Introduction

The genetic disorder Fragile X syndrome, which results from mutations in a gene on the X chromosome, is the most commonly inherited form of developmental and intellectual disability.

NICHD supports and conducts research on the diagnosis, treatment, management, prevention, and inheritance of Fragile X and its associated conditions, Fragile X-Associated Primary Ovarian Insufficiency (FXPOI) and Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). All three conditions result from changes in the same gene on the X chromosome.

About Fragile X Syndrome

Fragile X syndrome is a genetic disorder that affects a person’s development, especially that person’s behavior and ability to learn. In addition, Fragile X can affect:

Communication skills
Physical appearance
Sensitivity to noise, light, or other sensory information

Fragile X syndrome is the most common form of inherited intellectual and developmental disability (IDD).

People with Fragile X syndrome may not have noticeable symptoms, or they can have more serious symptoms that range from learning disabilities to cognitive and behavior problems.

What causes Fragile X syndrome?

Fragile X results from a change or mutation in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, which is found on the X chromosome. The gene normally makes a protein, called FMRP, that is important for creating and maintaining connections between cells in the brain and nervous system. The mutation causes the body to make only a little bit or none of the protein, which often causes the symptoms of Fragile X.

Not everyone with the mutated FMR1 gene has symptoms of Fragile X syndrome, because the body may still be able to make FMRP. A few things affect how much FMRP the body can make:

The size of the mutation. Some people have a smaller mutation (a lower number of repeats) in their FMR1 gene, while others have big mutations (a large number of repeats) in the gene. If the mutation is small, the body may be able to make some of the protein. Having the protein available makes the symptoms milder.
The number of cells that have the mutation. Because not every cell in the body is exactly the same, some cells might have the FMR1 mutation while others do not. This situation is called mosaicism. If the mutation is in most of the body’s cells, the person will probably have symptoms of Fragile X syndrome. If the mutation is in only some of the cells, the person might not have any symptoms at all or only mild symptoms.
Being female. Females have two X chromosomes (XX), while males have only one. In females, if the FMR1 gene on one X chromosome has the mutation, the FMR1 gene on the other X chromosome might not have the mutation. Even if one of the female’s genes has a very large mutation, the body can usually make at least some FMRP, leading to milder symptoms.

How is a change in the FMR1 gene related to Fragile X & associated disorders?

Fragile X syndrome and its associated conditions are caused by changes (mutations) in the FMR1 gene found on the X chromosome. This mutation affects how the body makes a protein called FMRP. The mutation causes the body to make only a little bit or none of the protein, which can cause the symptoms of Fragile X.

In 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 to start the process of building the protein.

The promoter part of the FMR1 gene includes many repeats—repeated instances of a specific DNA sequence called the CGG sequence. The FMR1 gene usually has between 6 and 40 repeats in the promoter; the average is 30 repeats.

People with between 55 and 200 repeats have a premutation of the gene. The premutation may cause the gene to not work properly, but it does not cause intellectual and developmental disability (IDD). The premutation is linked to the disorders FXPOI and FXTAS. However, not all people with the premutation show symptoms of FXPOI or FXTAS.

People with 200 or more repeats in the promoter part of the gene have a full mutation, meaning the gene might not work at all. People with a full mutation often have Fragile X syndrome.

The number of repeats, also called the “size of the mutation,” affects the type of symptoms and how serious the symptoms of Fragile X syndrome will be.

Inheriting Fragile X Syndrome

Fragile X syndrome is inherited, which means it is passed down from parents to children. Anyone with the FMR1 gene mutation can pass it to their children. However, a person who inherits the gene mutation may not develop Fragile X syndrome. Males will pass it down to all of their daughters and not their sons. Females have a 50/50 chance to pass it along to both their sons and daughters. In some cases, an FMR1 premutation can change to a full mutation when it is passed from parent to child. Read more about how FMR1 changes as it is passed from parent to child.

What are the symptoms of Fragile X syndrome?

People with Fragile X do not all have the same signs and symptoms, but they do have some things in common. Symptoms are often milder in females than in males.

Intelligence and learning. Many people with Fragile X have problems with intellectual functioning.
- These problems can range from the mild, such as learning disorders or problems with mathematics, to the severe, such as an intellectual or developmental disability.
- The syndrome may affect the ability to think, reason, and learn.
- Because many people with Fragile X also have attention disorders, hyperactivity, anxiety, and language-processing problems, a person with Fragile X may have more capabilities than his or her IQ (intelligence quotient) score suggests.
Physical. Most infants and younger children with Fragile X don’t have any specific physical features of this syndrome. When these children start to go through puberty, however, many will begin to develop certain features that are typical of those with Fragile X.
- These features include a narrow face, large head, large ears, flexible joints, flat feet, and a prominent forehead.
- These physical signs become more obvious with age.
Behavioral, social, and emotional. Most children with Fragile X have some behavioral challenges.
- They may be afraid or anxious in new situations.
- They may have trouble making eye contact with other people.
- Boys, especially, may have trouble paying attention or be aggressive.
- Girls may be shy around new people. They may also have attention disorders and problems with hyperactivity.
Speech and language. Most boys with Fragile X have some problems with speech and language.
- They may have trouble speaking clearly, may stutter, or may leave out parts of words. They may also have problems understanding other people’s social cues, such as tone of voice or specific types of body language.
- Girls usually do not have severe problems with speech or language.
- Some children with Fragile X begin talking later than typically developing children. Most will talk eventually, but a few might stay nonverbal throughout their lives.
Sensory. Many children with Fragile X are bothered by certain sensations, such as bright light, loud noises, or the way certain clothing feels on their bodies.
- These sensory issues might cause them to act out or display behavior problems.

How do healthcare providers diagnose Fragile X syndrome?

Healthcare providers often use a blood sample to diagnose Fragile X. The healthcare provider will take a sample of blood and will send it to a laboratory, which will determine what form of the FMR1 gene is present.¹

Prenatal Testing (During Pregnancy)

Pregnant women who have an FMR1 premutation or full mutation may pass that mutated gene on to their children. A prenatal test allows healthcare providers to detect the mutated gene in the developing fetus. This important information helps families and providers to prepare for Fragile X syndrome and to intervene as early as possible.

Possible types of prenatal tests include:

Amniocentesis. A healthcare provider takes a sample of amniotic fluid, which is then tested for the FMR1 mutation.
Chorionic villus sampling. A healthcare provider takes a sample of cells from the placenta, which is then tested for the FMR1 mutation.¹

Because prenatal testing involves some risk to the mother and fetus, if you or a family member is considering prenatal testing for Fragile X, discuss all the risks and benefits with your healthcare provider.

Prenatal testing is not very common, and many parents do not know they carry the mutation. Therefore, parents usually start to notice symptoms in their children when they are infants or toddlers. The average age at diagnosis is 36 months for boys and 42 months for girls.²

Diagnosis of Children

Many parents first notice symptoms of delayed development in their infants or toddlers. These symptoms may include delays in speech and language skills, social and emotional difficulties, and being sensitive to certain sensations. Children may also be delayed in or have problems with motor skills such as learning to walk.

A healthcare provider can perform developmental screening to determine the nature of delays in a child. If a healthcare provider suspects the child has Fragile X syndrome, he/she can refer parents to a clinical geneticist, who can perform a genetic test for Fragile X syndrome.

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Diagnosing Fragile X Syndrome