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Paediatric Laboratory Medicine
Paediatric Laboratory Medicine
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Fragile X Syndrome

Background
Who should be tested?
Testing Methodology
Potential Outcomes & Interpretation of Test Results
Cautions
For More Information

Background

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 mental retardation, 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 mentally retarded 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.

Who should be tested

  • individuals with a family history of Fragile X Syndrome, to determine the carrier status of unaffected individuals
  • a boy or girl with mental retardation or developmental delay of unknown etiology consistent with Fragile X Syndrome
  • a relative of an individual with a confirmed or possible diagnosis of Fragile X Syndrome

Testing Methodology

Direct Mutation Analysis: PCR and Southern blot analysis across the CGG repeat is used to measure the number of repeats in the FMR-1 gene and to determine if the region is abnormally methylated.

Test Sensitivity: Expansion of the FMR-1 repeat occurs in 99 per cent of individuals affected with Fragile X Syndrome. These cases will be detected by current testing procedures in place in the Molecular Genetics Laboratory.

Approximately one per cent of fragile X cases are caused by other types of mutations in the FMR-1 gene. These cases will not be diagnosed by this analysis.

Potential Outcomes & Interpretation of Test Results

FMR-1 Repeat Size

Expansion Range

Explanation

6-44

normal

  • This result does not support a diagnosis of Fragile X syndrome.

45-54

intermediate

  • This repeat does not cause disease. Although alleles of this size may be associated with Fragile X syndrome in future generations, there is no increased risk of an affected child in the next generation.

55-200

premutation

  • This repeat size is found in carrier mothers & normal transmitting males; the individual is not usually affected but may transmit the Fragile X syndrome to offspring.

Greater than 200

full mutation

  • This result supports a diagnosis of Fragile X syndrome.

Cautions

  • Up to one per cent of cases of Fragile X Syndrome do not show expansion within the FMR-1 gene. These cases will not be detected by the methodology in place in the Molecular Genetics Laboratory. Identification of these cases is important for the assessment of carrier status. Therefore, the presence of a CGG repeat expansion in an affected family member should be identified before carrier testing.
  • FMR-1 repeat sizes in the high normal to intermediate expansion range may be stably transmitted without change in some families or may increase in size from one generation to the next. Analysis of multiple family members may be necessary in order to distinguish between these two possibilities.
  • Due to the variable expression of the mutation, the test is not reliable for prenatal assessment of severity of disease. The clinical course or severity of symptoms cannot be predicted by molecular analysis.
  • This test will not identify other chromosome abnormalities that may play a role in developmental delay. Additional cytogenetic studies are indicated unless there is a documented history of Fragile X Syndrome in the patient's family.
  • This test was developed and its performance characteristics validated by the Molecular Genetics Laboratory at the Hospital for Sick Children. It has not been clear approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes.

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