Inheritance of a maternal preferentially inactivated X by a monosomy X conceptus
Only one X chromosome is active in any given cell in a normal female, with all other X chromosomes in excess of one being inactivated. Inactivation of the X is achieved by methylation of the whole chromosome apart from the pseudoautosomal regions.
Skewing of X inactivation has been suggested as a cause of repeated spontaneous miscarriage for some individuals. It has been hypothesised that the preferentially inactivated X may carry deleterious genes, or render the individual less fit to survive.
Monosomy X is the most common cytogenetic alteration observed in first trimester spontaneous miscarriages. However, monosomy X individuals, while infertile, may be undetected in the population with normal lifespans. Investigations of monosomy X individuals present and healthy in the population have demonstrated that 75% carry the maternal X chromosome.
The Androgen receptor locus is located close to the X inactivation centre at Xq13.2 on the X chromosome. It is methylation-sensitive, and exhibits 90% heterozygosity. This locus may be used as a tool to investigate X chromosomes for parental origin and X inactivation status.
We present a case of a monosomy X, (45,X), spontaneous miscarriage which was initially investigated by cytogenetic studies, followed by molecular investigations of parental X chromosomes and X inactivation status. The case was referred because the mother had experienced previous miscarriages, and was diagnosed with recurrent miscarriage. While the maternal cytogenetics on peripheral blood was normal 46,XX, molecular investigations demonstrated that the mother exhibited approximately 90% skewing of the X inactivation pattern in the blood, and that the conceptus had inherited the inactivated X. Investigations of maternal uterine tissue indicated a predominance of monosomy X tissue, which contained the inactive X.