Multi-Telomere FISH

  • Samantha J. L. Knight
  • Jonathan Flint
Part of the Methods in Molecular Biology™ book series (MIMB, volume 204)


The standard investigation for suspected chromosomal rearrangements in patients is cytogenetic analysis at a 400–550 band resolution, yet this cannot routinely detect rearrangements smaller than 5 Megabases (Mb), and much larger abnormalities escape notice if they occur in regions where the banding pattern is not distinctive. In the future, this problem will largely be solved by the use of high resolution micro-arrays that will allow the entire genome to be investigated for submicroscopic chromosomal rearrangements. However, until this technology becomes routine, the only way of achieving increased reliability and resolution is to focus on specific chromosomal regions such as the ends of chromosomes (telomeres).


Wash Solution Heating Block Telomere Probe Spontaneous Recurrent Miscarriage Subtelomeric Rearrangement 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Saccone S., De Sario A., Della Valle G., and Bernardi G. (1992) The highest gene concentrations in the human genome are in telomeric bands of metaphase chromosomes. Proc. Natl. Acad. Sci. USA 89, 4913–4917.CrossRefPubMedGoogle Scholar
  2. 2.
    Altherr M. R., Bengtsson U., Elder F. F. B., et al. (1991) Molecular Confirmation Of Wolf-Hirschhorn Syndrome With a Subtle Translocation Of Chromosome-4. Am. J. Hum. Genet. 49, 1235–1242.PubMedGoogle Scholar
  3. 3.
    Kuwano A., Ledbetter S. A., Dobyns W. B., Emanuel B. S., and Ledbetter D. H. (1991) Detection of deletions and cryptic translocations in Miller-Dieker syndrome by in situ hybridization. Am. J. Hum. Genet. 49, 707–714.PubMedGoogle Scholar
  4. 4.
    Lamb J., Harris P. C., Wilkie A. O. M., Wood W. G., Dauwerse J. G., and Higgs D. R. (1993) De novo truncation of chromosome 16p and healing with (TTAGGG)n in the α-thalassemia/mental retardation syndrome (ATR-16). Am. J. Hum. Genet. 52, 668–676.PubMedGoogle Scholar
  5. 5.
    Overhauser J., Bengtsson U., McMahon J., et al. (1989) Prenatal diagnosis and carrier detection of a cryptic translocation by using DNA markers from the short arm of chromosome 5. Am. J. Hum. Genet. 45, 296–303.PubMedGoogle Scholar
  6. 6.
    Wilkie A. O. M., Lamb J., Harris P. C., Finney R. D., and Higgs D. R. (1990) A truncated chromosome 16 associated with α-thalassaemia is stablised by the addition of telomeric repeats (TTAGGG)n. Nature. 346, 868–871.CrossRefPubMedGoogle Scholar
  7. 7.
    Wong A. C. C, Ning Y., Flint J., et al. (1997) Molecular characterization of a 130-kb terminal microdeletion in a child with mild mental retardation. Am. J. Hum. Genet. 60, 113–120.PubMedGoogle Scholar
  8. 8.
    Brown W. R. A., MacKinnon P. J., Villasanté A., Spurr N., Buckle V. J., and Dodson M. J. (1990) Structure and polymorphism of human telomere-associated DNA. Cell 63, 119–132.CrossRefPubMedGoogle Scholar
  9. 9.
    Royle N. J., Baird D. M., and Jeffreys A. J. (1994) A subterminal satellite located adjacent to telomeres in chimpanzees is absent from the human genome. Nat. Genet. 6, 52–56.CrossRefPubMedGoogle Scholar
  10. 10.
    Weber B., Collins C., Robbins C., et al. (1990) Characterization and organization of DNA sequences adjacent to the human telomere associated repeat (TTAGGG)n. Nucl. Acids Res. 18, 3353–3361.CrossRefPubMedGoogle Scholar
  11. 11.
    Wilkie A. O. M., Higgs D. R., Rack K. A., et al. (1991) Stable length polymorphism of up to 260 kb at the tip of the short arm of human chromosome 16. Cell 64, 595–606.CrossRefPubMedGoogle Scholar
  12. 12.
    Cross S., Lindsey J., Fantes J., McKay S., McGill N., and Cooke H. (1990) The structure of a subterminal repeated sequence present on many human chromosomes. Nucl. Acids Res. 18, 6649–6657.CrossRefPubMedGoogle Scholar
  13. 13.
