How do genes cause Fragile X–associated disorders?

Fragile X syndrome and its associated conditions are caused by mutations, or changes, in the FMR1 gene. The mutation affects how the gene functions in making a specific protein called FMRP.

On a gene, the information for making a protein has two parts: the introduction and the instructions for making the protein itself. Researchers call the introduction the promoter because of how it helps start the process of building the protein.

The promoter part of the FMR1 gene normally includes many repeats—repeated instances of a trio of DNA bases called a triplet repeat—in this case, many copies of the CGG triplet repeat—to help build the protein.

The number of repeats in the promoter varies from person to person.

• People who do not have the FMR1 triplet repeat expansion usually have between 6 and 40 repeats in the promoter; the average is 30 repeats.
• People whose FMR1 gene has between 55 and 200 repeats have a premutation.
• People whose FMR1 gene has more than 200 repeats have a full mutation.

Effects of Premutations Versus Full Mutations

Premutations and full mutations in the promoter region of the FMR1 gene can have different effects.

Premutations can cause specific disorders taht aren't found in people with the full mutation:

• Women with a premutation may have Fragile X-associated primary ovarian insufficiency (FXPOI).²
• People with a premutation may also have Fragile X-associated tremor and ataxia syndrome.¹

The number of repeats in the promoter region also affects the severity of a person's symptoms of Fragile X syndrome:

• People with a premutation may have milder symptoms of Fragile X syndrome, or they may have no symptoms at all.³
• People with a full mutation are more likely to have intellectual and developmental disabilities and other symptoms of Fragile X syndrome.³

Parents who have a FMR1 premutation may have no symptoms but still pass along the premutation to their children. That means their children could have Fragile X-associated disorders, including FXPOI. Also, the premutation can expand when it's passed along, so that a child of a parent with a premutation could have Fragile X syndrome.