Fragile X (FMR1) Genetic Testing
Testing may be performed in the following situations, especially if you have a family history of fragile X syndrome or relatives with intellectual or developmental disabilities and the causes have not been identified:
- When your child has signs and symptoms of autism, intellectual disability, or developmental delay
- As an adult with later-in-life onset of symptoms of a movement disorder or tremors
- When you are a woman with fertility problems, especially if you have female relatives whose ovaries stopped working at a young age (premature ovarian failure)
- When you are planning a pregnancy (preconception) or are pregnant in the context of optional carrier screening
- When you are a known carrier of a fragile X genetic variant and are pregnant, you may choose to have your fetus tested.
A blood sample drawn from a vein, or for prenatal testing, amniotic fluid obtained through amniocentesis, or a chorionic villus sample (sample of the placenta). Cautionary note: Testing for fragile X genetic variants in a chorionic villus tissue sample can lead to an indeterminate or unclear result and may require repeat testing later in pregnancy by amniocentesis. If you are considering prenatal diagnostic testing of your fetus, it is important to discuss the potential benefits and limitations of each method with your healthcare provider to select the best testing option for you.
Generally, no test preparation is needed. However, for prenatal diagnostic testing, some preparation may be necessary. For example, either a full or empty bladder may be required at the time an amniocentesis or chorionic villus sampling is performed. Talk to your healthcare practitioner and be sure to follow any instructions provided.
Fragile X syndrome is an inherited condition associated with a range of developmental delays, learning disabilities, thinking (cognitive) impairment, and behavioral issues. It is caused by a pathogenic (disease-causing) genetic variant. The variant is an expansion of repetitive DNA near the FMR1 gene. Genetic testing evaluates the FMR1 gene to detect this expansion that causes fragile X syndrome and FMR1-related conditions.
The FMR1 gene is located on the X chromosome, one of the chromosomes that determines your sex at birth (the other is the Y chromosome). The FMR1 gene makes instructions for a protein called FMRP that is necessary for normal brain development. The FMRP protein is involved in developing the specialized connections between nerve cells called synapses. When a change (genetic variant or mutation) near the FMR1 gene disrupts FMRP production, leading to absent or low FMRP levels, it affects the development of the nervous system, resulting in fragile X syndrome.
Very close to the FMR1 gene, there is a section of DNA that has multiple repeats of three DNA bases: cytosine-guanine-guanine (CGG). This is called a CGG triplet repeat. Genetic testing for fragile X syndrome determines the number of CGG repeats that are present.
- Normal—between 5 and 44 CGG repeats
- Intermediate—between 45 and 54 CGG repeats
- FMR1 premutation—between 55 and 200 CGG repeats (FMR1 premutation carrier)
- Full mutation—more than 200 CGG repeats
Since most men have one X chromosome and one Y chromosome, fragile X syndrome can affect them more seriously than most women. Women have two X chromosomes, so they are more likely to have at least one X chromosome with a normal FMR1 gene that makes enough functioning FMRP.
Individuals with an FMR1 premutation are at risk for developing a condition called fragile X-associated tremor ataxia syndrome (FXTAS), which causes "Parkinson-like" tremors usually after age 50.
Premutations are unstable, meaning that the number of repeats may increase as the gene passes from one generation to the next. Premutations can potentially expand into full mutations as the gene passes from mother to child, thus a mother who is a premutation carrier can have a child affected by fragile X syndrome. Premutations are not known to be unstable when passed from fathers to daughters.
For additional details, read the "What does the test result mean?" section and the article on Fragile X Syndrome.
How is the test used?
Genetic testing is used to evaluate the FMR1 gene and determine the number of CGG triplet repeats that are present. Testing is used to:
- Diagnose fragile X syndrome and FMR1-related conditions molecular testing for an abnormal FMR1 gene is the only way to diagnose fragile X syndrome.
- Determine whether you are a carrier of a FMR1 premutation or full mutation and determine the risk of passing any genetic variants to your children
- Diagnose fragile X syndrome or an FMR1-related condition in your fetus (prenatal diagnosis); prenatal diagnosis for fragile-X syndrome is not routine. The American College of Obstetricians and Gynecologists recommends it only for women who are known carriers of the FMR1 premutation.
When is it ordered?
