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Subtelomeric chromosome rearrangements are detected using an innovative 12-color FISH assay (M-TEL)

Nature Medicine volume 7, pages 497–501 (2001)Cite this article

Human chromosome telomeres are important for maintaining chromosome structure and function1. The adjacent subtelomeric chromosome regions are transcriptionally active, GC-rich and contain a high density of CpG islands and genes2,3. In addition, the frequency of genetic recombination increases towards the telomeres4. These features are reflected in the finding that telomeric chromosome rearrangements are common in a number of genetic diseases5. The detection of subtle chromosome rearrangements involving telomeric regions poses a particular problem for diagnostic cytogenetics. Conventional cytogenetic analysis relies on the interpretation of a monochrome G-banding pattern; however, the telomeric chromosome regions are usually G-band negative and small deletions or translocations with other chromosomal telomeric regions may be almost impossible to discriminate. Nevertheless, there is mounting evidence that many apparently normal karyotypes may contain subtle (cryptic) deletions or translocations involving telomeres, particularly in clinical referrals featuring mental retardation6,7. Similarly, an increasing number of studies report cryptic telomeric chromosome rearrangements in hematological malignancies8,9,10.

One approach to the accurate detection of chromosome abnormalities is the use of fluorescence in situ hybridization (FISH) with specific gene probes11. FISH is now a successful adjunct to conventional cytogenetic diagnosis, but requires a pre-existing knowledge of the region likely to be affected. Whole-genome screening is provided by the 24-color karyotyping methods multiplex FISH (M-FISH)12 and spectral karyotyping (SKY)13. However, the resolution of these whole-chromosome–painting techniques for subtle chromosome rearrangements is limited14,15. Similarly, comparative genomic hybridization (CGH) to metaphase chromosomes can only detect deletions of 10 Mb, based on approximately 80% of cells carrying the deletion16.

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Figure 1: Combinatorial labeling scheme for the M-TEL assay.
Figure 2: Color classification (goldFISH) analysis of the telomeric signals in metaphases from patient 3.
Figure 3: MacProbe v4.1 analysis of telomeric signals in metaphases from patient 3.
Figure 4: Color classification (goldFISH) analysis of bone-marrow metaphases with trisomy 8 from an AML patient.

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Acknowledgements

We thank J. Flint and S. Knight for supplying the second-generation subtelomeric probes; V. Buckle for critical reading of the manuscript; and M. Schulze for modifications to the MacProbe v4.1 software. This work was supported in part by the Leukaemia Research Fund, UK (to J.B.) and the Medical Research Council (to L.K). R.E. was supported by the German Minister for Education and Research (BMBF, BioFuture grant AZ 11880), the Deutsche Forschungsgemeinschaft (Ja 395/6-2; Ei-358/1-1) and the German-Israeli foundation for research and technology (GIF G-112-207.04/97).

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Authors and Affiliations

  1. MRC Molecular Haematology Unit, Institute of Molecular Medicine, Oxford, UK

    Jill Brown & Lyndal Kearney

  2. Interdisciplinary Center of Scientific Computing, University of Heidelberg, Germany

    Kaan Saracoglu & Roland Eils

  3. Institute for Anthropology and Human Genetics, University of Munich, Germany

    Sabine Uhrig & Michael R. Speicher

  4. Intelligent Bioinformatics Systems, German Cancer Research Center, Heidelberg, Germany

    Kaan Saracoglu & Roland Eils

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  1. Jill Brown
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Correspondence to Lyndal Kearney.

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Brown, J., Saracoglu, K., Uhrig, S. et al. Subtelomeric chromosome rearrangements are detected using an innovative 12-color FISH assay (M-TEL). Nat Med 7, 497–501 (2001). https://doi.org/10.1038/86581

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