The clinical significance of fragile sites on human chromosomes

Abstract

Fragile X syndrome is now a well established common clinical entity and most of those who are aware of the condition probably know that it takes its name from a rare fragile site (FRAXA) on the X chromosome. This is the best known fragile site and its clinical significance is clear. Similar, but a little less known is FRAXE, a fragile site close to that associated with fragile X syndrome, but in this case associated with a mild form of non-specific X-linked mental retardation. These are the only two fragile sites that are unequivocally of clinical significance. A fragile site within the CBL2 oncogene on chromosome 11 has been mapped very close to the deletion breakpoint in a handful of patients with Jacobsen syndrome. It is doubtful that parents with FRA11B are at increased risk of having children with Jacobsen syndrome, but this cannot be ruled out. The common fragile sites have been implicated in oncogenesis since shortly after their discovery in the early 1980s. While a couple of these are within genes that have been implicated in cancer it is unclear whether either the fragile sites, or the genes in which they are located are important in cancer. It may be that the common fragile sites are regions of genomic instability and that this instability is increased in malignant cells, analogous to the enhanced instability seen at microsatellite loci in a number of tumours. Since we all have the common fragile sites there is no suggestion that they give anyone an increased risk of developing malignant disease. In dealing with patients who are found to have fragile sites, other than FRAXA, FRAXE and possibly FRA11B, considerable reassurance can be given that they are not at increased risk of having children with congenital disease or developing disease themselves because of their fragile sites.

Chromosomal abnormalities and mental illness

“…It is therefore possible that these fragile sites either represent artefacts or are coincidental findings of no clinical significance. 90 …”

Premature condensation induces breaks at the interface of early and late replicating chromosome bands bearing common fragile sites

“…Their activation also triggers and drives intrachromosomal gene amplification (18). In tumors, with a few exceptions suggesting a relationship with inherited diseases (13,19,20), AphS were essentially correlated with somatic events leading to deletions, translocations (1)(2)(3)(4), and oncogene amplification (21,22). The physiological impact on tumor development of deletions targeting AphS was best demonstrated by FRA3B, which encompasses the FHIT gene (23).…”

“…A statistical correlation has been established between genome remodeling and DNA breaks at chromosomal sequences termed common fragile sites (1)(2)(3)(4). Cytogenetically, these sites appear as loci displaying recurrent breaks, gaps, or constrictions (BGCs) in cells grown under specific tissue culture conditions (5), notably exposure to various mutagens and carcinogens (6).…”

Predominance of constitutional chromosomal rearrangements in human chromosomal fragile sites

“…Supporting this association in vitro is the fact that following induction of the fragile site, a proportion of cells from individuals with rare fragile sites are found to have various duplications or deletions of material distal to the fragile site [21]. This is considered to be the result of breakage at the fragile site followed by nondisjunction of the distal chromosomal material [21]. Also, common fragile sites have been shown to display a number of characteristics of unstable and highly recombinogenic DNA in vitro, including chromosome rearrangements [22].…”

“…Both types of fragile sites display common molecular characteristics associated with chromosomal rearrangements, both in vitro and in vivo (for review see [4]). Supporting this association in vitro is the fact that following induction of the fragile site, a proportion of cells from individuals with rare fragile sites are found to have various duplications or deletions of material distal to the fragile site [21]. This is considered to be the result of breakage at the fragile site followed by nondisjunction of the distal chromosomal material [21].…”