Skewed X Inactivation Phenomenon is Present in FMR1 Premutation Carriers

Introduction: X chromosome inactivation (XCI) is required for female development and has implications for human disease. In somatic cells, XCI is generally random, with maternal and parental X having an equal probability of inactivation, but in some cases, especially in X linked disease, there is a bias or preferential inactivation (80:20 or 90:10) of one of the two X chromosomes.

Aim: the aim of this study was to evaluate XCI phenomenon in FMR1 premutation carriers.

Material and Methods: FMR1 premutation carriers (n=14) undergoing IVF – PGD treatment were included in this study. For each women XCI was evaluate in peripheral blood as well as in cumulus cells obtained during follicular aspiration. The control group (n=6) include women with less than 55 CGG repeats undergoing IVF for male factor infertility. Allelic XCI ratios were determined by examining DNA methylation in the vicinity of a polymorphic (CAG)n repeat in the first exon of the human androgen receptor (AR) gene. DNA methylation across this region of the AR gene is highly correlated with X-inactivation status.

Results: 2/14 (14%) FMR1 premutation carriers had skewed XCI in their cumulus cells and 3/14 (21%) had skewed XCI in their peripheral blood. One woman had skewed XCI both in cumulus cells and in peripheral blood. None of the women in the control group had skewed XCI in peripheral blood or in cumulus cells.

Conclusions: As in other X linked disease skewed X Inactivation is present in some FMR1 premutation carriers. The significance of this phenomenon is yet to be determined.