    Rouyer F., de la Chapelle A., Andersson M., and Weissenbach J. (1990) A interspersed repeated sequence specific for human subtelomeric regions. EMBO J. 9, 505–514.PubMedGoogle Scholar
  14. 14.
    Knight S. J. L., Horsley S. W., Regan R., et al. (1997) Development and clinical application of an innovative fluorescence in situ hybridization technique which detects submicroscopic rearrangements involving telomeres. Eur. J. Hum. Genet. 5, 1–8.PubMedGoogle Scholar
  15. 15.
    National Institutes of Health, Institute of Molecular Medicine Collaboration (1996) A complete set of human telomeric probes and their clinical application. Nat. Genet. 14, 86–89.CrossRefGoogle Scholar
  16. 16.
    Giraudeau F., Aubert D., Young I., et al. (1997) Molecular-cytogenetic detection of a deletion of 1p36.3. J. Med. Genet. 34, 314–317.CrossRefPubMedGoogle Scholar
  17. 17.
    Youngman S., Bates G., Williams S., et al. (1992). The telomeric 60 kb of chromosome arm 4p is homologous to telomeric regions on 13p, 15p, 21p and 22p. Genomics 14, 350–356.CrossRefPubMedGoogle Scholar
  18. 18.
    Wright T. J., Wijmenga C., Clark L. N., Frants R. R., Williamson R., and Hewitt J. E. Fine mapping of the FSHD gene region orientates the rearranged fragment detected by the probe p13E-11. Hum. Mol. Genet. 2, 1673–1678.Google Scholar
  19. 19.
    Riethman H. C., Spais C., Buckingham J., Grady D., and Moyzis R. K. (1993) Physical analysis of the terminal 240 kb of DNA from human chromosome 7q. Genomics 17, 25–32.CrossRefPubMedGoogle Scholar
  20. 20.
    Ning Y., Rosenberg M., Biesecker L. G., and Ledbetter D. H. (1996) Isolation of the human chromosome 22q telomere and its application to detection of cryptic chromosomal abnormalities. Hum. Genet. 97, 765–769.CrossRefPubMedGoogle Scholar
  21. 21.
    Nesslinger N. J., Gorski J. L., Kurczynski T. W., et al. (1994) Clinical, cytogenetic, and molecular characterization of seven patients with deletions of chromosome 22q13.3. Am. J. Hum. Genet. 54, 464–472.PubMedGoogle Scholar
  22. 22.
    Cooke H. J., Brown W. R., and Rappold G. A. (1985) Hypervariable telomeric sequences from the human sex chromosomes are pseudoautosomal. Nature 317, 687–692.CrossRefPubMedGoogle Scholar
  23. 23.
    Kvaloy K., Galvagni F., and Brown W. R. (1994) The sequence organization of the long arm pseudoautosomal region of the human sex chromosomes. Hum. Mol. Genet. 3, 771–778.CrossRefPubMedGoogle Scholar
  24. 24.
    Knight S. J., Lese C. M., Precht K. S., et al. (2000) An optimized set of human telomere clones for studying telomere integrity and architecture. Am. J. Hum. Genet. 67, 320–332.CrossRefPubMedGoogle Scholar
  25. 25.
    Knight S. J., Regan R., Nicod A., et al. (1999) Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet 354, 1676–1681.CrossRefPubMedGoogle Scholar
  26. 26.
    Brackley K. J., Kilby M. D., Morton J., Whittle M. J., Knight S. J., and Flint J. (1999) A case of recurrent congenital fetal anomalies associated with a familial subtelomeric translocation. Prenat. Diagn. 19, 570–574.CrossRefPubMedGoogle Scholar
  27. 27.
    de Vries B. B., Bitner-Glindzicz M., Knight S. J., et al. (2000) A boy with a submicroscopic 22qter deletion, general overgrowth and features suggestive of FG syndrome. Clin. Genet. 58, 483–487.CrossRefPubMedGoogle Scholar
  28. 28.
    Warburton P., Mohammed S., and Ogilvie C. M. (2000) Detection of submicroscopic subtelomeric chromosome translocations: a new case study. Am. J. Med. Genet. 6, 51–55.CrossRefGoogle Scholar
  29. 29.
