title: A novel X chromosome-linked genetic cause of recurrent spontaneous abortion.
abstract: OBJECTIVE
  Unexplained recurrent spontaneous abortion is a common women's health problem that affects approximately 1 of every 200 women who wish to have 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 recessive disorders that result in the loss of male pregnancies.
  
  
  METHODS
  X chromosome inactivation patterns, an assay used to detect women who are likely to be carriers of X-linked recessive cell-lethal traits, were compared between 105 female patients with idiopathic recurrent pregnancy loss and 101 women (control subjects) with a single successful pregnancy and no history of pregnancy loss. Inheritance patterns and gender of offspring 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). Female patients with highly skewed X chromosome inactivation showed a significant decrease in male children. Four of 6 families that were studied showed maternal inheritance of the skewed inactivation trait.
  
  
  CONCLUSIONS
  We found the 14% of women with unexplained recurrent pregnancy loss show highly skewed X inactivation, which suggests that they are carriers of X-linked recessive lethal traits. Furthermore, the observed gender bias 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 such female carriers is important for the reproductive counseling and treatment of these women.
authors.affiliation: Department of Molecular Genetics and Biochemistry, University of Pittsburgh, School of Medicine, PA, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Lanasa
authors.forename: W A
authors.initials: WA
authors.lastname: Hogge
authors.forename: C J
authors.initials: CJ
authors.lastname: Kubik
authors.forename: R B
authors.initials: RB
authors.lastname: Ness
authors.forename: J
authors.initials: J
authors.lastname: Harger
authors.forename: T
authors.initials: T
authors.lastname: Nagel
authors.forename: T
authors.initials: T
authors.lastname: Prosen
authors.forename: N
authors.initials: N
authors.lastname: Markovic
authors.forename: E P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D000026:Abortion, Habitual / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020868:Gene Silencing; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D010375:Pedigree; D012016:Reference Values; D017678:Sex Distribution; D014960:X Chromosome