The association of skewed X chromosome inactivation with aneuploidy in humans

Bretherick, Karla L.; Gair, Jane; Robinson, Wendy P.

doi:10.1159/000086898

Cited by 20 publications

(16 citation statements)

References 78 publications

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“…One cause of a decrease in the number of precursor cells that may also result in primary amenorrhea is trisomy mosaicism confined predominantly to the placenta [Robinson et al, 2001; Bretherick et al, 2005b]. Skewed XCI is commonly observed in the diploid cell line arising from a trisomy rescue event [Lau et al, 1997; Penaherrera et al, 2000], and it has been shown that the oocytes may contain high levels of trisomic cells even when other fetal tissues are not affected by trisomy [Stavropoulos et al, 1998].…”

Section: Discussionmentioning

confidence: 99%

Skewed X‐chromosome inactivation is associated with primary but not secondary ovarian failure

Bretherick

Metzger

Chanoine

et al. 2007

American J of Med Genetics Pt A

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Premature ovarian failure (POF) is the occurrence of menopause before the age of 40, and may present with either primary or secondary amenorrhea. Numerous cases of POF in women with X-chromosome deletions or translocations have been reported; thus, it is possible that smaller rearrangements undetectable by conventional cytogenetics may contribute to POF in some patients. In females with an abnormal X chromosome, cells with inactivation of the normal X may be selected against, causing skewed X-chromosome inactivation (XCI). We therefore assessed XCI by methylation sensitive restriction digestion and PCR amplification at the androgen receptor (AR) locus, in 4 primary and 55 secondary POF patients and 109 control women. In samples heterozygous at AR and therefore informative for the skewing assay, the frequency of skewed XCI among the women with secondary amenorrhea was identical to that in control women, with 4 out of 48 (8.3%) secondary ovarian failure patients and 8 out of 97 (8.2%) control women having > or =90% skewing. Notably, all three primary amenorrhea patients that were informative at AR had skewed XCI > or =90% (P = 0.001 vs. control women; Fisher's exact test). To investigate whether X-chromosome copy number alterations were responsible, DNA from selected patients with skewed XCI was examined by high resolution DNA microarray, however no potential regions of DNA addition or deletion were confirmed by FISH or PCR. X-chromosome abnormalities undetectable by array, or reduced follicular pool due to an early trisomic rescue event, may explain the skewed XCI observed in POF patients presenting with primary amenorrhea.

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Section: Discussionmentioning

confidence: 99%

Skewed X‐chromosome inactivation is associated with primary but not secondary ovarian failure

Bretherick

Metzger

Chanoine

et al. 2007

American J of Med Genetics Pt A

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“…An association of skewed X inactivation with repeated miscarriage has been reported by several groups (see Bretherick et al, 2005). Skewing can be caused by X chromosomal mutations or subtle chromosome rearrangements (Pergoraro et al, 1997) that could also lead to increased oocyte atresia (Warburton and Kline, 2001).…”

Section: Rates Of Aneuploidy In Women With Reduced Oocyte Pool Sizementioning

confidence: 93%

“…Thus, the association of X inactivation skewing with miscarriage could be due to an increased frequency of trisomic conceptions. Preliminary data (Beever et al, 2003;Bretherick et al, 2005) suggest that this may be so. Further studies are ongoing in our laboratory and others to investigate this question.…”

Section: Rates Of Aneuploidy In Women With Reduced Oocyte Pool Sizementioning

confidence: 95%

Biological aging and the etiology of aneuploidy

Warburton¹

2005

Cytogenet Genome Res

104

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A prevalent hypothesis concerning the cause of the rise in aneuploid conceptions with maternal age is that the changes that accompany normal ovarian aging increase the rate of meiotic errors in the oocyte. Biological aging of the ovary is accompanied by a decline in both the total oocyte pool and the number of antral follicles maturing per cycle, as well as changes in the levels of circulating reproductive hormones. The biological aging hypothesis predicts that aneuploidy rates should be higher in women with a prematurely reduced oocyte pool, and that women with trisomic conceptions should show signs of earlier ovarian aging than women of the same chronological age without trisomic conceptions. Comprehensive studies of aneuploidy in groups of women with known causes of premature ovarian failure remain to be done, though anecdotal evidence does suggest increased rates of pregnancy loss and aneuploidy. Smoking, which is a well-documented cause of earlier ovarian aging, is not associated with an increase in aneuploid conceptions. Evidence from women with unilateral ovariectomies is inconsistent. Support for the biological aging hypothesis was provided by one study showing that menopause occurred about a year earlier in women with a trisomic spontaneous abortion compared to women with chromosomally normal conceptions. Associations between high FSH and pregnancies with Down syndrome and chromosomally abnormal spontaneous abortions have also been reported. However, the most direct test of the hypothesis, which compared antral follicle counts and hormonal levels in women with trisomic pregnancies and those with chromosomally normal pregnancies, failed to find a difference in the expected direction. A prospective study of FSH levels in women with subfertility also failed to find an association with the rate of pregnancy loss. The bulk of evidence thus suggests that, if the processes of biological aging are indeed related to aneuploidy, they probably involve factors other than those measured by oocyte or antral follicle pool size and reproductive hormone levels.

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“…One explanation could be loss of male fetuses in female carriers of undiagnosed X-linked lethal disorders. Furthermore, an excess of trisomic losses has been reported in women with RSA and skewed XCI, compared with women with RSA and random XCI (Beever et al 2003;Bretherick et al 2005). Skewed XCI was more strongly associated with a trisomic pregnancy than with RSA in general.…”

Section: Recurrent Spontaneous Abortionsmentioning

confidence: 98%

“…This Wnding could theoretically be explained by a reduction in the size of the follicular pool. However, maternal XCI analysis was not considered indicated in the investigation of fetal trisomies (Bretherick et al 2005).…”

Section: Recurrent Spontaneous Abortionsmentioning

confidence: 99%

X chromosome inactivation in clinical practice

Ørstavik

2009

Hum Genet

113

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X chromosome inactivation (XCI) is the transcriptional silencing of the majority of genes on one of the two X chromosomes in mammalian females. Females are, therefore, mosaics for two cell lines, one with the maternal X and one with the paternal X as the active chromosome. The relative proportion of the two cell lines, the X inactivation pattern, may be analyzed by simple assays in DNA from available tissues. This review focuses on medical issues related to XCI in X-linked disorders, and on the value of X inactivation analysis in clinical practice.

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The association of skewed X chromosome inactivation with aneuploidy in humans

Cited by 20 publications

References 78 publications

Skewed X‐chromosome inactivation is associated with primary but not secondary ovarian failure

Skewed X‐chromosome inactivation is associated with primary but not secondary ovarian failure

Biological aging and the etiology of aneuploidy

X chromosome inactivation in clinical practice

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