Semin Reprod Med 2001; 19(2): 175-182
DOI: 10.1055/s-2001-15397
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Skewed X Inactivation and Recurrent Spontaneous Abortion

W. P. Robinson1 , C. Beever1 , C. J. Brown1 , M. D. Stephenson2 3
  • 1Department of Medical Genetics, University of British Columbia
  • 2Department of Obstetrics and Gynecology, University of British Columbia
  • 3Children's & Women's Health Centre of British Columbia, Vancouver, BC, Canada
Further Information

Publication History

Publication Date:
31 December 2001 (online)

ABSTRACT

Recent studies show that women experiencing recurrent spontaneous abortion exhibit nonrandom X-chromosome inactivation (XCI) more often than in controls. This suggests that genetic factors may be important in explaining the losses in this subset of women. Nonetheless there are a number of possible explanations for this finding and the underlying causes may be heterogeneous. One hypothesis commonly cited is that a mutation on the X chromosome results in both preferential inactivation of the mutated X as well as lethality of male embryos inheriting this mutated X. However, this hypothesis does not explain the increase in chromosome abnormalities observed in the karyotyped losses from women with recurrent pregnancy loss and skewed XCI. This finding leads us to suggest that the mechanism involved may be associated with a reduction in number of ovarian follicles, either due to X mutations affecting oocyte atresia or a restriction in precursor pool size during development.

