A trisomic germ cell line and precocious chromatid segregation leads to recurrent trisomy 21 conception

Cozzi, J.; Conn, C.M.; Harper, Joyce; Winston, R. M. L.; Rindl, M.; Farndon, Peter; Delhanty, Joy D. A.

doi:10.1007/s004390050905

Cited by 49 publications

(45 citation statements)

References 25 publications

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“…Younger couples with three or more conceptions with the same trisomy are good candidates for gonadal mosaicism, as has been clearly demonstrated by several studies (Sachs et al, 1990;Cozzi et al, 1999;Somprasit et al, 2004). Prospective studies on oocytes have also demonstrated that some women have a high risk of producing aneuploid oocytes.…”

Section: Predisposition To Aneuploidymentioning

confidence: 73%

“…Without further investigation it is not possible to determine whether this preexisting aneuploidy arose during the premeiotic divisions (germinal mosaicism) or if it was present initially in the embryonic gonad (gonadal mosaicism). Cytologically proven gonadal mosaicism was reported by Cozzi et al (1999) in a woman with three previous conceptions with trisomy 21 and for whom preimplantation diagnosis was performed. FISH analysis of unfertilised oocytes and corresponding 1 st PBs proved that gonadal mosaicism was the cause of the repeatedly abnormal conceptions.…”

Section: Studies On Mature Oocytesmentioning

confidence: 99%

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Mechanisms of aneuploidy induction in human oogenesis and early embryogenesis

Delhanty¹

2005

Cytogenet Genome Res

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The mechanisms of aneuploidy induction in human oogenesis mainly involve nondisjunction arising during the first and second meiotic divisions. Nondisjunction equally affects both whole chromosomes and chromatids, in the latter case it is facilitated by “predivision” or precocious centromere division. Karyotyping and CGH studies show an excess of hypohaploidy, which is confirmed in studies of preimplantation embryos, providing evidence in favour of anaphase lag as a mechanism. Preferential involvement of the smaller autosomes has been clearly shown but the largest chromosomes are also abnormal in many cases. Overall, the rate of chromosomal imbalance in oocytes from women aged between 30 and 35 has been estimated at 11% from recent karyotyping data but accruing CGH results suggest that the true figure should be considerably higher. Clear evidence has been obtained in favour of germinal or gonadal mosaicism as a predisposing factor. Constitutional aneuploidy in embryos is most frequent for chromosomes 22, 16, 21 and 15; least frequently involved are chromosomes 14, X and Y, and 6. However, embryos of women under 37 are far more likely to be affected by mosaic aneuploidy, which is present in over 50% of 3-day-old embryos. There are two main types, diploid/aneuploid and chaotic mosaics. Chaotic mosaics arise independently of maternal age and may be related to centrosome anomalies and hence of male origin. Aneuploid mosaics most commonly arise by chromosome loss, followed by chromosome gain and least frequently by mitotic nondisjunction. All may be related to maternal age as well as to lack of specific gene products in the embryo. Partial aneuploidy as a result of chromosome breakage affects a minimum of 10% of embryos.

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Section: Predisposition To Aneuploidymentioning

confidence: 73%

Section: Studies On Mature Oocytesmentioning

confidence: 99%

Mechanisms of aneuploidy induction in human oogenesis and early embryogenesis

Delhanty¹

2005

Cytogenet Genome Res

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“…These studies suggest that both, whole-chromosome nondisjunction as well as single-chromatid nondisjunction, contribute to the formation of numerical chromosomal abnormalities during first meiotic division (Munné et al, 1995Dailey et al, 1996;Verlinsky et al, 1996Verlinsky et al, , 1999Má rquez et al, 1998;Cozzi et al, 1999;Mahmood et al, 2000;Sandalinas et al, 2002). As reviewed by Pellestor et al (2003), many FISH studies have reported implausibly high rates of aneuploidy ranging from 37 to 44 % (Dailey et al, 1996;Dyban et al, 1996;Martini et al, 1997Martini et al, , 2000.…”

Section: Discussionmentioning

confidence: 99%

Multi-locus (ML)-FISH is a reliable tool for nondisjunction studies in human oocytes

