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.
PurposeMolecular cytogenetic analysis has confirmed that a proportion of apparently meiotic aneuploidy may be present in the germ cells prior to the onset of meiosis, but there is no clear perception of its frequency. The aim of this review is to assess the evidence for premeiotic aneuploidy from a variety of sources to arrive at an estimate of its overall contribution to oocyte aneuploidy in humans.MethodsRelevant scientific literature was covered from 1985 to 2018 by searching PubMed databases with search terms: gonadal/germinal mosaicism, ovarian mosaicism, premeiotic aneuploidy, meiosis and trisomy 21. Additionally, a key reference from 1966 was included.ResultsData from over 9000 cases of Down syndrome showed a bimodal maternal age distribution curve, indicating two overlapping distributions. One of these matched the pattern for the control population, with a peak at about 28 years and included all cases that had occurred independently of maternal age, including those due to germinal mosaicism, about 40% of the cohort. The first cytological proof of germinal mosaicism was obtained by fluorescence in situ hybridisation analysis. Comparative genomic hybridisation analysis of oocyte chromosomes suggests an incidence of up to 15% in premeiotic oocytes. Direct investigation of fetal ovarian cells led to variable results for chromosome 21 mosaicism.ConclusionsOocytes with premeiotic errors will significantly contribute to the high level of preimplantation and prenatal death. Data so far available suggests that, depending upon the maternal age, up to 40% of aneuploidy that is present in oocytes at the end of meiosis I may be due to germinal mosaicism.
Chromosome breakage is a fairly widespread phenomenon in preimplantation embryos affecting at least 10% of day 3 cleavage stage embryos. It may be detected during preimplantation genetic diagnosis (PGD). For carriers of structural chromosomal abnormalities, PGD involves the removal and testing of single blastomeres from cleavage stage embryos, aiming towards an unaffected pregnancy. Twenty-two such couples were referred for PGD, and biopsied blastomeres on day 3 and untransferred embryos (day 5/6) were tested using fluorescence in situ hybridisation (FISH) with appropriate probes. This study investigated whether chromosome breakage (a) was detected more frequently in cases where the breakpoint of the aberration was in the same chromosomal band as a fragile site and (b) was influenced by maternal age, sperm parameters, reproductive history, or the sex of the carrier parent. The frequency of breakage seemed to be independent of fragile sites, maternal age, reproductive history, and sex of the carrier parent. However, chromosome breakage was very significantly higher in embryos from male carriers with poor sperm parameters versus embryos from male carriers with normal sperm parameters. Consequently, embryos from certain couples were more prone to chromosome breakage, fragment loss, and hence chromosomally unbalanced embryos, independently of meiotic segregation.
Diagnostic application of array comparative genomic hybridization (aCGH) in preimplantation genetic diagnosis for reciprocal and Robertsonian translocations has revealed 55-65% embryos with additional aneuploidies with or without translocation-related imbalances. The occurrence of these extra abnormalities with the balanced form of the translocation reduces the number of embryos suitable for transfer. Eighty-three embryos were followed up on days 5-7 of development from 23 infertile or sub-fertile carriers for whole chromosome and segmental aneuploidies present in addition to the balanced or unbalanced translocations detected on aCGH diagnosis. Embryos were analysed by fluorescence in-situ hybridization (n = 63) and aCGH (n = 20). Meiotic aneuploidy affected 35% of embryos and 47% had mitotic events; 15% had both types. Meiotic and mitotic events were almost equal (60 versus 64), 97 affected whole chromosomes (58 meiotic, 39 mitotic) and 27 were segmental (two meiotic, 25 mitotic). In 85.5% of embryos with whole chromosome additional aneuploidies, the aneuploidy was present throughout or in more than 50% of cells. All embryos diagnosed as abnormal (translocation balanced or unbalanced) after aCGH diagnosis at cleavage stage would have remained unsuitable for transfer if tested at later stages of development. Additional aneuploidies merit full consideration when considering the choice of embryos to transfer.
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