Ring X and Other Structural X Chromosome Abnormalities: X Inactivation and Phenotype

ABSTRACT

Patients who carry a structural abnormality of the X chromosome are a fascinating group who have provided opportunities to evaluate genotype/phenotype correlation in relation to X chromosome content and inactivation. Turner syndrome (TS) is most commonly associated with a 45,X karyotype and presents with an array of phenotypes, the main ones being poor viability in utero, ovarian failure and infertility, short stature, lymphedema, and other congenital malformations but usually not mental retardation. In some TS patients the karyotype shows both a normal X and a structurally rearranged X chromosome. These structural abnormalities, which include deletions, duplications, inversions, translocations, and rings, are associated with chromosome breaks and significant imbalance of gene content of the X chromosome. However, such abnormalities are generally well tolerated because of the preferential inactivation of the abnormal X, which can restore, at least in part, a balanced genetic makeup. This beneficial effect of X inactivation results in a mild phenotype in most patients with structural abnormalities of the X, similar to that found in TS patients with a 45,X karyotype. However, in cases of ring X chromosomes and of X/autosome translocations the incidence of mental retardation and other congenital abnormalities can be significantly higher than in TS. These abnormal phenotypes can be ascribed to failed or partial X inactivation and/or incomplete selection in favor of cells with normal balance of gene expression. In this article, we present phenotype/genotype correlation in female patients with structural abnormalities of the X and address the role of X inactivation and cell selection in the phenotypic findings. Our review emphasizes a subset of rare patients with ring X chromosomes who have provided evidence of a direct role for X inactivation in determining phenotypes.

KEYWORD

X chromosome - chromosome anomalies - ring X - X inactivation

REFERENCES

• 1 Sybert V P. The Adult Patient with Turner's Syndrome. Turner Syndrome in a Life Span Perspective: Research and Clinical Aspects. Proceedings of the 4th International Symposium on Turner Syndrome, Gothenburg, Sweden, May 18-21, 1995 Amsterdam: Elsevier; 1995
• 2 Ogata T, Matsuo N. Turner syndrome and female sex chromosome aberrations: deduction of the principal factors involved in the development of clinical features.  Hum Genet . 1995;  95 607-629
• 3 Rao E, Weiss B, Fukami M. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome.  Nat Genet . 1997;  16 54-63
• 4 Ellison J W, Wardak Z, Young M F, Gehron Robey P, Laig-Webster M, Chiong W. PHOG, a candidate gene for involvement in the short stature of Turner syndrome.  Hum Mol Genet . 1997;  6 1341-1347
• 5 Shears D J, Vassal H J, Goodman F R. Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis.  Nat Genet . 1998;  19 70-73
• 6 Belin V, Cusin V, Viot G. SHOX mutations in dyschondrosteosis (Leri-Weill syndrome).  Nat Genet . 1998;  19 67-69
• 7 Bione S, Sala C, Manzini C. A human homologue of the Drosophila melanogaster diaphanous gene is disrupted in a patient with premature ovarian failure: evidence for conserved function in oogenesis and implications for human sterility.  Am J Hum Genet . 1998;  62 533-541
• 8 Brown C J, Ballabio A, Rupert J L. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome.  Nature . 1991;  349 38-44
