A novel X chromosome-linked genetic cause of recurrent spontaneous abortion

OBJECTIVE: Unexplained recurrent spontaneous abortion is a common women's h ealth problem that affects approximately 1 of every 200 women who wish to h ave children. It has long been assumed that a large proportion of recurrent spontaneous abortion results from genetic problems, but no causative genes have been identified to date. Here, we tested the hypothesis that a subset of women with recurrent spontaneous abortion are carriers of X-linked rece ssive disorders that result in the loss of male pregnancies. STUDY DESIGN: X chromosome inactivation patterns, an assay used to detect w omen who are likely to be carriers of X-linked recessive cell-lethal traits , were compared between 105 female patients with idiopathic recurrent pregn ancy loss and 101 women (control subjects) with a single successful pregnan cy and no history of pregnancy loss. Inheritance patterns and gender of off spring were studied in relevant subsets of participants. RESULTS: Female patients showed a highly statistically significant increase in the frequency of skewed X chromosome inactivation (90%; P < .0005). Fem ale patients with highly skewed X chromosome inactivation showed a signific ant decrease in male children. Four of 6 families that were studied showed maternal inheritance of the skewed inactivation trait. CONCLUSION: We found the 14% of women with unexplained recurrent pregnancy loss show highly skewed X inactivation, which suggests that they are carrie rs of X-linked recessive lethal traits. Furthermore, the observed gender bi as among women with highly skewed X inactivation suggests selective loss of male conceptions, which is consistent with an X chromosome-linked genetic defect that leads to cell death or growth disadvantage. Identification of s uch female carriers is important for the reproductive counseling and treatm ent of these women.