Recurrent pregnancy loss, experienced by 2-3% of couples who wish to have children, is becoming more common as women postpone pregnancy to later in their reproductive lives. There are few established causes of such loss and even fewer effective treatments. Recent reports suggest that highly skewed X inactivation (HSXI) is about threefold more common among women with recurrent abortion than among comparison samples. While these reports are provocative, all publications have been preliminary. Little is known about the karyotype of the losses associated with HSXI, information essential for understanding likely pathogenetic mechanisms. All studies are limited to women with recurrent losses, but the findings could also pertain to women with fewer losses. Comparison samples have also been largely those of convenience, without rigorous adjustment for maternal age. Two hypotheses have been proposed to explain an association of HSXI with recurrent loss. The first suggests that an X chromosomal defect leads both to HSXI and to loss of male conceptions. The second implicates maternal mosaicism as the cause of the HSXI and recurrent trisomy. We propose a third hypothesis: X-chromosomal defects lead both to HSXI and to an increase in trisomy due to premature ovarian aging. The primary goal of this study is to test this hypothesis. In addition we will explore associations with chromosomally normal male loss and examine whether associations with HSXI are limited to women with recurrent loss. We will study X inactivation skewing in 450 cases defined by the kaiyotype of an index spontaneous abortion, and a similar number of controls with an index live birth. Primary analyses will examine whether the proportion of HSXI differs between women with trisomic losses and controls: we will also examine HSXI in normal male losses, and test whether any association is confined to women with repeat losses. Lastly, we will investigate the mechanism of the observed HSXI by screening for X chromosome rearrangements, including microdeletions, in all women with HSXI. This may provide important leads for the identification of genes involved in ovarian maintenance.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042745-05
Application #
7072182
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Taymans, Susan
Project Start
2002-09-26
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
5
Fiscal Year
2006
Total Cost
$459,153
Indirect Cost
Name
Columbia University (N.Y.)
Department
Genetics
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Kline, Jennie K; Kinney, Ann M; Levin, Bruce et al. (2014) Intermediate CGG repeat length at the FMR1 locus is not associated with hormonal indicators of ovarian age. Menopause 21:740-8
Jobanputra, V; Levy, B; Kinney, A et al. (2012) Copy number changes on the X chromosome in women with and without highly skewed X-chromosome inactivation. Cytogenet Genome Res 136:264-9
Kline, J; Kinney, A; Brown, S et al. (2012) Trisomic pregnancy and intermediate CGG repeat length at the FMR1 locus. Hum Reprod 27:2224-32
Jobanputra, Vaidehi; Esteves, Cecilia; Sobrino, Antonio et al. (2011) Using FISH to increase the yield and accuracy of karyotypes from spontaneous abortion specimens. Prenat Diagn 31:755-9
Kline, J K; Kinney, A M; Levin, B et al. (2011) Trisomic pregnancy and elevated FSH: implications for the oocyte pool hypothesis. Hum Reprod 26:1537-50
Warburton, Dorothy; Kline, Jennie; Kinney, Ann et al. (2009) Skewed X chromosome inactivation and trisomic spontaneous abortion: no association. Am J Hum Genet 85:179-93