{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T02:56:29Z","timestamp":1767840989165,"version":"3.49.0"},"reference-count":24,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2014,1,28]],"date-time":"2014-01-28T00:00:00Z","timestamp":1390867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>It has now been over 50 years since it was discovered that Down syndrome is caused by an extra chromosome 21, i.e., trisomy 21. In the interim, it has become clear that in the majority of cases, the extra chromosome is inherited from the mother, and there is, in this respect, a strong maternal age effect. Numerous investigations have been devoted to clarifying the underlying mechanism, most recently suggesting that this situation is exceedingly complex, involving both biological and environmental factors. On the other hand, it has also been proposed that germinal trisomy 21 mosaicism, arising during the very early stages of maternal oogenesis with accumulation of trisomy 21 germ cells during subsequent development, may be the main predisposing factor. We present data here on the incidence of trisomy 21 mosaicism in a cohort of normal fetal ovarian samples, indicating that an accumulation of trisomy 21 germ cells does indeed take place during fetal oogenesis, i.e., from the first to the second trimester of pregnancy. We presume that this accumulation of trisomy 21 (T21) cells is caused by their delay in maturation and lagging behind the normal cells. We further presume that this trend continues during the third trimester of pregnancy and postnatally, up until ovulation, thereby explaining the maternal age effect in Down syndrome.<\/jats:p>","DOI":"10.3390\/jcm3010167","type":"journal-article","created":{"date-parts":[[2014,1,28]],"date-time":"2014-01-28T11:30:32Z","timestamp":1390908632000},"page":"167-175","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Maternal Germinal Trisomy 21 in Down Syndrome"],"prefix":"10.3390","volume":"3","author":[{"given":"Maj","family":"Hult\u00e9n","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm S-171 76, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linn","family":"\u00d6ijerstedt","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Care Sciences and Society, KI Alzheimer Disease Research Center, Karolinska University Hospital, Huddinge, Stockholm S-141 86, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik","family":"Iwarsson","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm S-171 76, Sweden"},{"name":"Department of Clinical Genetics, Karolinska University Hospital, Stockholm S-171 76, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon","family":"Jonasson","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Link\u00f6ping University, LMC, University Hospital, Link\u00f6ping S-581 85, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2014,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1095\/biolreprod.111.094367","article-title":"Meiotic origins of maternal age-related aneuploidy","volume":"86","author":"Chiang","year":"2012","journal-title":"Biol. Reprod."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1016\/j.bbadis.2012.07.007","article-title":"Molecular origin of female meiotic aneuploidies","volume":"1822","author":"Handyside","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1016\/j.yexcr.2012.02.012","article-title":"Chromosomal, metabolic, environmental, and hormonal origins of aneuploidy in mammalian oocytes","volume":"318","author":"Jones","year":"2012","journal-title":"Exp. Cell Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/nrg3245","article-title":"Human aneuploidy: Mechanisms and new insights into an age-old problem","volume":"13","author":"Nagaoka","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1155\/2012\/693864","article-title":"Maternal risk for Down syndrome is modulated by genes involved in folate metabolism","volume":"32","author":"Zampieri","year":"2012","journal-title":"Dis. Markers"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Hult\u00e9n, M.A., Patel, S.D., Tankimanova, M., Westgren, M., Papadogiannakis, N., Jonsson, A.M., and Iwarsson, E. (2008). On the origin of trisomy 21 Down syndrome. Mol. Cytogenet., 1.","DOI":"10.1186\/1755-8166-1-21"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF00210736","article-title":"Oocyte selection: A new model for the maternal-age dependence of Down syndrome","volume":"90","author":"Zheng","year":"1992","journal-title":"Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1530\/REP-09-0088","article-title":"On the origin of the maternal age effect in trisomy 21 Down syndrome: The oocyte mosaicism selection