Handbook of Genetic Counseling/Spontaneous Pregnancy Loss and X-chromosome Inactivation

Spontaneous Pregnancy Loss and X-chromosome Inactivation

General Information about Pregnancy LossEdit

  • Common problem
    • Approximately 50% of all conceptions spontaneously lost
    • Often occurs before pregnancy is diagnosed
    • Miscarriage occurs in 20% of confirmed pregnancies
  • Recurrent pregnancy loss affects 1 in 100 (1%) of couples who wish to have children
  • Potential causes of pregnancy loss
    • Most miscarriages due to sporadic chromosome abnormalities
    • About 50% of women experiencing recurrent pregnancy loss of "non-genetic" explanation
      • Anatomical problems of female reproductive tract
      • Infectious diseases
      • Hormonal problems
    • About 20% of women with recurrent pregnancy loss may have a mutation on their X-chromosome causing skewed X-inactivation
    • Many couples have no explanation for their recurrent pregnancy loss

Skewed X-Chromosome Inactivation (SXCI)Edit

  • Pattern of X-inactivation weighted heavily toward one chromosome
    • Would expect random inactivation to inactivate each chromosome about 50% of the time
    • Highly skewed is defined as >90% of cells with same active X-chromosome
  • May be caused by mutation in an essential gene on one X-chromosome that causes the chromosome to be selected against by the body
    • Mutation probably causes the cells that express it to have a growth disadvantage
    • The gene must be essential so that cells die when it doesn't function properly
  • Usually causes no health problems in females
    • If other X-chromosome also has an X-linked recessive mutation, female will be a manifesting carrier
    • Have seen women with Duchenne muscular dystrophy, Lesch-Nyhan, and hemophilia that are as severely affected as men
    • Mutation on active X-chromosome can be new mutation inherited from father's sperm or mutation that affects her father also
  • Mutation that causes skewed X-inactivation inherited from mother's side
    • May be family history of pregnancy loss on mothers side affecting male conceptions
      • Studies show consistently more females in families with skewed X-inactivation than males
      • Mutation lethal in males who don't have second X-chromosome to compensate
    • Females with SXCI have 32% risk to lose pregnancy compared to 15% risk in general population
    • In families with SXCI, females who inherit their mother's inactive X will inactivate the same X chromosome

X-Chromosome Inactivation Study (X-CIS)Edit

  • Coordinated by Dr. Eric Hoffman at Children's National Medical Center In Washington, DC and Dr. Allen Hogge at Magee-Women's Hospital in Pittsburgh
  • Will conduct linkage studies on families that show heritable highly skewed XCI and have enough members for significant LOD score
  • Participation requirements (Must have one of the following)
    • Women who have had more than 1 miscarriage
    • Women with at least one spontaneous abortion of a male conceptus
    • Manifesting carriers of X-linked recessive disorders or asymptomatic carriers of X-linked dominant disorders
    • Females with X-chromosome rearrangements, including X-autosome translocations, deletions, duplications, inversions
  • Sample requirements
    • Send 7-10 ml blood in 2 purple top (EDTA) tubes at room temperature
    • Send overnight mail
    • Cost of blood draw and shipping covered by research lab
    • Lab will supply kits including vacutainers upon request
  • When sending blood, include pedigree, completed intake form, and any pertinent clinical information
  • Requires signed consent form for each participant
  • Results take 3–5 weeks
  • Linkage studies will be done on families of females with highly skewed XCI in more than two generations

Contact informationEdit

Phone: 866-252-4460
Email: xcis@cnmcresearch.org
Web: http://www.cnmresearch.org/xcis/
Send samples to:
Attention: Melissa Thouin
CRI/Center III
Children's National Medical Center
111 Michigan Avenue, NW
Washington, DC 20010


The information in this outline was last updated in 2002.