Fragile Sites and Human Disease


Fragile sites are the cytogenetic manifestation of a peculiar genome structure. Two fundamentally different types occur: rare fragile sites that are characterized by repeat expansion and common fragile sites that consist of AT (adenine/thymidine)‐rich regions which may stretch over megabases and that are prone to chromosomal rearrangements. In contrast to common fragile sites that are presumably present in all individuals, rare fragile sites are found in maximally 5% of the population. A relationship between the rare fragile site at Xq27.3 and fragile X syndrome, the most common form of inherited mental retardation has been well established. In addition, causative genomic rearrangements within the two most frequently observed common fragile sites in specific tumours were demonstrated. Currently, more than 100 different fragile sites have been described and a potential role for additional fragile sites in human disease, including mental retardation, neurodegeneration, cancer and chromosome truncation syndromes, is emerging.

Key concepts

  • Fragile sites are the cytogenetic expression of a peculiar genome architecture.

  • Rare fragile sites are caused by repeat expansion.

  • Common fragile sites consist of large genomic AT‐rich ‘flexible’ regions, without repeat expansion.

  • Rare fragile sites may be associated with mental retardation and neurodegeneration.

  • Common fragile sites are associated with chromosomal rearrangements in tumour cells.

  • Fragile sites may be involved in chromosome breakage.

Keywords: fragile sites; mental retardation repeat expansion; neurodegeneration; cancer

Figure 1.

Overview of all chromosomal fragile sites as listed in the NCBI map viewer. Common fragile sites are indicated with arrows to the left of the chromosome, rare fragile sites with arrows to the right of the chromosome.

Figure 2.

Examples of the recently cloned fragile sites FRA11A and FRA18C, visualized after direct Giemsa staining of the metaphase chromosomes.

Figure 3.

The average cytogenetic expression of the fragile site FRA12A in mentally handicapped patients and nonretarded carriers. Data are taken from Winnepenninckx et al..

Figure 4.

A compilation of five cytogenetic studies comparing the frequency of fragile sites between a population of the mentally handicapped and controls. Only established autosomal, rare, folate‐sensitive fragile sites listed in Table are included for comparison. Data are taken from Chudley et al., Kähkönen et al., Mavrou et al. and Sutherland .



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Further Reading

Gécz J and Sutherland GR (eds) (2003) Nucleotide and Protein Expansions and Human Disease. Basel, Switzerland: S. Karger AG.

Hagerman RJ and Hagerman PJ (eds) (2002) Fragile X Syndrome: Diagnosis, Treatment and Research. Baltimore, MA: Johns Hopkins University Press.

Kooy RF, Oostra BA and Willems PJ (1998) The fragile X syndrome and other fragile site disorders. Results and Problems in Cell Differentiation 21: 1–46.

Sutherland GR and Hecht F (1985) Fragile Sites on Human Chromosomes. New York: Oxford University Press.

Wells RD and Ashizawa T (eds) (2006) Genetic Instabilities and Neurological Diseases, 2nd edn, Burlington, MA: Academic Press.

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Frank Kooy, R(Mar 2009) Fragile Sites and Human Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021457]