Eckel

Kleinstein²,

Stümm³

2003

Cytogenet Genome Res

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In the present study, we developed a fluorescence in situ hybridization (FISH) strategy, which allows a reliable determination of the chromatid number of specific chromosomes in mature human oocytes. 168 unfertilized oocytes were analyzed by dual-color FISH with two direct-labeled locus-specific DNA probes for chromosome 13 and 21. To exclude FISH failures, metaphases with abnormal signal patterns were reanalyzed by multi-locus-FISH (ML-FISH) for chromosome 13 and 21. Following dual-color FISH, abnormal signal patterns were detected in 21 out of 108 metaphases (19.4%). 17 of these metaphases were reanalyzed by ML-FISH. In contrast to the first FISH, seven metaphases showed normal signal patterns after rehybridization, whereas ten metaphases remained abnormal. Out of these real aneuploid metaphases, five showed gain or loss of a single signal (= chromatid), two showed missing double signals (= chromosome) and three showed both. In conclusion, locus-specific FISH probes facilitate differentiation between first meiotic nondisjunction of whole chromosomes and prematurely divided chromatids. Moreover, simultaneous hybridization with a second locus-specific probe on the same chromatid (ML-FISH) helps to differentiate between FISH failures and real meiotic division errors and therefore, allows a more reliable analysis of aneuploidies in human oocytes.

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“…This premeiotic mechanism was found to be responsible for the presence of trisomic cells together with the euploid ones, when mature oocytes and embryos from euploid women were analysed. 11,12 Other authors have confirmed the existence of these premeiotic alterations as non-complementary results between 1PB-MII oocyte doublets in studies where the whole-chromosome complement was evaluated. Non-complementary rates between 1 and 15.5% have been described.…”

Section: Introductionmentioning

confidence: 90%

Non-meiotic chromosome instability in human immature oocytes

et al. 2013

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Aneuploidy has been a major issue in human gametes and is closely related to fertility problems, as it is known to be present in cleavage stage embryos and gestational losses. Pre-meiotic chromosome abnormalities in women have been previously described. The aim of this study is to assess the whole-chromosome complement in immature oocytes to find those abnormalities caused by mitotic instability. For this purpose, a total of 157 oocytes at the germinal vesicle or metaphase I stage, and discarded from IVF cycles, were analysed by CGH. Fifty-six women, between 18 and 45 years old (mean 32.5 years), including 32 IVF patients (25-45 years of age) and 24 IVF oocyte donors (18-33 years of age), were included in the study. A total of 25/157 (15.9%) of the oocytes analysed, obtained from three IVF clinics, contained chromosome abnormalities, including both aneuploidy (24/157) and structural aberrations (9/157). Independently of the maternal age, the incidence of abnormal oocytes which originated before meiosis is 15.9%, and these imbalances were found in 33.9% of the females studied. This work sheds light on the relevance of mitotic instability responsible for the generation of the abnormalities present in human oocytes. European Journal of Human Genetics ( Keywords: premeiotic instability; immature oocytes; aneuploidy; segmental imbalances; germline mitotic abnormalities INTRODUCTION Aneuploidy has been a major issue in human gametes, and is highly related to fertility problems. It is known to be present in cleavage stage embryos and gestational losses. 1,2 The prevailing mechanism causing aneuploidy in humans concerns maternal meiotic mal-segregation. Several studies have focused their interest on oocyte aneuploidy, mainly those which originate during the first and second meiotic divisions. 1 For this purpose, first and second polar bodies (1PB and 2PB) and the corresponding metaphase II (MII) oocytes have been analysed, describing aneuploidies of meiotic origin, mainly caused by chromosome non-disjunction and/ or sister chromatid predivision. 3 Meiotic studies have been performed in oocytes using a great variety of cytogenetic methodologies. R-banding karyotyping on 1397 oocytes showed aneuploidies in 10.8% of the cells studied. 4 An aneuploidy rate of 47.5% was observed when 1PB-MII oocyte doublets were analysed by 9-chr FISH. 5 In studies where the wholechromosome complement was assessed by spectral karyotyping, aneuploidy rates from 16.7% (10/60) 6 to 42.5% (20/47) 7 were detected. Using comparative genomic hybridisation (CGH), a great variability of aneuploidy rates was found, when different wholegenome amplification methodologies were used to amplify the DNA from single cells, and aneuploidy rates found in 1PB-MII oocyte doublets varied from 3% in oocyte donors 8 to 65% in IVF patients. 9

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A trisomic germ cell line and precocious chromatid segregation leads to recurrent trisomy 21 conception

Cited by 49 publications

References 25 publications

Mechanisms of aneuploidy induction in human oogenesis and early embryogenesis

Mechanisms of aneuploidy induction in human oogenesis and early embryogenesis

Multi-locus (ML)-FISH is a reliable tool for nondisjunction studies in human oocytes

Non-meiotic chromosome instability in human immature oocytes

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