A genetic test for fragile X syndrome may be ordered when:
- Your child has signs and symptoms of an autism spectrum disorder (ASD), intellectual disability, or developmental delay, especially if you have signs and symptoms related to fragile X syndrome, a family history of fragile X syndrome, or relatives with intellectual or developmental disabilities and the causes have not been identified
- You are an adult with later-in-life onset of symptoms such as tremors or lack of muscle control or coordination, especially if you also have a family history of movement disorders, fragile X syndrome, or intellectual or developmental disabilities with unidentified causes
- You are a woman with fertility problems linked to elevated follicle stimulating hormone (FSH) levels, especially if you have female relatives whose ovaries stopped working at a young age (premature ovarian failure), or a family history of fragile X syndrome, or intellectual or developmental disabilities with undetermined causes
- You are planning a pregnancy (preconception) or when you are pregnant, especially if you have had fertility problems and a family history of fragile X syndrome, or relatives with intellectual or developmental disabilities and the causes have not been identified
- You are a known carrier of a fragile X premutation or full mutation and are pregnant; you may choose to have your fetus tested.
What does the test result mean?
It is recommended that anyone seeking or receiving fragile X testing do so in consultation with a genetic counselor or other genetic health professional to fully understand the implications of the results.
The laboratory report typically includes an interpretation of results.
For most women, two repeat sizes are reported because they have two X chromosomes. For most men, one repeat size is reported because they have one X chromosome and one Y chromosome. There are four possible ranges for repeat size, depending on the number of CGG triplet repeats:
Normal: 5 to 44 CGG repeats
- Not affected by fragile X syndrome or FMR1-related condition
- Not a carrier and not at risk of having a child with fragile X syndrome or related condition
Intermediate: 45 to 54 CGG repeats
- Not affected by fragile X syndrome or an FMR1-related condition
- A female with a repeat expansion in the intermediate range has a higher chance of passing a larger triplet expansion (a premutation – see below) to her children.
- The CGG repeat may expand and lead to fragile X syndrome after multiple generations, but it will not expand to a full fragile X mutation in one generation.
Premutation: 55 to about 200 CGG repeats
- Some women are at risk for fragile X-associated premature ovarian insufficiency (FXPOI).
- About 17% of women and 47% of men older than age 50 with a premutation are at risk for fragile X tremor/ataxia syndrome (FXTAS).
- With each pregnancy, women who are fragile X premutation carriers have a 50% chance of passing the X chromosome with the expanded FMR1 gene to their child. When this happens, there is a chance that the number of repeats will grow larger (expand) and surpass 200 when it is passed on, leading to the full mutation and fragile X syndrome. The chance that the premutation will expand to the full mutation range when it is passed on depends on its starting size. Premutations with more than 90 repeats almost always expand to full fragile X syndrome in the next generation.
- Fathers pass on either an X chromosome or a Y chromosome to their children. Fathers with an FMR1 premutation on their X chromosome will pass it to all their daughters. The premutation is not likely to expand when passed on by fathers. Since Y chromosomes do not have the FMR1 gene, fathers do not pass a premutation to their sons.
Full mutation: Usually more than 200 CGG repeats
- All males with a full mutation are affected with fragile X syndrome to some degree.
- Females with a full mutation can experience a wide range of signs and symptoms, and they can vary in severity.
- Even if fragile X syndrome is diagnosed prenatally in a fetus, it is impossible to predict which symptoms a child will have, or their severity.
- With each pregnancy, a mother with a full mutation has a 50% chance of passing it to her child.
- Men with full mutations and a diagnosis of fragile X syndrome do not commonly have children. If they do have children, fathers do not pass a full mutation to their sons since Y chromosomes do not have the FMR1 gene. It appears that fathers cannot pass on full mutations to their daughters, but scientists don't know why.
What are the signs and symptoms of fragile X syndrome?
- Impaired thinking (cognition), ranging from relatively mild learning disabilities to severe intellectual disability
- Development delays
- Delay in speech and language skills, especially in boys
- Attention deficit hyperactivity disorder (ADHD)
- Features of autism spectrum disorder (ASD) that affect communication and social interaction
- Behavioral issues related to ADHD or ASD include, for example, hand flapping, anxiety, sensitivity to touch, not making eye contact, difficulty paying attention, acting and speaking without thinking, and being very active.
- Anxiety, depression, aggression, obsessive compulsive disorder (OCD)
- Chronic ear infections
- Distinctive physical features, especially in males as they get older, including a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and enlarged testicles after puberty
How common is fragile X syndrome?
Fragile X syndrome is the most common inherited intellectual disability in men and is a significant cause of intellectual disability in women. It occurs in approximately 1 in 4,000 men and 1 in 8,000 women. About half of people with fragile X syndrome also have autism spectrum disorder. Fragile X syndrome accounts for about 2 to 5 percent of all people with autism spectrum disorder.
Is there a cure for fragile X syndrome?
Currently, there is no way to cure or prevent fragile X syndrome. However, there are educational and occupational therapies as well as symptom support available to improve quality of life for people with the condition.
Does anything else besides an expanded triplet repeat cause fragile X syndrome?