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Causes of Fragile X Syndrome

What causes Fragile X syndrome?

Fragile X syndrome (FXS) is caused by a change (mutation) in a gene on the X chromosome. Genes contain codes, or recipes, for proteins. Proteins are very important biological components (parts) in all forms of life. The gene on the X chromosome that causes FXS is called the Fragile X Mental Retardation 1 (FMR1) gene. The FMR1 gene makes a protein that is needed for normal brain development. In FXS, the protein is not made. Please see About genes and mutations for more information.

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How is FXS different from other genetic disorders?

Most genetic disorders are caused by changes (mutations) in a gene that causes a change in the recipe for its protein. This causes the protein to be made incorrectly so that it does not work normally. Some genetic disorders are caused by making too much or too little of a protein due to a single change in the part of the gene that controls how much protein is made. FXS is one of a small class of genetic disorders, called trinucleotide repeat disorders, which is caused by a more complicated change in the gene. In the case of FXS, this complex change turns off the gene so no protein product is made.

DNA is made up of four chemical building blocks called nucleotides: A, C, T, and G (for more details, see About genes and mutations). Trinucleotide repeat disorders have a chain of three of these nucleotides that are repeated over and over again. In most people, the number of repeats is small. If the number of repeats is large, the gene does not work properly. In FXS, the pattern of CGG is repeated over and over again in the FMR1 gene, and when it reaches a certain number of repeats, the gene is turned off. A normal FMR1 gene has between about 6 and 45 CGG repeats. People with FXS have over 200 CGG repeats. When there are over 200 CGG repeats, this is referred to as a full mutation. The gene turns off because of a process called methylation. When the gene is turned off, no protein is made. Without the protein, the person develops FXS.

When the number of CGG repeats falls between the normal range and the full mutation, then a person is said to have a premutation (about 55-200 repeats). People who have a premutation do not have FXS because the FMR1 gene still works even with so many repeats. Until recently, people who carried the premutation were not thought to have any health problems related to FXS. However, in the past 10 years, researchers have discovered that both men and women who have a premutation may have specific health problems including nervous system disorders, infertility, and problems with learning and behavior.

When there are about 45 to 55 CGG repeats in the FMR1 gene, it is in the intermediate or gray zone range. People with intermediate or gray zone changes have a slightly higher chance of having learning disabilities.


Are full mutations the only cause of FXS?
Over 95% of people with FXS have a full mutation. However, a small number of people with FXS have a normal number of repeats. Instead, they have a small change (mutation) somewhere else in the FMR1 gene that causes a faulty protein to be made. Because the protein does not work, the symptoms are the same as in FXS due to full mutations, but it will run in families in a slightly different way. In these families, FXS will be inherited like other X-linked disorders (for more details, see About X-linked conditions).

There is also another gene that is very similar to FMR1. It is called FMR2 and it also makes a protein that is needed for brain development. Changes in the FMR2 gene are much less common, but they cause FXS-like intellectual disability, also known as mental retardation. FMR2 is also on the X chromosome, so FMR2 intellectual disability is inherited in families like other X-linked disorders (for more details, see About X-linked conditions). This means that intellectual disability caused by FMR2 changes run in the family in patterns similar to FXS. Therefore, families with FMR2 intellectual disability are sometimes mistakenly believed to have FXS.  Genetic testing can distinguish between the two conditions.