• 9 Penny G D, Kay G F, Sheardown S A, Rastan S, Brockdorff N. Requirement for Xist in X chromosome inactivation.  Nature . 1996;  379 131-137
• 10 Lee J T, Strauss W M, Dausman J A, Jaenisch R. A 450 kb transgene displays properties of the mammalian X-inactivation center.  Cell . 1996;  86 83-94
• 11 Avner P, Heard E. X-chromosome inactivation: counting, choice and initiation.  Nat Rev Gemet . 2001;  2 59-67
• 12 Gartler S M, Riggs A D. Mammalian X-chromosome inactivation.  Annu Rev Genet . 1983;  17 155-190
• 13 Lyon M F. X-chromosome inactivation: a repeat hypothesis.  Cytogenet Cell Genet . 1998;  80 133-137
• 14 Brown C J, Willard H F. The human X-inactivation centre is not required for maintenance of X-chromosome inactivation.  Nature . 1994;  368 154-156
• 15 Rack K A, Chelly J, Gibbons R J. Absence of the XIST gene from late-replicating isodicentric X chromosomes in leukaemia.  Hum Mol Genet . 1994;  3 1053-1059
• 16 Gartler S M, Dyer K A, Goldman M A. Mammalian X chromosome inactivation.  Mol Genet Med . 1992;  2 121-160
• 17 Jeppesen P, Turner B M. The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cytogenetic marker for gene expression.  Cell . 1993;  74 281-289
• 18 Costanzi C, Pehrson J R. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals.  Nature . 1998;  393 599-601
• 19 Hansen R S, Canfield T K, Fjeld A D, Gartler S M. Role of late replication timing in the silencing of X-linked genes.  Hum Mol Genet . 1996;  5 1345-1353
• 20 Latt S A, Willard H F, Gerald P S. BrdU-33258 Hoechst analysis of DNA replication in human lymphocytes with supernumerary or structurally abnormal X chromosomes.  Chromosoma . 1976;  57 135-153
• 21 Carrel L, Cottle A A, Goglin K C, Willard H F. A first-generation X-inactivation profile of the human X chromosome.  Proc Natl Acad Sci U S A . 1999;  96 14440-14444
• 22 Disteche C M. Escape from X inactivation in human and mouse.  Trends Genet . 1995;  11 17-22
• 23 Disteche C M. Escapees on the X chromosome.  Proc Natl Acad Sci U S A . 1999;  96 14180-14182
• 24 Zinn A R, Page D C, Fisher E M. Turner syndrome: the case of the missing sex chromosome.  Trends Genet . 1993;  9 90-93
• 25 Disteche C M, Swisshelm K, Forbes S, Pagon R A. X-inactivation patterns in lymphocytes and skin fibroblasts of three cases of X-autosome translocations with abnormal phenotypes.  Hum Genet . 1984;  66 71-76
• 26 Gartler S M, Sparkes R S. The Lyon-Beutler hypothesis and isochromosome X patients with the Turner syndrome.  Lancet . 1963;  411
• 27 Disteche C M, Eicher E M, Latt S A. Late replication in an X-autosome translocation in the mouse: correlation with genetic inactivation and evidence for selective effects during embryogenesis.  Proc Natl Acad Sci U S A . 1979;  76 5234-5238
• 28 Migeon B R. Non-random X chromosome inactivation in mammalian cells.  Cytogenet Cell Genet . 1998;  80 142-148
• 29 Dallapiccola B, Bruni L, Boscherini B, Pasquino A M, Chessa L, Vignetti P. Segregation of an X ring chromosome in two generations.  J Med Genet . 1980;  17 306-308
• 30 Blumenthal A L, Allanson J E. Turner syndrome in a mother and daughter: r(X) and fertility.  Clin Genet . 1997;  52 187-191
• 31 Uehara S, Nata M, Obara Y, Niinuma T, Funato T, Yajima A. A Turner syndrome woman with a ring X chromosome [45,X/46,X,r(X)(p22.3q27)] whose child also had a ring X chromosome.  Fertil Steril . 1997;  67 576-579