REFERENCES

  • 1 Stirrat G M. Recurrent miscarriage II: clinical associations, causes, and management.  Lancet . 1990;  336 728-733
  • 2 Roman E. Fetal loss rates and their relation to pregnancy order.  J Epidemiol Community Health . 1984;  38 29-35
  • 3 Sangha K K, Stephenson M D, Brown C J, Robinson W P. Extremely skewed X-chromosome inactivation is increased in women with recurrent spontaneous abortion.  Am J Hum Genet . 1999;  65 913-917
  • 4 Lanasa M C, Hogge W A, Kubik C, Blancato J, Hoffman E P. Highly skewed X-chromosome inactivation is associated with idiopathic recurrent spontaneous abortion.  Am J Hum Genet . 1999;  65 252-254
  • 5 Hassold T, Abruzzo M, Adkins K. Human aneuploidy: incidence, origin and etiology.  Environ Mol Mutagen . 1996;  28 167-175
  • 6 Hassold T, Jacobs P. Trisomy in man.  Annu Rev Genet . 1984;  18 69-97
  • 7 Hassold T, Chiu D. Maternal age-specific rates of numerical chromosome abnormalities with special reference to trisomy.  Hum Genet . 1985;  70 11-17
  • 8 Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous miscarriages.  Fertil Steril . 2000;  73 300-304
  • 9 Stephenson M. Frequency of factors associated with habitual abortion.  Fertil Steril . 1996;  66 24-29
  • 10 Lyon M F. Gene action in the X-chromosome of the mouse (Mus musculus L).  Nature . 1961;  190 372-373
  • 11 Gardner R L, Lyon M F. X chromosome inactivation studied by injection of a single cell into the mouse blastocyst.  Nature . 1971;  231 385-386
  • 12 Tan S-S, Williams E A, Tam P PL. X-chromosome inactivation occurs at different times in different tissues of the post-implantation mouse embryo.  Nat Genet . 1993;  3 170-174
  • 13 Sharp A, Robinson D, Jacobs P. Age- and tissue-specific variation of X chromosome inactivation ratios in normal women.  Hum Genet . 2000;  107 343-349
  • 14 Abkowitz J L, Taboada M, Shelton G H, Catlin S N, Gutorp P, Kiklevich J V. An X-chromosome gene regulates hematopoietic stem cell kinetics.  Proc Natl Acad Sci U S A . 1998;  95 3862-3866
  • 15 Christensen K, Kristiansen M, Hagen-Larsen H. X-linked genetic factors regulate hematopoietic stem-cell kinetics in females.  Blood . 2000;  95 2449-2451
  • 16 Gale R E, Fielding A K, Harrison C N, Linch D C. Acquired skewing of X-chromosome inactivation patterns in myeloid cells of the elderly suggests stochastic clonal loss with age.  Br J Haematol . 1997;  98 512-519
  • 17 Beever C L, Stephenson M D, Papovska V. Clinical associations of women experiencing recurrent spontaneous abortion (RSA) and exhibiting skewed X chromosome inactivation (XCI).  Am J Hum Genet Suppl . 2000;  67 166
  • 18 Busque L, Mio R, Mattioli J. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age.  Blood . 1996;  88 59-65
  • 19 Luzzatto L, Usanga E A, Bienzle U, Esan G FJ, Fasuan F A. Imbalance in X-chromosome expression: evidence for a human X-linked gene affecting growth of hemopoietic cells.  Science . 1979;  205 1418-1420
  • 20 Schmidt M, Du Sart D. Functional disomies of the X-chromosome influence the cell selection and hence the X-inactivation pattern in females with balanced X-autosome translocations.  Am J Med Genet . 1992;  42 161-169
  • 21 Migeon B R, Moser H W, Moser A B, Axelman J, Sillence D, Norum R A. Adrenoleukodystrophy: evidence for X linkage, inactivation, and selection favoring the mutant allele in heterozygous cells.  Proc Natl Acad Sci U S A . 1981;  78 5066-5070
  • 22 Pegoraro E, Whitakerr J, Mowery-Rushton P, Surti U, Lanasa M, Hoffman E P. Familial skewed X-inactivation: a molecular trait associated with high spontaneous abortion rate maps to Xq28.  Am J Hum Genet . 1997;  61 160-170
  • 23 Belmont J W. Genetic control of X inactivation and processes leading to X-inactivation skewing.  Am J Hum Genet . 1996;  58 1101-1108
  • 24 Gaal M, Laszlo J. X inactivation pattern in an unbalanced X-autosome translocation with gonadal dysgenesis.  Hum Hered . 1977;  27 396-402
  • 25 Portnoi M F, Joye N, Van Den Akker J, Morlie G, Taillemite J L. Karyotypes of 1142 couples with recurrent abortion.  Obstet Gynecol . 1988;  72 31-34
  • 26 Parrish J E, Scheuerle A E, Lewis R A, Levy M L, Nelson D L. Selection against mutant alleles in blood leukocytes is a consistent feature in incontinentia pigmenti type 2.  Hum Mol Genet . 1996;  5 1777-1783
  • 27 Migeon B R, Axelman J, de Beur J S, Valle D, Mitchell G A, Rosenbaum K N. Selection against lethal alleles in females heterozygous for incontinentia pigmenti.  Am J Hum Genet . 1989;  44 100-106
  • 28 Evsikov S, Verlinsky Y. Mosaicism in the inner cell mass of human blastocysts.  Hum Reprod . 1998;  11 3151-3155
