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

Abstract

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.

Skewed X-chromosome inactivation and shorter telomeres associate with idiopathic premature ovarian insufficiency

“…This leads to several diseases, including the fragile X syndrome (9,28). Skewed XCI has been previously related to POI (28,29). We have also found that this phenomenon is more frequent in women with POI, including patients with extreme XCI (>90%).…”

“…However, skewed XCI (>70%) can arise owing to alterations on the X chromosome. This leads to several diseases, including the fragile X syndrome (9,28). Skewed XCI has been previously related to POI (28,29).…”

Extreme Clonality in Lymphoblastoid Cell Lines with Implications for Allele Specific Expression Analyses

“…Indeed, the pattern of XCI is relatively constant across populations (see [10], [11], [12], [13], [14], [15] and Table 1) and ethnic differences are unlikely to explain the strong differences we observe.…”

X chromosome inactivation does not define the development of premature ovarian failure in fragile X premutation carriers

“…Recently, several studies were performed to assess whether XCI might be a relevant factor in idiopathic POF development, whereas Sato et al 2006 observed more extremely skewed XCI in 43 women with POF, Bione et al 2006, Bretherick et al 2007, and Yoon et al 2008 failed to find any significant differences in the degree and frequency of skewed XCI in extended POF cohorts (59–151 women with POF). Therefore, an association between XCI and idiopathic POF seems unlikely.…”