An association between skewed X-chromosome inactivation and abnormal outcome in mosaic trisomy 16 confined predominantly to the placenta

Skewed X-chromosome inactivation (XCI) is frequently found in the diploid f etal tissues of individuals with mosaic trisomy that originated from a 'tri somic zygote rescue' event. This may result from a high number of trisomic cells in the embryonic cell pool at the time of XCI, which are subsequently eliminated by selection. We hypothesize that extremely skewed XCI in these mosaic cases will be associated with a poor fetal outcome due to failure t o completely eliminate the trisomy from all fetal tissues. To test this hyp othesis, XCI status was evaluated in 17 cases of prenatally detected trisom y 16 mosaicism. Ten of the 15 informative cases showed extreme XCI skewing (greater than or equal to 90% inactivation of one allele) in blood or other diploid fetal tissues compared to six of the 111 controls (p < 0.001). Amo ng these 10 'skewed' cases, 6 showed an abnormal outcome, defined as develo pmental abnormalities and/or intrauterine or neonatal death. In contrast, o f the 5 cases without extreme skewing, none showed abnormal outcome, althou gh outcome information was incomplete in 1 case. An additional 6 cases anal yzed, involving trisomy mosaicism for other chromosomes, showed similar res ults. Further studies are warranted to determine if XCI status adds useful information to the prediction of pregnancy outcome in prenatally detected m osaic trisomy.