May anomalous X chromosome methylation be responsible for the spontaneous abortion of a male foetus?

Abstract

Pregnancy loss is an important reproductive problem which appears to be highly associated with genetic factors. A spontaneous abortion occurred before prenatal diagnosis could be performed, in a woman who carried a fragile X full mutation. DNA extracted from formalin-fixed para ffin-embedded chorionic villi preparations indicated that it was a male embryo with an apparently methylated X chromosome. The previous analysis of the family showed that her daughter, who also carried a full mutation, exhibited an extremely skewed X inactivation of the normal allele (100%) and a severe fragile X phenotype. Thus, we speculate that the aberrant pattern of X chromosome methylation in this family may provoke the spontaneous miscarriage of this pregnancy that could be explained by at least partial inactivation of the unique X chromosome in a male foetus. Spontaneous abortion occurs quite frequently in humans, and recurrent pregnancy loss is a significant problem in women’s health (Christiansen 2006). Many cases of spontaneous abortion defy diagnosis and genetic factors have been proposed as a major contribution (Lanasa and Hogge 2000; Sierra and Stephenson 2006). The X chromosome inactiva tion (XCI) is the process in which one of the two X chromosomes present in each cell of female mammals is inactivated during early embryogenesis, to achieve dosage compensation with males (Avner and Heard 2001; Heard 2004). Initial steps of XCI involve a ‘counting process’, which senses the X chromosome/autosome ratio that restricts XCI to female embryos and, thereafter, the choice of which chromosome is inactivated (Morey et al . 2004).Skewed XCI leads to an expression of X-linked recessive disorders in females (Plenge et al. 2002; Mart´ınez et al. 2005; Renault et al. 2007). Another form of X-inactivation called meiotic sex chromosome inactivation (MSCI), takes place in males, during spermatogenesis and is a manifestation of the general meiotic-silencing mechanism (Turner 2007). In this study, we report the spontaneous abortion of a male foetus with an apparently methylated X chromosome, and propose that anomalous inactivation of its uniqueX chromosome could explain nonviability of the embryo and pregnancy loss. Therefore, we strongly suggest, as a follow up, that the methylation status of the X chromosome be tested in early spontaneous abortion of males in the absence of any other known genetic or nongenetic cause.