title: Skewed X-chromosome inactivation is common in fetuses or newborns associated with confined placental mosaicism.
abstract: The inactivation of one X chromosome in females is normally random with regard to which X is inactivated. However, exclusive or almost-exclusive inactivation of one X may be observed in association with some X-autosomal rearrangements, mutations of the XIST gene, certain X-linked diseases, and MZ twinning. In the present study, a methylation difference near a polymorphism in the X-linked androgen-receptor gene was used to investigate the possibility that nonrandom X inactivation is increases in fetuses and newborns that are associated with confined placental mosaicism (CPM) involving an autosomal trisomy. Extreme skewing was observed in 7 (58%) of 12 cases with a meiotic origin of the trisomy, but in none of 10 cases examined with a somatic origin of the trisomy, and in only 1 (4%) of 27 control adult females. In addition, an extremely skewed X-inactivation pattern was observed in 3 of 10 informative cases of female uniparental disomy (UPD) of chromosome 15. This may reflect the fact that a proportion of UPD cases arise by "rescue" of a chromosomally abnormal conceptus and are therefore associated with CPM. A skewed pattern of X inactivation in CPM cases is hypothesized to result from a reduction in the size of the early-embryonic cell pool, because of either poor early growth or subsequent selection against the trisomic cells. Since approximately 2% of pregnancies detected by chorionic villus sampling are associated with CPM, this is likely a significant contributor to both skewed X inactivation observed in the newborn population and the expression of recessive X-linked diseases in females.
authors.affiliation: Department of Pathology, University of British Columbia, Vancouver, Canada.
authors.forename: A W
authors.initials: AW
authors.lastname: Lau
authors.forename: C J
authors.initials: CJ
authors.lastname: Brown
authors.forename: M
authors.initials: M
authors.lastname: Peñaherrera
authors.forename: S
authors.initials: S
authors.lastname: Langlois
authors.forename: D K
authors.initials: DK
authors.lastname: Kalousek
authors.forename: W P
authors.initials: WP
authors.lastname: Robinson
mesh_terms: D000328:Adult; D015193:Chorionic Villi Sampling; D019175:DNA Methylation; D004303:Dosage Compensation, Genetic; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005333:Fetus / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007231:Infant, Newborn; D008423:Maternal Age; D008540:Meiosis; D009030:Mosaicism; D009928:Organ Specificity; D010920:Placenta / Q000648:ultrastructure*; D011247:Pregnancy; D011944:Receptors, Androgen / Q000235:genetics; D014314:Trisomy
chemical_list: D011944:Receptors, Androgen