# 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

## 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-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 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.