Fragile Sites and Human Disease

Abstract

Abstract 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.