Origin of trisomy: no evidence to support the ovarian mosaicism theory

Morris, Charlotte Rose; Haigh, Shaun; Cuthbert, Gavin; Crosier, Moira; Harding, Fiona; Wolstenholme, John

doi:10.1002/pd.3885

Cited by 7 publications

(9 citation statements)

References 30 publications

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“…More recently, Robles and colleagues examined seven euploid fetuses and identified trisomy 21 in 1/425 (0.2%) leptotene cells but in none of 985 zygotene or pachytene cells [Robles et al, ]. Finally, in the only study conducted after that of Hultén and colleagues [Hulten et al, ], Morris and colleagues analyzed both fetal ovarian and skin samples, and observed extremely low levels of trisomy 21 mosaicism in each of the two tissue types (2/8,365 = 0.02% in ovarian cells and 5/8,245 = 0.06% in skin cells) [Morris et al, ]. Thus, taken together, the results of four different analyses suggest that—for reasons that are unclear—the original report of Hulten et al [] markedly overestimated the incidence of trisomy 21 in fetal oocytes.…”

Section: Resultsmentioning

confidence: 99%

“…Unfortunately, only one subsequent study has attempted to repeat the study. In an analysis of eight samples and 51,146 cells, Morris and colleagues were unable to replicate the original observations [Morris et al, ]. However, neither the original study nor the study of Morris and colleagues analyzed different stages of meiotic prophase, and Hulten et al [] did not analyze chromosomes other than 21.…”

Section: Introductionmentioning

confidence: 97%

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Germline mosaicism does not explain the maternal age effect on trisomy

Rowsey

Kashevarova

Murdoch

et al. 2013

American J of Med Genetics Pt A

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A variety of hypotheses have been proposed to explain the association between trisomy and increasing maternal age in humans, virtually all of which assume that the underlying mechanisms involve meiotic errors. However, recently Hultén and colleagues [Hulten et al., 2010b] proposed a provocative model—the Oocyte Mosaicism Selection Model (OMSM)—that links age-dependent trisomy 21 to pre-meiotic errors in the ovary. Specifically, they propose that nondisjunctional events occur in a proportion of germ cells as they mitotically proliferate, resulting in mosaicism for trisomy 21. Assuming that the presence of an additional chromosome 21 delays meioticprogression, these cells would be ovulated later in reproductive life, resulting in an age-dependent increase in aneuploid eggs. Because this model has important clinical implications, we initiated studies to test it. We first analyzed oocytes from two trisomy 21 fetuses, combining immunostaining with FISH to determine the likelihood of detecting the additional chromosome 21 at different stages of meiosis. The detection of trisomy was enhanced during the earliest stage of prophase (leptotene), before homologs synapsed. Accordingly, in subsequent studies we examined the chromosome content of leptotene oocytes in seven second trimester female fetuses, analyzing three chromosomes commonly associated with human trisomies (i.e., 13, 16, and 21). In contrast to the prediction of the OMSM, we found no evidence of trisomy mosaicism for any chromosome. We conclude that errors in premeiotic germ cells are not a major contributor to human aneuploidy and do not provide an explanation for the age-related increase in trisomic conceptions.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Germline mosaicism does not explain the maternal age effect on trisomy

Rowsey

Kashevarova

Murdoch

et al. 2013

American J of Med Genetics Pt A

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“…Morris et al [2012] essentially repeated the work of Hultén's group but with the use of alternative probes. In the second study, preliminary work was first carried out on fetal ovarian tissue from fetuses diagnosed with trisomy 21 to determine the optimal meiotic stage for detecting trisomic cells.…”

