Paediatric Laboratory Medicine
Paediatric Laboratory Medicine


Who should be tested?
Testing Methodology
Potential Outcomes & Interpretation of Test Results
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FRAXE is a cytogenetically visible fragile site located at Xq28 that has been reported to be associated with mild mental handicap in fragile site-positive individuals. The FRAXE phenotype is quite variable, and tends to include slow learning, hyperactivity, and language delay.

The gene associated with FRAXE is called FMR-2 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 CCG repeat). Although variable in the general population, the number of repeats is usually inherited without change from generation to generation. The principal mutation causing FRAXE is an expansion of the CCG repeat sequence within the FMR-2 gene. The mutation is also associated with abnormal methylation of the FMR-2 gene. Methylation interferes with normal FMR-2 gene expression, resulting in the FRAXE phenotype.

In normal individuals the number of CCG repeats within the FMR-2 gene ranges in size from 6-30 repeats, whereas patients affected with FRAXE show expansion ranges greater than 200 repeats (full mutation). Expansions in the number of repeats between 61 to 200 are called premutations and usually do not result in any symptoms of FRAXE 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 the FRAXE phenotype. Expansions of 31-60 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.

Who should be tested

  • Any boy or girl with mental retardation or developmental delay with unknown etiology who was found to be negative for the fragile X syndrome.
  • Any relative of an individual with mental retardation, developmental delay or autism.

Testing Methodology

  • Direct Analysis: PCR and/or Southern blot analysis across the (CCG)n repeat of the FMR-2 gene is used to detect an expansion at the FRAXE locus.
  • Test Sensitivity: Expansion of the FMR-2 repeat occurs in over 99 per cent of individuals affected with an expansion at the FRAXE locus. These cases will be detected by current testing procedures in place in the Molecular Genetics Laboratory.

Potential Outcomes & Interpretation of Test Results

FMR-2 (CCG)n
Repeat Size





  • This patient does not have an expansion at the FRAXE locus.



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



  • This repeat size is found in carrier mothers; the individual is not usually affected but may transmit the FRAXE expansion to offspring.


full mutation

  • This patient does have an expansion at the FRAXE locus.


  • FMR-2 repeat sizes in the inconclusive expansion range may be found in normal individuals, but indicate a premutation in others. Analysis of multiple family members may be necessary in order to distinguish between these two possibilities.
  • 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 family history of FRAXE 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 cleared or 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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