated-orcid":false,"given":"S H","family":"Thomsen","sequence":"first","affiliation":[{"name":"Center for Fetal Diagnostics, Department of Clinical Medicine, Aarhus University , Aarhus N,","place":["Denmark"]},{"name":"Department of Clinical Genetics, Aarhus University Hospital , Aarhus N,","place":["Denmark"]},{"name":"Department of Clinical Genetics, Aalborg University Hospital , Aalborg,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"van Berkel","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"van Veen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"van Koetsveld","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4443-4690","authenticated-orcid":false,"given":"M","family":"Joosten","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2637-9998","authenticated-orcid":false,"given":"K E M","family":"Diderich","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"van den Born","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3429-6156","authenticated-orcid":false,"given":"M I","family":"Srebniak","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3895-6775","authenticated-orcid":false,"given":"D","family":"Van Opstal","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, University Medical Center , Rotterdam,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,12,3]]},"reference":[{"key":"2026020300513780800_deaf235-B1","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/ajmg.c.31449","article-title":"Wolf-Hirschhorn syndrome: a review and update","volume":"169","author":"Battaglia","year":"2015","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"2026020300513780800_deaf235-B2","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.ajhg.2021.02.012","article-title":"De novo structural mutation rates and gamete-of-origin biases revealed through genome sequencing of 2,396 families","volume":"108","author":"Belyeu","year":"2021","journal-title":"Am J Hum Genet"},{"key":"2026020300513780800_deaf235-B3","doi-asserted-by":"crossref","first-page":"11165","DOI":"10.1038\/ncomms11165","article-title":"Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential","volume":"7","author":"Bolton","year":"2016","journal-title":"Nat Commun"},{"key":"2026020300513780800_deaf235-B4","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13039-022-00600-6","article-title":"Mechanisms of structural chromosomal rearrangement formation","volume":"15","author":"Burssed","year":"2022","journal-title":"Mol Cytogenet"},{"key":"2026020300513780800_deaf235-B5","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1136\/jmg.2006.045476","article-title":"Molecular characterisation of a mosaicism with a complex chromosome rearrangement: evidence for coincident chromosome healing by telomere capture and neo-telomere formation","volume":"44","author":"Chabchoub","year":"2007","journal-title":"J Med Genet"},{"key":"2026020300513780800_deaf235-B6","doi-asserted-by":"crossref","first-page":"e174483","DOI":"10.1172\/JCI174483","article-title":"Single-cell DNA sequencing reveals a high incidence of chromosomal abnormalities in human blastocysts","volume":"134","author":"Chavli","year":"2024","journal-title":"J Clin Invest"},{"key":"2026020300513780800_deaf235-B7","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1093\/hmg\/ddq003","article-title":"Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis","volume":"19","author":"Conlin","year":"2010","journal-title":"Hum Mol Genet"},{"key":"2026020300513780800_deaf235-B8","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/s41586-021-03345-1","article-title":"Inherent mosaicism and extensive mutation of human placentas","volume":"592","author":"Coorens","year":"2021","journal-title":"Nature"},{"key":"2026020300513780800_deaf235-B9","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/pd.6499","article-title":"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","volume":"44","author":"Donze","year":"2024","journal-title":"Prenat Diagn"},{"key":"2026020300513780800_deaf235-B10","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1093\/humupd\/dmab009","article-title":"Confined placental mosaicism and the association with pregnancy outcome and fetal growth: a review of the literature","volume":"27","author":"Eggenhuizen","year":"2021","journal-title":"Hum Reprod Update"},{"key":"2026020300513780800_deaf235-B11","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.placenta.2024.06.008","article-title":"Confined placental mosaicism: distribution of chromosomally abnormal cells over the term placenta","volume":"154","author":"Eggenhuizen","year":"2024","journal-title":"Placenta"},{"key":"2026020300513780800_deaf235-B12","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.bpobgyn.2017.02.004","article-title":"Chromosomal mosaicism in the fetoplacental unit","volume":"42","author":"Grati","year":"2017","journal-title":"Best Pract Res Clin Obstet Gynaecol"},{"key":"2026020300513780800_deaf235-B13","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1002\/pd.5049","article-title":"Discordant non-invasive prenatal testing (NIPT)\u2014a systematic review","volume":"37","author":"Hartwig","year":"2017","journal-title":"Prenat Diagn"},{"key":"2026020300513780800_deaf235-B14","doi-asserted-by":"crossref","first-page":"e1004139","DOI":"10.1371\/journal.pgen.1004139","article-title":"Large inverted duplications in the human genome form via a fold-back mechanism","volume":"10","author":"Hermetz","year":"2014","journal-title":"PLoS Genet"},{"key":"2026020300513780800_deaf235-B9907814","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/s41431-018-0271-7","article-title":"Fetal fraction evaluation in non-invasive prenatal screening (NIPS)","volume":"27","author":"Hestand","year":"2019","journal-title":"Eur J Hum Genet"},{"key":"2026020300513780800_deaf235-B15","doi-asserted-by":"crossref","first-page":"8342","DOI":"10.1038\/srep08342","article-title":"Extensive load of somatic CNVs in the human placenta","volume":"5","author":"Kasak","year":"2015","journal-title":"Sci