    Bacino C. A., Kashork C. D., Davino N. A., and Shaffer L. G. (2000) Detection of a cryptic translocation in a family with mental retardation using FISH and telomere regionspecific probes. Am. J. Med. Genet. 92, 250–255.CrossRefPubMedGoogle Scholar
  30. 30.
    Praphanphoj V., Goodman B. K., Thomas G. H., and Raymond G. V. (2000) Cryptic subtelomeric translocations in the 22q13 deletion syndrome. J. Med. Genet. 37, 58–61.CrossRefPubMedGoogle Scholar
  31. 31.
    Knight-Jones E., Knight S., Heussler H., Regan R., Flint J., and Martin K. (2000) Neurodevelopmental profile of a new dysmorphic syndrome associated with submicroscopic partial deletion of 1p36.3. Dev. Med. Child Neurol. 4, 2201–2206.Google Scholar
  32. 32.
    Kleefstra T., van de Zande G., Merkx G., Mieloo H., Hoovers J. M., and Smeets D. (2000) Identification of an unbalanced cryptic translocation between the chromosomes 8 and 13 in two sisters with mild mental retardation accompanied by mild dysmorphic features. Eur. J. Hum. Genet. 8, 637–640.CrossRefPubMedGoogle Scholar
  33. 33.
    Vogels A., Devriendt K., Vermeesch J. R., et al. (2000) Cryptic translocation t(5;18) in familial mental retardation. Ann. Genet. 43, 117–123.PubMedGoogle Scholar
  34. 34.
    de Vries B. B. A., Knight S. J. L., Homfray T., Smithson S. F., Flint J., and Winter R. M. (2001) Submicroscopic subtelomeric 1qter deletions: a recognisable phenotype? J Med Genet. 38, 175–178.CrossRefPubMedGoogle Scholar
  35. 35.
    Viot G., Gosset P., Fert S., et al. (1999) Cryptic subtelomeric rearrangements detected by FISH in mentally retarded and dysmorphic patients. Am. J. Hum. Genet. 63, Supplement: A10.Google Scholar
  36. 36.
    Slavotinek A., Rosenberg M., Knight S., et al. (1999) Screening for submicroscopic chromosome rearrangements in children with idiopathic mental retardation using microsatellite markers for the chromosome telomeres. J. Med. Genet. 36, 405–411.PubMedGoogle Scholar
  37. 37.
    Rossi E., Piccini F., Zollino M., et al. (2001) Cryptic telomeric rearrangements in subjects with chromosomal phenotype and mental retardation. J. Med. Genet. 38, 417–420.CrossRefPubMedGoogle Scholar
  38. 38.
    Anderlid B., Annerén G., Blennow E., and Nordenskjöld M. (1998) Subtelomeric rearrangements detected by FISH in patients with idiopathic mental retardation. Am. J. Hum. Genet. 65, Suppl: A67.Google Scholar
  39. 39.
    Riegel M., Baumer A., Jamar M., et al. (2001) Submicropic terminal deletions and duplications in retarded patient with unclassified malformation syndromes. Hum. Genet. 109, 286–294.CrossRefPubMedGoogle Scholar
  40. 40.
    Colleaux L., Rio M., Heuertz S., et al. (2001) A Novel automated strategy for screening cryptic telomeric rearrangements in children with idiopathic mental retardation. Eur. J. Hum. Genet. 9, 319–327.CrossRefPubMedGoogle Scholar
  41. 41.
    Fan Y. S., Zhang Y., Speevak M., Farrell S., Jung H. J., and Siu V. M. (2001) Detection of submicroscopic aberrations in patients with unexplained mental retardation by fluorescence in situ hybridization using multiple subtelomeric probes. Genet. Med. 3, 416–421.CrossRefPubMedGoogle Scholar
  42. 42.
    Clarkson B., Pavenski K., Dupuis L., et al. (2002) Detecting rearrangements in children using subtelomeric FISH and SKY. Am. J. Med. Genet. 107, 267–274.CrossRefPubMedGoogle Scholar
  43. 43.
    Baker E., Hinton L., Callen D. F., et al. (2002) Study of 250 childrren with idiopathic mental retardation reveals nine cryptic and diverse subtelomeric chromosome anomalies. Am. J. Med. Genet. 107, 285–293.CrossRefPubMedGoogle Scholar
  44. 44.
