Spontaneous Pregnancy Loss and X-chromosome Inactivation

General Information about Pregnancy Loss

• 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)

• 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)

• Coordinated by Dr. Eric Hoffman at Children's National Medical Center In Washington, DC and Dr. Allen Hogge at Magee-Womens 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 information

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

Notes

The information in this outline was last updated in 2002.