Rep"},{"key":"2026020300513780800_deaf235-B16","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1007\/s00439-020-02186-8","article-title":"The involvement of U-type dicentric chromosomes in the formation of terminal deletions with or without adjacent inverted duplications","volume":"139","author":"Kato","year":"2020","journal-title":"Hum Genet"},{"key":"2026020300513780800_deaf235-B17","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/pd.5931","article-title":"Chromosomal mosaicism: origins and clinical implications in preimplantation and prenatal diagnosis","volume":"41","author":"Levy","year":"2021","journal-title":"Prenat Diagn"},{"key":"2026020300513780800_deaf235-B18","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1002\/pd.5584","article-title":"Prevalence of mosaicism in uncultured chorionic villus samples after chromosomal microarray and clinical outcome in pregnancies affected by confined placental mosaicism","volume":"40","author":"Lund","year":"2020","journal-title":"Prenat Diagn"},{"key":"2026020300513780800_deaf235-B19","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1002\/pd.5938","article-title":"Mosaicism for copy number variations in the placenta is even more difficult to interpret than mosaicism for whole chromosome aneuploidy","volume":"41","author":"Lund","year":"2021","journal-title":"Prenat Diagn"},{"key":"2026020300513780800_deaf235-B20","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1750-1172-4-9","article-title":"Jacobsen syndrome","volume":"4","author":"Mattina","year":"2009","journal-title":"Orphanet J Rare Dis"},{"key":"2026020300513780800_deaf235-B21","doi-asserted-by":"crossref","first-page":"e1001061","DOI":"10.1371\/journal.pgen.1001061","article-title":"Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes","volume":"6","author":"Stimpson","year":"2010","journal-title":"PLoS Genet"},{"key":"2026020300513780800_deaf235-B22","doi-asserted-by":"crossref","first-page":"101497","DOI":"10.1016\/j.ajogmf.2024.101497","article-title":"Placental mosaicism for autosomal trisomies: comprehensive follow-up of 528 Danish cases (1983-2021)","volume":"6","author":"Thomsen","year":"2024","journal-title":"Am J Obstet Gynecol MFM"},{"key":"2026020300513780800_deaf235-B23","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1002\/pd.5354","article-title":"Unexpected finding of uniparental disomy mosaicism in term placentas: is it a common feature in trisomic placentas?","volume":"38","author":"Van Opstal","year":"2018","journal-title":"Prenat Diagn"},{"key":"2026020300513780800_deaf235-B24","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1586\/14737159.2016.1152890","article-title":"Cytogenetic confirmation of a positive NIPT result: evidence-based choice between chorionic villus sampling and amniocentesis depending on chromosome aberration","volume":"16","author":"Van Opstal","year":"2016","journal-title":"Expert Rev Mol Diagn"},{"key":"2026020300513780800_deaf235-B25","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1002\/pd.5531","article-title":"Placental studies elucidate discrepancies between NIPT showing a structural chromosome aberration and a differently abnormal fetal karyotype","volume":"39","author":"Van Opstal","year":"2019","journal-title":"Prenat Diagn"},{"key":"2026020300513780800_deaf235-B26","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1016\/j.ajhg.2022.04.018","article-title":"Clinical impact of additional findings detected by genome-wide non-invasive prenatal testing: follow-up results of the TRIDENT-2 study","volume":"109","author":"van Prooyen Schuurman","year":"2022","journal-title":"Am J Hum Genet"},{"key":"2026020300513780800_deaf235-B27","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nm.1924","article-title":"Chromosome instability is common in human cleavage-stage embryos","volume":"15","author":"Vanneste","year":"2009","journal-title":"Nat Med"},{"key":"2026020300513780800_deaf235-B28","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1002\/humu.21502","article-title":"Breakage-fusion-bridge cycles leading to inv dup del occur in human cleavage stage embryos","volume":"32","author":"Voet","year":"2011","journal-title":"Hum Mutat"},{"key":"2026020300513780800_deaf235-B29","doi-asserted-by":"crossref","first-page":"3918","DOI":"10.1038\/s41467-025-59245-9","article-title":"Chromosomal instability in human trophoblast stem cells and placentas","volume":"16","author":"Wang","year":"2025","journal-title":"Nat Commun"},{"key":"2026020300513780800_deaf235-B30","doi-asserted-by":"crossref","first-page":"R66","DOI":"10.1530\/RAF-21-0095","article-title":"Preimplantation chromosomal mosaics, chimaeras and confined placental mosaicism","volume":"3","author":"West","year":"2022","journal-title":"Reprod Fertil"},{"key":"2026020300513780800_deaf235-B31","doi-asserted-by":"crossref","first-page":"104532","DOI":"10.1016\/j.ejmg.2022.104532","article-title":"The embryo battle against adverse genomes: are de novo terminal deletions the rescue of unfavorable zygotic imbalances?","volume":"65","author":"Zuffardi","year":"2022","journal-title":"Eur J Med Genet"}],"container-title":["Human Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/41\/2\/168\/65729596\/deaf235.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/41\/2\/168\/65729596\/deaf235.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T05:51:46Z","timestamp":1770097906000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/humrep\/article\/41\/2\/168\/8363949"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,3]]},"references-count":32,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,12,3]]},"published-print":{"date-parts":[[2026,2,1]]}},"URL":"https:\/\/doi.org\/10.1093\/humrep\/deaf235","relation":{},"ISSN":["0268-1161","1460-2350"],"issn-type":[{"value":"0268-1161","type":"print"},{"value":"1460-2350","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,2]]},"published":{"date-parts":[[2025,12,3]]}}}