    Lamb A. N., Lytle C. H., Aylsworth A. S., et al. (1998) Low proportion of subtelomeric rearrangements in a population of patients with mental retardation and dysmorphic features. Am. J. Hum. Genet. 65, Suppl: A169.Google Scholar
  45. 45.
    Vorsanova S. G., Koloti D., Sharonin V. O., Soloviev V., and Yurov Y. B. (1998) FISH analysis of microaberrations at telomeric and subtelomeric regions in chromosomes of children with mental retardation. Am. J. Hum. Genet. 65, Suppl: A154.Google Scholar
  46. 46.
    Joyce C. A., Hart H. H., Fisher A. M., and Browne C. E. (1999) Use of subtelomeric FISH probes to detect abnormalities in patients with idiopathic mental retardation and characterize rearrangements at the limit of cytogenetic resolution. J. Med. Genet. 36, Suppl: S16.Google Scholar
  47. 47.
    Ballif B. C., Kashork C. D., and Shaffer L. G. (2000) The promise and pitfalls of telomere region-specific probes. Am. J. Hum. Genet. 67, 1356–1359.PubMedGoogle Scholar
  48. 48.
    Anderlid B-M, Schoumans J., Annerén G., et al. (2002) Subtelomeric rearrangements detected in patients with idiopathic mental retardation. Am. J. Med. Genet. 107, 275–284.CrossRefPubMedGoogle Scholar
  49. 49.
    de Vries B. B., White S. M., Knight S. J., et al. (2001) Clinical studies on submicroscopic subtelomeric rearrangements: a checklist. J. Med. Genet. 38, 145–150.CrossRefPubMedGoogle Scholar
  50. 50.
    Knight S. J. and Flint J. (2000) Perfect endings: a review of subtelomeric probes and their use in clinical diagnosis. J. Med. Genet. 37, 401–409.CrossRefPubMedGoogle Scholar
  51. 51.
    Joyce C. A., Dennis N. R., Cooper S., and Browne C. E. (2001) Subtelomeric rearrangements: results from a study of selected and unselected probands with idiopathic mental retardation and control individuals by using high-resolution G-binding and FISH. Hum. Genet. 109, 440–451.CrossRefPubMedGoogle Scholar
  52. 52.
    Horsley S. W., Knight S. J. L., Nixon J., et al. (1998) Del(18p) shown to be a cryptic translocation using a multiprobe FISH assay for subtelomeric chromosome rearrangements. J. Med. Genet. 35, 722–726.Google Scholar
  53. 53.
    Brkanac Z., Cody J. D., Leach R. J., and DuPont B. R. (1998) Identification of cryptic rearrangements in patients with 18q-deletion syndrome. Am. J. Hum. Genet. 62, 1500–1506.CrossRefPubMedGoogle Scholar
  54. 54.
    Benzacken B., Monier-Gavelle F., Pierre Siffroi J., Agbo P., Chalvon A., and Philippe Wolf J. (2001) Acrocentric chromosome polymorphisms: beware of cryptic translocations. Prenat. Diagn. 21, 96–98.CrossRefPubMedGoogle Scholar
  55. 55.
    Tosi S., Scherer S. W., Giudici G., Czepulkowski B., Biondi A., and Kearney L. (1999) Delineation of multiple deleted regions in 7q in myeloid disorders. Gene. Chromosom. Canc. 25, 384–392.CrossRefGoogle Scholar
  56. 56.
    Tosi S., Giudici G., Rambaldi A., et al. (1999) Characterization of the human myeloid leukemia-derived cell line GF-D8 by multiplex fluorescence in situ hybridization, subtelomeric probes, and comparative genomic hybridization. Gene. Chromosom. Canc. 24, 213–221.CrossRefGoogle Scholar
  57. 57.
    Jaju R. J., Haas O. A., Neat M., et al. (1999) A new recurrent translocation, t(5;11)(q35;p15.5), associated with del(5q) in childhood acute myeloid leukemia. Blood 94, 773–780.PubMedGoogle Scholar
  58. 58.
    Foot N., Neat M. J., Kearney L et al. (1999) Multiple FISH technology to clarify abnormal leukaemic karyotypes. J. Med. Genet. 36, S38.Google Scholar
  59. 59.
