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Chromosome instability syndromes

Nature Reviews Disease Primers volume 5, Article number: 64 (2019) Cite this article

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Abstract

Fanconi anaemia (FA), ataxia telangiectasia (A-T), Nijmegen breakage syndrome (NBS) and Bloom syndrome (BS) are clinically distinct, chromosome instability (or breakage) disorders. Each disorder has its own pattern of chromosomal damage, with cells from these patients being hypersensitive to particular genotoxic drugs, indicating that the underlying defect in each case is likely to be different. In addition, each syndrome shows a predisposition to cancer. Study of the molecular and genetic basis of these disorders has revealed mechanisms of recognition and repair of DNA double-strand breaks, DNA interstrand crosslinks and DNA damage during DNA replication. Specialist clinics for each disorder have provided the concentration of expertise needed to tackle their characteristic clinical problems and improve outcomes. Although some treatments of the consequences of a disorder may be possible, for example, haematopoietic stem cell transplantation in FA and NBS, future early intervention to prevent complications of disease will depend on a greater understanding of the roles of the affected DNA repair pathways in development. An important realization has been the predisposition to cancer in carriers of some of these gene mutations.

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Fig. 1: Repair of DNA interstrand crosslinks.
Fig. 2: DNA double-strand break repair.
Fig. 3: DNA end resection of the 5′ end.
Fig. 4: Dissolution of double Holliday junctions.
Fig. 5: Characteristic features of the chromosome instability syndromes.
Fig. 6: The natural history of the chromosome breakage disorders.

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Acknowledgements

Fanconi anaemia studies in the laboratory of A.S. are supported by RO1HL120922 and R01CA204127. A.S. is a Howard Hughes Medical Institute faculty scholar.

Author information

Authors and Affiliations

  1. Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK

    A. Malcolm R. Taylor & Grant S. Stewart

  2. A-T Children’s Project, Coconut Creek, FL, USA

    Cynthia Rothblum-Oviatt

  3. The University of Arizona Cancer Center, Tucson, AZ, USA

    Nathan A. Ellis

  4. Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark

    Ian D. Hickson

  5. Stem Cell and Leukaemia Proteomics Laboratory, and Paediatric and Adolescent Oncology, Institute of Cancer Sciences, University of Manchester, Manchester, UK

    Stefan Meyer

  6. Department of Paediatric and Adolescent Haematology and Oncology, Royal Manchester Children’s Hospital and The Christie NHS Trust, Manchester, UK

    Stefan Meyer

  7. Department of Neurology and Pediatrics, Johns Hopkins University, Baltimore, MD, USA

    Thomas O. Crawford

  8. Laboratory of Genome Maintenance, Rockefeller University, New York, NY, USA

    Agata Smogorzewska

  9. Department of Immunology, The Children’s Memorial Health Institute, Warsaw, Poland

    Barbara Pietrucha

  10. Department of Pediatrics (Pediatric Immunology), Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, Netherlands

    Corry Weemaes

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Contributions

Introduction (A.M.R.T.); epidemiology (A.M.R.T., N.A.E., I.D.H., S.M., C.R.-O. and C.W.); mechanisms/pathophysiology (N.A.E., I.D.H., A.S. and G.S.S.); diagnosis, screening and prevention (T.O.C., N.A.E., I.D.H., S.M., B.P., C.R.-O. and C.W.); management (T.O.C., N.A.E., I.D.H., S.M., B.P., C.R.-O. and C.W.); quality of life (T.O.C., N.A.E., I.D.H., S.M., B.P., C.R.-O. and C.W.); outlook (T.O.C., N.A.E., I.D.H., S.M., B.P., C.R.-O. and C.W.); overview of the Primer (A.M.R.T.).

Corresponding author

Correspondence to A. Malcolm R. Taylor.

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The authors declare no competing interests.

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Informed consent

The authors affirm that human research participants provided informed consent (by their guardians) for publication of the images in Figure 5.

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Nature Reviews Disease Primers thanks P. Andreassen, A. Di Masi, M. Grompe, M. Lavi, S. Sharma and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Taylor, A.M.R., Rothblum-Oviatt, C., Ellis, N.A. et al. Chromosome instability syndromes. Nat Rev Dis Primers 5, 64 (2019). https://doi.org/10.1038/s41572-019-0113-0

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