• 32 Matsuo M, Muroya K, Adachi M. Clinical and molecular studies in 15 females with ring X chromosomes: implications for r(X) formation and mental development.  Hum Genet . 2000;  107 433-439
• 33 Van Dyke L D, Wiktor A, Palmer C G. Ullrich-Turner syndrome with a small ring X chromosome and presence of mental retardation.  Am J Med Genet . 1992;  43 996-1005
• 34 Dennis N R, Collins A L, Crolla J A, Cockwell A E, Fisher A M, Jacobs P A. Three patients with ring (X) chromosomes and a severe phenotype.  J Med Genet . 1993;  30 482-486
• 35 Turner C, Dennis N R, Skuse D H, Jacobs P A. Seven ring (X) chromosomes lacking the XIST locus, six with an unexpectedly mild phenotype.  Hum Genet . 2000;  106 93-100
• 36 Collins A L, Cockwell A E, Jacobs P A, Dennis N R. A comparison of the clinical and cytogenetic findings in nine patients with a ring (X) cell line and 16 45,X patients.  J Med Genet . 1994;  31 528-533
• 37 El Abd S, Patton M A, Turk J, Hoey H, Howlin P. Social, communicational, and behavioral deficits associated with ring X Turner syndrome.  Am J Med Genet . 1999;  88 510-516
• 38 Kushnick T, Irons T G, Wiley J E, Gettig E A, Rao K W, Bowyer S. 45X/46X,r(X) with syndactyly and severe mental retardation.  Am J Med Genet . 1987;  28 567-574
• 39 Guttenbach M, Kohler J, Schmid M. Cytogenetic and molecular characterization of a small ring chromosome in the complex karyotype of a girl with Turner syndrome.  Hum Genet . 1991;  87 680-684
• 40 Grompe M, Rao N, Elder F F, Caskey C T, Greenberg F. 45,X/46,X,+r(X) can have a distinct phenotype different from Ullrich-Turner syndrome.  Am J Med Genet . 1992;  42 39-43
• 41 Cole H, Huang B, Salbert B A. Mental retardation and Ullrich-Turner syndrome in cases with 45,X/46X,+mar: additional support for the loss of the X-inactivation center hypothesis.  Am J Med Genet . 1994;  52 136-145
• 42 McGinniss M J, Brown D H, Burke L W, Mascarello J T, Jones M C. Ring chromosome X in a child with manifestations of Kabuki syndrome.  Am J Med Genet . 1997;  70 37-42
• 43 Kawame H, Hannibal M C, Hudgins L, Pagon R A. Phenotypic spectrum and management issues in Kabuki syndrome.  J Pediatr . 1999;  134 480-485
• 44 Migeon B R, Jeppesen P, Torchia B S. Lack of X inactivation associated with maternal X isodisomy: evidence for a counting mechanism prior to X inactivation during human embryogenesis.  Am J Hum Genet . 1996;  58 161-170
• 45 Guillen D R, Lowichik A, Schneider N R, Cohen D S, Garcia S, Zinn A R. Prune-belly syndrome and other anomalies in a stillborn fetus with a ring X chromosome lacking XIST.  Am J Med Genet . 1997;  70 32-36
• 46 Nowaczyk M J, Ramsay J A, Mohide P, Tomkins D J. Multi ple congenital anomalies in a fetus with 45,X/46,X,r(X) (p11.22q12) mosaicism.  Am J Med Genet . 1998;  77 306-309
• 47 Tsuchiya K, Reijo R, Page D C, Disteche C M. Gonadoblastoma: molecular definition of the susceptibility region on the Y chromosome.  Am J Hum Genet . 1995;  57 1400-1407
• 48 Wolff D J, Brown C J, Schwartz S, Duncan A M, Surti U, Willard H F. Small marker X chromosomes lack the X inactivation center: implications for karyotype/phenotype correlations.  Am J Hum Genet . 1994;  55 87-95
• 49 Jani M M, Torchia B S, Pai G S, Migeon B R. Molecular characterization of tiny ring X chromosomes from females with functional X chromosome disomy and lack of cis X inactivation.  Genomics . 1995;  27 182-188
• 50 Wong C, Kazazian H H, Stetten G, Earnshaw W C, Van Keuren L M, Antonarakis S E. Molecular mechanism in the formation of a human ring chromosome 21.  Proc Natl Acad Sci U S A . 1989;  86 1914-1918
