SKEWED X-CHROMOSOME INACTIVATION IS COMMON IN FETUSES OR NEWBORNS ASSOCIATED WITH CONFINED PLACENTAL MOSAICISM

The inactivation of one X chromosome in females is normally random wit h regard to which X is inactivated. However, exclusive or almost-exclu sive 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 differ ence near a polymorphism in the X-linked androgen-receptor gene was us ed to investigate the possibility that nonrandom X inactivation is inc reases in fetuses and newborns that are associated with confined place ntal mosaicism (CPM) involving an autosomal trisomy. Extreme skewing w as observed in 7 (58%) of 12 cases with a meiotic origin of the trisom y, but in none of 10 cases examined with a somatic origin of the triso my, and in only 1 (4%) of 27 control adult females. In addition, an ex tremely skewed X-inactivation pattern was observed in 3 of 10 informat ive cases of female uniparental disomy (UPD) of chromosome 15. This ma y reflect the fact that a proportion of UPD cases arise by ''rescue'' of a chromosomally abnormal conceptus and are therefore associated wit h 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 po ol, because of either poor early growth or subsequent selection agains t the trisomic cells. Since similar to 2% of pregnancies detected by c horionic villus sampling are associated with CPM, this is likely a sig nificant contributor to both skewed X inactivation observed in the new born population and the expression of recessive X-linked diseases in f emales.