  • 29 Harrison R H, Kuo H C, Scriven P N, Handyside A H, Ogilvie C M. Lack of cell cycle checkpoints in human cleavage stage embryos revealed by a clonal pattern of chromosomal mosaicism analyzed by sequential multicolour FISH.  Zygote . 2000;  8 217-224
  • 30 Ruangvutilert P, Delhanty J DA, Serhal P, Simopoulou M, Rodeck C H, Harper J C. FISH analysis on day 5 post-insemination of human arrested and blastocyst stage embryos.  Prenat Diagn . 2000;  20 552-560
  • 31 Mark H F, Bier J A. Disappearing trisomy 8 mosaicism.  Ann Clin Lab Sci . 1997;  27 293-298
  • 32 Serra A, Arpaia E, Bova R. Kinetics of 21-trisomic lymphocytes.  Hum Genet . 1978;  41 157-67
  • 33 Wilson M G, Towner J W, Forsman I. Decreasing mosaicism in Down's syndrome.  Clin Genet . 1980;  17 335-340
  • 34 Howard P J, Cramp C E, Fryer A E. Trisomy 1 mosaicism only detected on a direct chromosome preparation in a neonate.  Clin Genet . 1995;  48 313-316
  • 35 Kalousek D K.. The effect of confined placental mosaicism on development of the human aneuploid conceptus. In: Blastogenesis: Normal and Abnormal Vol 29(1). New York: Wiley-Liss 1993: 39-51
  • 36 Lau A W, Brown C J, Langlois S, Kalousek D K, Robinson W P. Skewed X-chromosome inactivation is common in fetuses or newborns associated with confined placental mosaicism.  Am J Hum Genet . 1997;  61 1353-1361
  • 37 Peñaherrera M S, Barrett I J, Brown C J. An association between skewed X-chromosome inactivation and abnormal outcome in mosaic trisomy 16 confined predominantly to the placenta.  Clin Genet . 2000;  58 436-446
  • 38 Buehr M. The primordial germ cells of mammals: some current perspectives.  Exp Cell Res . 1997;  232 194-207
  • 39 Stavropoulos D J, Bick D, Kalousek D K. Molecular cytogenetic detection of confined gonadal mosaicism in a conceptus with trisomy 16 placental mosaicism.  Am J Hum Genet . 1998;  63 1912-1914
  • 40 Satge D, Geneix A, Goburdhun J. A history of miscarriages and mild prognathism as possible mode of presentation of mosaic trisomy 18 in women.  Clin Genet . 1996;  50 470-473
  • 41 Kohn G, Shohat M. Trisomy 18 mosaicism in an adult with normal intelligence.  Am J Med Genet . 1987;  26 929-931
  • 42 Nielsen K G, Poulsen H, Mikkelsen M, Steuber E. Multiple recurrence of trisomy 21 Down syndrome.  Hum Genet . 1988;  78 103-105
  • 43 Sachs E S, Jahoda M G, Los F J, Pijpers L, Wladimiroff J W. Trisomy 21 mosaicism in gonads with unexpectedly high recurrence risks.  Am J Med Genet Suppl . 1990;  7 186-188
  • 44 Gersdorf E, Utermann B, Uttermann G. Trisomy 18 mosaicism in an adult woman with normal intelligence and history of miscarriage.  Hum Genet . 1990;  84 298-299
  • 45 Pangalos C G, Talbot C C, Lewis J G. DNA polymorphism analysis in families with recurrence of free trisomy 21.  Am J Hum Genet . 1992;  51 1015-1027
  • 46 Tseng L H, Chuang S M, Lee T Y, Ko T M. Recurrent Down's syndrome due to maternal ovarian trisomy 21 mosaicism.  Arch Gynecol Obstet . 1994;  255 213-216
  • 47 Schupf N, Zigman W, Kapell D, Lee J H, Kline J, Levin B. Early menopause in women with Down's syndrome.  J Intellect Disabil Res . 1997;  41 264-267
  • 48 Freeman S B, Yang Q, Allran K, Taft L F, Sherman S L. Women with a reduced ovarian complement may have an increased risk for a child with Down syndrome.  Am J Hum Genet . 2000;  66 1680-1683
  • 49 Kline J, Kinney A, Levin B, Warburton D. Trisomic pregnancy and earlier age at menopause.  Am J Hum Genet . 2000;  67 395-404
  • 50 Canipari R. Oocyte-granulosa cell interactions.  Hum Reprod Update . 2000;  6 279-289
  • 51 Delhanty J DA, Harper J C, Ao A, Hanyside A H, Winston R ML. Multicolour FISH detects frequent chromosomal mosaicism and chaotic division in normal preimplantation embryos from fertile patients.  Hum Genet . 1997;  99 755-760
  • 52 Wells D, Delhanty J D. Comprehensive chromosomal analysis of human preimplantation embryos using whole genome amplification and single cell comparative genomic hybridization.  Mol Hum Reprod . 2000;  6 1055-1061
  • 53 Plenge R M, Hendrich B D, Schwartz C. A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation.  Nat Genet . 1997;  17 353-356
  • 54 Kristiansen M, Knudsen G P, Hagen C B, ;oFrstavik K H. X inactivation pattern in females with recurrent spontaneous abortions. International symposium on X-chromosome inactivation in mammals. Novosibirsk, Russia, September 6-12, 1999
  • 55 Nelson L M, Branch W, Ward K. Highly-skewed X- inactivation patterns are associated with many patients presenting with idiopathic recurrent pregnancy loss.  Am J Hum Genet . 2000;  67 43
  • 56 Brown C J, Robinson W P. The causes and consequences of random and nonrandom X chromosome inactivation in humans.  Clin Genet . 2000;  58 353-363