model","volume":"139","author":"Patel","year":"2010","journal-title":"Reproduction"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1159\/000323606","article-title":"Inherited aneuploidy: Germline mosaicism","volume":"133","author":"Delhanty","year":"2011","journal-title":"Cytogenet. Genome Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/BF00285162","article-title":"Somatic pairing of chromosome 1 centromeres in interphase nuclei of human cerebellum","volume":"83","author":"Arnoldus","year":"1989","journal-title":"Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1369\/jhc.4A6419.2005","article-title":"An approach for quantitative assessment of fluorescence in situ hybridization (FISH) signals for applied human molecular cytogenetics","volume":"53","author":"Iourov","year":"2005","journal-title":"J. Histochem. Cytochem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Hult\u00e9n, M.A., Patel, S.D., Westgren, M., Papadogiannakis, N., Jonsson, A.M., Jonasson, J., and Iwarsson, E. (2010). On the paternal origin of trisomy 21 Down syndrome. Mol. Cytogenet., 3.","DOI":"10.1186\/1755-8166-3-4"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S1383-5718(02)00163-8","article-title":"Detection of mosaicism in lymphocytes of parents of free trisomy 21 offspring","volume":"520","author":"Frias","year":"2002","journal-title":"Mutat. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kovaleva, N.V. (2010). Germ-line transmission of trisomy 21: Data from 80 families suggest an implication of grandmaternal age and a high frequency of female-specific trisomy rescue. Mol. Cytogenet., 3.","DOI":"10.1186\/1755-8166-3-7"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1159\/000324233","article-title":"Whole-chromosome aneuploidy analysis in human oocytes: Focus on comparative genomic hybridization","volume":"133","author":"Obradors","year":"2011","journal-title":"Cytogenet. Genome Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/embor.2012.54","article-title":"Age-related aneuploidy through cohesion exhaustion","volume":"13","author":"Jessberger","year":"2012","journal-title":"EMBO Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/j.1741-4520.2011.00350.x","article-title":"Molecular basis of maternal age-related increase in oocyte aneuploidy","volume":"52","author":"Kurahashi","year":"2012","journal-title":"Congenit. Anom."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.1016\/j.cub.2010.08.023","article-title":"Age-related meiotic segregation errors in mammalian oocytes are preceded by depletion of cohesin and Sgo2","volume":"20","author":"Lister","year":"2010","journal-title":"Curr. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Merriman, J.A., Jennings, P.C., McLaughlin, E.A., and Jones, K.T. (2010). Effect of aging on superovulation efficiency, aneuploidy rates, and sister chromatid cohesion in mice aged up to 15 months. Biol. Reprod., 86.","DOI":"10.1095\/biolreprod.111.095711"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2316","DOI":"10.1093\/humrep\/deq180","article-title":"Dynamics of cohesin proteins REC8, STAG3, SMC1\u0392 and SMC3 are consistent with a role in sister chromatid cohesion during meiosis in human oocytes","volume":"25","author":"Brieno","year":"2010","journal-title":"Hum. Reprod."},{"key":"ref_21","first-page":"26","article-title":"Correlation of fetal age and measurements between 10 and 26 weeks of gestation","volume":"63","author":"Hern","year":"1984","journal-title":"Obstet. Gynecol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ajog.2007.08.027","article-title":"Lack of aneuploidy for chromosomes 15, 16, and 18 in placentas from small-for-gestational-age liveborn infants","volume":"198","author":"Papadogiannakis","year":"2008","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1093\/humrep\/16.2.236","article-title":"Effect of 4-octylphenol on germ cell number in cultured human fetal gonads","volume":"16","author":"Bendsen","year":"2001","journal-title":"Hum. Reprod."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1002\/ajmg.a.36120","article-title":"Germline mosaicism does not explain the maternal age effect on trisomy","volume":"161","author":"Rowsey","year":"2013","journal-title":"Am. J. Med. Genet."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/3\/1\/167\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:07:50Z","timestamp":1760216870000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/3\/1\/167"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,1,28]]},"references-count":24,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2014,3]]}},"alternative-id":["jcm3010167"],"URL":"https:\/\/doi.org\/10.3390\/jcm3010167","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,1,28]]}}}