    Wakui K., Tanemura M., Suzumori K., Hidaka E., Ishikawa M., Kubota T., et al. (1999) Clinical applications of two-color telomeric fluorescence in situ hybridization for prenatal diagnosis: identification of chromosomal translocation in five families with recurrent miscarriages or a child with multiple congenital anomalies. J. Hum. Genet. 44, 85–90.CrossRefPubMedGoogle Scholar
  60. 60.
    Scriven P. N., Handyside A. H., and Ogilvie C. M. (1998) Chromosome translocations: segregation modes and strategies for preimplantation genetic diagnosis. Prenat. Diagn. 18, 1437–1449.CrossRefPubMedGoogle Scholar
  61. 61.
    Handyside A. H., Scriven P. N., and Ogilvie C. M. (1998) The future of preimplantation genetic diagnosis. Hum. Reprod. 13Suppl 4, 249–255.PubMedGoogle Scholar
  62. 62.
    Mackie-Ogilvie C., Harrison R. H., Handyside A. H., and Scriven P. N. (1999) The use of subtelomeric probes in preimplantation genetic diagnosis. J. Med. Genet. 36, Supplement: S15.Google Scholar
  63. 63.
    Lese C. M., Zhang X., Pinkel D., et al. (1999) Comparative genomic hybridization arrays: Towards a “telomere chip.” Am. J. Hum. Genet. 65, 41.Google Scholar
  64. 64.
    Ghaffari S. R., Boyd E., Tolmie J. L., Crow Y. J., Trainer A. H., and Connor J. M. (1998) A new strategy for cryptic telomeric translocation screening in patients with idiopathic mental retardation. J. Med. Genet. 35, 225–233.CrossRefPubMedGoogle Scholar
  65. 65.
    Rosenberg M. J., Vaske D., Killoran C. E., et al. (2000) Detection of chromosomal aberrations by a whole-genome microsatellite screen. Am. J. Hum. Genet. 66, 419–427.CrossRefPubMedGoogle Scholar
  66. 66.
    Borgione E., Giudice M. L., Galesi O., et al. (2001) How microsatellite analysis can be exploited for subtelomeric chromosomal rearrangement analysis in mental retardation. J. Med. Genet. 38, E1.CrossRefPubMedGoogle Scholar
  67. 67.
    Rosenberg M. J., Killoran C., Dziadzio L., et al. (2001) Scanning for telomeric deletions and duplications and uniparental disomy using genetic markers in 120 children with malformations. Hum. Genet. 109, 311–318.CrossRefPubMedGoogle Scholar
  68. 68.
    Armour J. A., Sismani C., Patsalis P. C., and Cross G. (2000) Measurement of locus copy number by hybridisation with amplifiable probes. Nucl. Acids Res. 28, 605–609.CrossRefPubMedGoogle Scholar
  69. 69.
    Sismani C., Armour J. A., Flint J., Girgallia C., Regan R., and Patsalis P. C. (2001) Screening for subtelomeric chromosome abnormalities in children with idiopathic mental retardation using the multiprobe telomere FISH and the new MAPH telomeric assays. Eur. J. Hum. Genet. 9, 527–532.CrossRefPubMedGoogle Scholar
  70. 70.
    Granzow M., Popp S., Keller M., et al. (2000) Multiplex FISH telomere integrity assay identifies an unbalanced cryptic translocation der(5)t(3;5)(q27;p15.3) in a family with three mentally retarded individuals. Hum. Genet. 107, 51–57.CrossRefPubMedGoogle Scholar
  71. 71.
    Brown J., Saracoglu K., Uhrig S., Speicher M. R., Eils R., and Kearney L. (2001) Subtelomeric chromosome rearrangements are detected using an innovative 12-color FISH assay (M-TEL). Nat. Med. 7, 497–501.CrossRefPubMedGoogle Scholar
  72. 72.
    Brown J., Horsley S. W., Jung C., et al. (2000) Identification of a subtle t(16;19)(p13.3;p13.3) in an infant with multiple congenital abnormalities using a 12-colour multiplex FISH telomere assay, M-TEL. Eur. J. Hum. Genet. 8, 903–910.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2002

Authors and Affiliations

  • Samantha J. L. Knight
    • 1
  • Jonathan Flint
    • 2
  1. 1.John Radcliffe HospitalHeadingtonUK
  2. 2.Welcome Trust Center for Human GeneticsChurchill HospitalHeadingtonUK

Personalised recommendations