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Skewed X‐chromosome inactivation is associated with primary but not secondary ovarian failure
Author(s) -
Bretherick Karla L.,
Metzger Daniel L.,
Chanoine JeanPierre,
Panagiotopoulos Constadina,
Watson Spencer K.,
Lam Wan L.,
Fluker Margo R.,
Brown Carolyn J.,
Robinson Wendy P.
Publication year - 2007
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.31679
Subject(s) - premature ovarian failure , skewed x inactivation , biology , x inactivation , y chromosome microdeletion , x chromosome , chromosomal translocation , genetics , andrology , chromosome , medicine , endocrinology , karyotype , gene
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 ≥90% skewing. Notably, all three primary amenorrhea patients that were informative at AR had skewed XCI ≥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. © 2007 Wiley‐Liss, Inc.