Basic Facts About the Genetics of Fragile X
By Hilary Rosselot
Think back to your high school biology class when you were drawing Punnett squares and learning the basics of genetics. You may have been introduced to genetic conditions like Down syndrome and, if you were lucky, Fragile X.
Fragile X is one of the more complicated conditions to explain, and we frequently get questions about the biology and genetics that make up Fragile X. We’re going to assume the unique details about Fragile X were not covered in biology class. Here are seven basic facts about the genetics of Fragile X:
1. Everyone has the FMR1 gene.
Everyone has an FMR1 gene on each of their X chromosomes. In the DNA of the FMR1 gene, there’s a repeated sequence of chemical bases known by the letters CGG. This sequence repeats multiple times and most people have fewer than 55 copies of the CGG repeat.
2. The FMR1 gene makes the Fragile X protein.
The FMR1 gene makes a very important protein called FMRP (fragile X messenger ribonucleoprotein) that is found in all of our cells and performs very specific tasks. This protein is especially important for brain development.
Fragile X is caused by an atypical expansion in the DNA of the FMR1 gene, which can impact our body’s ability to make this important protein.
3. Fragile X is X-linked.
This means the FMR1 gene is on the X chromosome. Males have one X and one Y chromosome and females have two X chromosomes. Fragile X is inherited in an X-linked dominant pattern. Typically, girls have two copies of the gene and boys have one, however, a single copy of the gene difference (increase in CGG repeat number) is enough to cause Fragile X in both males and females.
4. Fragile X status is determined by the CGG repeat number.
In testing for Fragile X, we look at the CGG repeats in the DNA of the gene. You can learn your Fragile X status by a simple DNA blood test that measures your CGG repeats. There are several categories that test results fall into:
- Typical or Non-Fragile X: Typical as in “most people,” with non-Fragile X meaning less than 45 CGG repeats.
- Intermediate or Gray Zone: 45–54 CGG repeats
- Fragile X Premutation: 55–200 CGG repeats
- Fragile X Full Mutation: Over 200 CGG repeats
Note: Girls typically have 2 repeat numbers and boys have 1 number. Fragile X syndrome is not known to be more severe with a higher repeat number. For example, we would not expect someone with a CCG repeat of 700 to be more affected than someone with a repeat number of 205.
5. Fragile X is a genetic diagnosis that is hereditary.
Fragile X is genetic, meaning it is caused by a change in the gene. Fragile X is also hereditary, meaning that this gene change can be passed from one generation to the next.
6. “Fragile X” includes a group of conditions — it’s not just one.
Fragile X syndrome (FXS) is caused by a full mutation (over 200 CGG repeats) of the FMR1 gene and is considered a rare disease (less than 200,000 individuals in the U.S. have this diagnosis). Fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI) are different conditions that can affect individuals who have a Fragile X premutation (55–200 CGG repeats). Additional conditions associated with the Fragile X premutation are being further researched.
7. The term “Fragile X carrier” is a misnomer.
In other genetic conditions, being a carrier of that condition means the individual “carries” the condition, that is, they may pass that condition to other generations but are asymptomatic themselves (not at risk for nor has symptoms of the condition). For most conditions, both biological parents need to be carriers with both passing it on for the condition to be present in their child.
Fragile X is different. In Fragile X, only one of the biological parents needs to have an atypical expansion of CGG repeats in the FMR1 gene to pass on Fragile X. (Check out this short, two-minute video that helps explain how the Fragile X premutation or full mutation is passed on to sons and daughters.)