Fragile X Syndrome

Fragile X syndrome is an X-linked disorder with variable expression in carrier males and females. It is more severe in males than in females, although females are more likely to transmit the disease to their children. Affected males usually have intellectual disability, behaviour problems and speech and language delays. They may also have a number of physical characteristics of the syndrome. Approximately 35 per cent of females who carry the mutation are intellectually delayed to varying degrees, although usually less than affected males. Many show emotional and problem solving difficulties as well as learning disabilities.

The gene responsible for Fragile X Syndrome is called FMR-1 and is located on the X chromosome. The normal gene contains a three base pair sequence, which is repeated on each X chromosome (called a CGG repeat). Although variable in the general population, the number of repeats is usually inherited without change from generation to generation. The principal mutation causing Fragile X Syndrome is an expansion of the CGG repeat sequence within the FMR-1 gene. The mutation is also associated with abnormal methylation of the FMR-1 gene. Methylation interferes with normal FMR-1 gene expression, resulting in the Fragile X phenotype.

In normal individuals the number of CGG repeats within the FMR-1 gene ranges in size from six to 44 repeats, whereas patients affected with the Fragile X Syndrome show expansion ranges greater than 200 repeats (full mutation). Expansions in the number of repeats between 55 to 200 are called premutations and usually do not result in any symptoms of Fragile X in females or in males (called 'carrier females' and 'transmitting males'). However, premutations are unstable and may expand further when transmitted to offspring, resulting in a full mutation and Fragile X Syndrome. Expansions of 45-54 repeats are considered intermediate. Alleles in this range are stable in some families but unstable in others and may lead to premutations in subsequent generations. In approximately one per cent of Fragile X cases, point mutations or deletions, rather than expansions, in the FMR-1 gene are the cause of the syndrome.

See related information sheet: FMR1-Related Disorders