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