Section: Discussionmentioning

confidence: 99%

The Contribution of Germinal Mosaicism to Human Aneuploidy

Ghevaria

SenGupta

Sarna

et al. 2014

Cytogenet Genome Res

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Germinal mosaicism in a parent is considered to be a rare cause of aneuploidy in the offspring. The aim of this study was to assess the incidence of pre-meiotic errors, indicative of germinal mosaicism, leading to aneuploidy compared with those that occur at meiosis I. The material consisted of 126 oocytes, unexposed to sperm, donated by 57 women with an average maternal age of 35. The oocytes were at various stages of maturity and were analysed by array comparative genomic hybridisation. Of these, 102 gave conclusive results, comprising 47 that were immature, at the germinal vesicle (GV) or metaphase I stage (MI); 34 complete metaphase II-first polar body (MII-PB) complexes together with 21 incomplete complexes. Oocytes at the GV or MI stage provide direct evidence of pre-meiotic aneuploidy. Complete MII-PB complexes with the expected reciprocal gains/losses provide information on MI errors; those with non-reciprocal gains have pre-meiotic errors. Overall, 29 oocytes were aneuploid, and the source of the error was known for 21. In 8 (from 7 women) the error was pre-meiotic consisting of 4 MI oocytes and 4 MII-PB complexes with non-reciprocal gains. The remaining 13 were the result of errors at meiosis I. Although pre-meiotic errors occurred in only 10% of informative oocytes, most notable was the fact that for those oocytes where the source of the error was known, 38% were caused by germinal mosaicism compared with 62% that were the outcome of a meiosis I error. None of the women with germinal mosaicism were infertile.

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“…Some question the Oocyte Mosaicism Selection model. In 2012, Morris et al found no evidence of fetal oocyte mosaicism for trisomies 16, 21 and 22. They analyzed eight karyotypically normal female fetuses between 10 and 14 gestational weeks; they used FISH to find the possibly trisomic cells in ovarian tissues without differentiating the meiotic and pre‐meiotic cells with immune reactions, and used skin samples from all fetuses for karyotyping and control.…”

Section: Discussionmentioning

confidence: 99%

Evidence for the Oocyte Mosaicism Selection model on the origin of Patau syndrome (trisomy 13)

Babay

Horányi

Győrffy

et al. 2019

Acta Obstet Gynecol Scand

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Introduction In 2008, Hultén et al hypothesized that maternal ovarian trisomy 21 mosaicism might be the primary causative factor for fetal Down syndrome. We hypothesize that this theory can be extended to trisomy 13. Material and methods We collected fetal ovarian tissue from seven female fetuses between 16 and 23 gestational weeks, following the termination of the pregnancy for non‐genetic reasons. All procedures were performed with informed consent and ethical approval from the local ethics committee. We used touch preparation techniques from fetal ovarian tissues and an anti‐stromal antigen 3 antibody against the meiosis‐specific stromal antigen 3 protein to differentiate between germ cells, ovarian stromal cells and the cells entering their first meiotic prophase. We used fluorescence in situ hybridization analysis to determine chromosome 13 numbers in each cell. Results We were able to detect a proportion of trisomy 13 cells in all cases. The average incidence of trisomy 13 cells was 2.04% in stromal antigen 3‐positive and 0.91% in the stromal antigen 3‐negative cells. The number of the trisomic cells increased significantly with gestational age (for stromal antigen 3‐positive cells r = 0.93, P = 0.0038, for stromal antigen 3‐negative cells r = 0.85, P = 0.0071). Conclusions This study indicates that besides trisomy 21, the Oocyte Mosaicism Selection model could be extended to trisomy 13 as well. The crucial factor for trisomy 13 seems to be the pre‐meiotic/mitotic trisomy 13 mosaicism, leading to a so‐called secondary meiotic nondisjunction of those oocytes having three copies of chromosome 13.

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Origin of trisomy: no evidence to support the ovarian mosaicism theory

Abstract: This study found no evidence of fetal ovarian mosaicism for trisomies 16, 21 and 22.

Cited by 7 publications

References 30 publications

Germline mosaicism does not explain the maternal age effect on trisomy

Germline mosaicism does not explain the maternal age effect on trisomy

The Contribution of Germinal Mosaicism to Human Aneuploidy

Evidence for the Oocyte Mosaicism Selection model on the origin of Patau syndrome (trisomy 13)

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