• 51 McGinniss M J, Kazazian H H, Stetten G. Mechanisms of ring chromosome formation in 11 cases of human ring chromosome 21.  Am J Hum Genet . 1992;  50 15-28
• 52 Fang Y Y, Eyre H J, Bohlander S K. Mechanisms of small ring formation suggested by the molecular characterization of two small accessory ring chromosomes derived from chromosome 4.  Am J Hum Genet . 1995;  57 1137-1142
• 53 Yorifuji T, Muroi J, Kawai M. Uniparental and functional X disomy in Turner syndrome patients with unexplained mental retardation and X derived marker chromosomes.  J Med Genet . 1998;  35 539-544
• 54 Schinzel A A, Robinson W P, Binkert F, Torresani T, Werder E A. Exclusively paternal X chromosomes in a girl with short stature.  Hum Genet . 1993;  92 175-178
• 55 Quan F, Janas J, Toth-Fejel S, Johnson D B, Wolford J K, Popovich B W. Unparental disomy of the entire X chromosome in a female with Duchenne muscular dystrophy.  Am J Hum Genet . 1997;  60 160-165
• 56 Fryns J P, Kleczkowska A, Van Den Berghe H. High incidence of mental retardation in Turner syndrome patients with ring chromosome X formation.  Genet Couns . 1990;  1 161-165
• 57 Lindgren V, Chen C P, Bryke C R, Lichter P, Page D C, Yang-Feng T L. Cytogenetic and molecular characterization of marker chromosomes in patients with mosaic 45,X karyotypes.  Hum Genet . 1992;  88 393-398
• 58 Migeon B R, Luo S, Stasiowski B A. Deficient transcription of XIST from tiny ring X chromosomes in females with severe phenotypes.  Proc Natl Acad Sci U S A . 1993;  90 12025-12029
• 59 Latt S A. Microfluorometric detection of deoxyribonucleic acid replication in human metaphase chromosomes.  Proc Natl Acad Sci U S A . 1973;  70 3395-3399
• 60 Migeon B R, Luo S, Jani M, Jeppesen P. The severe phenotype of females with tiny ring X chromosomes is associated with inability of these chromosomes to undergo X inactivation.  Am J Hum Genet . 1994;  55 497-504
• 61 Allen R C, Zoghbi H Y, Moseley A B, Rosenblatt H M, Belmont J W. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation.  Am J Hum Genet . 1992;  51 1229-1239
• 62 Migeon B R, Ausems M, Giltay J. Severe phenotypes associated with inactive ring X chromosomes.  Am J Med Genet . 2000;  93 52-57
• 63 Callen D F, Eyre H J, Dolman G. Molecular cytogenetic characterisation of a small ring X chromosome in a Turner patient and in a male patient with congenital abnormalities: role of X inactivation.  J Med Genet . 1995;  32 113-116
• 64 Leppig K A, Brown C J, Bressler S L. Mapping of the distal boundary of the X-inactivation center in a rearranged X chromosome from a female expressing XIST.  Hum Mol Genet . 1993;  2 883-887
• 65 Walker C L, Cargile C B, Floy K M, Delannoy M, Migeon B R. The Barr body is a looped X chromosome formed by telomere association.  Proc Natl Acad Sci U S A . 1991;  88 6191-6195
• 66 Hansen R S, Stoger R, Wijmenga C. Escape from gene silencing in ICF syndrome: evidence for advanced replication time as a major determinant.  Hum Mol Genet . 2000;  9 2575-2587
• 67 Hansen R S, Canfield T K, Gartler S M. Reverse replication timing for the XIST gene in human fibroblasts.  Hum Mol Genet . 1995;  4 813-820
• 68 Matsuo M, Muroya K, Nanao K. Mother and daughter with 45,X/46,X,r(X)(p22.3q28) and mental retardation: analysis of the X-inactivation patterns.  Am J Med Genet . 2000;  91 267-272
