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

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

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

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

Phone: 866-252-4460

Email: xcis@cnmcresearch.org

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.