Diagnosis of Fragile X

Due to the variability of symptoms among patients, as well as some similarities with other conditions, genetic testing is the only method that allows for a conclusive diagnosis of fragile X syndrome.

Moreover, such DNA testing is reliable in identifying individuals who are carriers of fragile X, meaning they can pass the disease on to their children but generally suffer no ill effects from it themselves.

Fragile X is caused by low to no levels of the FMRP protein, which is involved in brain development. Mutations in the FMR1 gene, located on the X chromosome — one of the sex chromosomes, with the other being the Y chromosome — cause the disorder.

Genetic tests

A fragile X DNA test analyzes the FMR1 gene sequence to look for excessive repeats of three nucleotides — specifically, CGG — which are the cause of the disease in more than 99% of cases. Nucleotides are the building blocks of DNA, in which the C stands for cytosine and G for guanine.

While a healthy gene normally contains five to about 40 CGG repeats, the presence of more than 200 repeats is considered a full mutation. Such a full mutation is associated with methylation, a chemical modification that “turns off” the gene, leading to fragile X.

Notably, 55 to 200 CGG repeats are classified as a premutation, which does not cause the full disease but increases an individual’s risk of developing late-onset fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). FXTAS is more frequent and severe in males than females, while FXPOI affects only women.

Given that CGG repeats define the disease, genetic testing is highly reliable not only to confirm a fragile X diagnosis, but also to identify individuals with the premutation, known as carriers.

The DNA used for genetic testing is usually taken from the blood cells, generally acquired via a blood draw.

DNA testing can be performed with two different methods, Southern blot and polymerase chain reaction (PCR), with their combination resulting in the most accurate and reliable approach.

Southern blot analysis is the method of choice for identifying full mutations and large premutations and for determining whether the gene was “turned off” through methylation. It also evaluates whether a patient has a mixture of cells with and without the mutation.

PCR analysis can determine the actual number of CGG repeats, which is particularly helpful in allowing a more precise distinction between a normal FMR1 gene and a premutation.

Who should get tested?

Genetic testing should be conducted for the following patients:

  • Any male or female with symptoms suggestive of fragile X syndrome, such as intellectual disabilities, developmental delays, learning disabilities, speech and language delays, or autism or autistic-related features of unknown cause
  • Any adult older than 50 with features of FXTAS, including low-frequency tremors, impaired movement coordination, memory loss, cognitive decline, or personality change, especially in combination with a positive history of fragile X in the family
  • Any woman with symptoms suggesting FXPOI, such as irregular or absent menstrual cycles, infertility, high levels of FSH — a hormone involved in sexual development and functioning — and other menopause symptoms before 40 years of age
  • Anyone with a history of fragile X syndrome, fragile X-related disorders, intellectual or learning disabilities, autism, or infertility or premature menopause of unknown cause in the family, as well as those with blood relatives carrying the FMR1 premutation

Fragile X DNA testing also can be done before birth to see if an unborn baby has an FMR1 premutation or a full mutation. Such testing also can determine a person’s carrier status, which can aid in evaluate the individual’s chances of having a child affected by the disease.

Men who carry the premutation will pass it to all of their daughters — who will be carriers — but not to a son. That is because boys receive a Y sex chromosome from their fathers, instead of an X chromosome.

In turn, female carriers have a 50% chance of passing on the premutation — which can expand to the full mutation in cells that develop into eggs — to their children, who therefore may be either carriers or develop fragile X.


Last updated: April 9, 2021


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