• 69 Therman E, Susman B. The similarity of phenotypic effects caused by Xp and Xq deletions in the human female: a hypothesis.  Hum Genet . 1990;  85 175-183
• 70 James R S, Coppin B, Dalton P. A study of females with deletions of the short arm of the X chromosome.  Hum Genet . 1998;  102 507-516
• 71 Zinn A R, Tonk V S, Chen Z. Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1  Am J Hum Genet . 1998;  63 1757-1766
• 72 Carrozzo R, Arrigo G, Rossi E. Multiple congenital anomalies, brain hypomyelination, and ocular albinism in a female with dup(X) (pter→q24::q21.32→qter) and random X inactivation.  Am J Med Genet . 1997;  72 329-334
• 73 Matsuo M, Muroya K, Kosaki K. Random X-inactivation in a girl with duplication Xp11.21-p21.3: report of a patient and review of the literature.  Am J Med Genet . 1999;  86 44-50
• 74 Zinman B, Kabiawu S I, Moross T. Endocrine, cytogenetic and psychometric features of patients with X-isochromosome 46,X,i(Xq) Turner's syndrome: a preliminary study in nine patients.  Clin Invest Med . 1984;  7 135-141
• 75 Sullivan B A, Willard H F. Stable dicentric X chromosomes with two functional centromeres.  Nat Genet . 1998;  20 227-228
• 76 Dalton P, Coppin B, James R, Skuse D, Jacobs P. Three patients with a 45,X/46,X,psu dic(Xp) karyotype.  J Med Genet . 1998;  35 519-524
• 77 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: a review of 122 cases.  Am J Med Genet . 1992;  42 161-169
• 78 Jacobs P A, Hunt P A, Mayer M, Bart R D. Duchenne muscular dystrophy (DMD) in a female with an X/autosome translocation: further evidence that the DMD locus is at Xp21.  Am J Hum Genet . 1981;  33 513-518
• 79 Keitges E A, Palmer C G. Analysis of spreading of inactivation in eight X autosome translocations utilizing the high resolution RBG technique.  Hum Genet . 1986;  72 231-236
• 80 White W M, Willard H F, Van Dyke L D, Wolff D J. The spreading of X inactivation into autosomal material of an X/autosome translocation: evidence for a difference between autosomal and X-chromosomal DNA.  Am J Hum Genet . 1998;  63 20-28
• 81 Keohane A M, Barlow A L, Waters J, Bourn D, Turner B M. H4 acetylation, XIST RNA and replication timing are coincident and define x/autosome boundaries in two abnormal X chromosomes.  Hum Mol Genet . 1999;  8 377-383
• 82 El Abd E S, Wilson L, Howlin P, Patton M A, Wintgens A M, Wilson R. Agenesis of the corpus callosum in Turner syndrome with ring X.  Dev Med Child Neurol . 1997;  39 119-124
• 83 Cantu E S, Jacobs D F, Pai G S. An atypical Turner syndrome patient with ring X chromosome mosaicism.  Ann Clin Lab Sci . 1995;  25 60-65
• 84 Berkovitz G, Stamberg J, Plotnick L P, Lanes R. Turner syndrome patients with a ring X chromosome.  Clin Genet . 1983;  23 447-453
• 85 Lin C C, Meyne J, Sasi R. Determining the origins and the structural aberrations of small marker chromosomes in two cases of 45,X/46,X, + mar by use of chromosome-specific DNA probes.  Am J Med Genet . 1990;  37 71-78
• 86 Johnson V P, McDonough P G, Cheung S W, Sun L. Sex chromosome marker: clinical significance and DNA characterization.  Am J Med Genet . 1991;  39 97-101
• 87 Tharapel S A, Wilroy R S, Keath A M, Rivas M L, Tharapel A T. Identification of the origin of ring/marker chromosomes in patients with Ullrich-Turner syndrome using X and Y specific alpha satellite DNA probes.  Am J Med Genet . 1992;  42 720-723
• 88 Koch J, Kolvraa S, Hobolt N. A case of 46,XX,r(X) (p1q1) diagnosed by in situ hybridization.  Clin Genet . 1990;  37 216-220