Fragile X Genetic Testing Basics
Fragile X Syndrome
What is fragile X syndrome?
Fragile X syndrome is the most common cause of inherited intellectual disability (historically called mental retardation). Infants and toddlers with fragile X are likely to have delayed development of body movement (called motor skills) and delayed speech abilities. For instance, boys with fragile X walk and say their first words when they are an average age of about 20 months old; unaffected boys walk and talk at an average age of about 12 – 13 months. A child with fragile X may not learn words as quickly as other children of the same age do. The child may also have difficulty understanding instructions. Boys with fragile X have more severe problems compared to girls with the disease.
Children with fragile X syndrome typically have more difficulty with behaviors, such as temper tantrums and hyperactivity. Many children with fragile X show autism-like symptoms, such as poor eye contact with others.
Although children with fragile X usually do not have unusual physical characteristics as infants, such features might appear as they grow older. A school-aged child with fragile X might have a long face with a prominent jaw, prominent forehead or relatively large ears.
Gender plays a role in the symptoms and severity of fragile X. Boys with the syndrome have moderate or severe intellectual disability, while girls with fragile X have milder intellectual disability. Boys are also more likely to have the unusual facial features mentioned above.
Fragile X Syndrome
How common is fragile X syndrome?
Fragile X syndrome occurs in about one of every 5,000 males and about one of every 10,000 females.
Who is at risk of fragile X syndrome?
Family history is the key to determining your risk of fragile X syndrome. Women who are carriers are at risk of having children with fragile X. Men who are carriers are at risk of having children who are also carriers. Fragile X can affect people from any ethnic group.
Is there a cure?
No. The gene that causes fragile X syndrome makes a protein needed by the brain. Studies on animals have shown that absence of this protein causes changes in the connections between nerve cells within the brain. Nerve cells send neurotransmitters across these connections to communicate with neighboring cells. Some scientists think that medication to control neurotransmitter levels might help patients with fragile X. It would take several years to test such a treatment.
In the meantime, while it’s OK to be hopeful about the possibility of treatment, it’s important to remember that fragile X is a lifelong condition. Children with fragile X may need speech therapy and extra support and attention in school. Treatment for behavioral issues might include medication and counseling.
The Gene For Fragile X Syndrome
What is the fragile X gene?
The gene responsible for fragile X syndrome is called Fragile X Mental Retardation-1 (FMR1). The FMR1 gene tells the body how to make a protein called Fragile X Mental Retardation Protein (FMRP). Although scientists are still trying to understand its exact function, the FMRP protein is important to the health of nerve cells in the brain.
What goes wrong with the fragile X gene?
A gene is like a recipe for making a protein. The DNA molecules that make up a gene are like the words in a recipe. In one part of the fragile X gene, three "letters" are repeated several times. A few repeats of this sequence doesn't cause a problem, any more than adding a few extra dashes of salt to a recipe would ruin it. Too many repeats, however, creates havoc when a cell tries to "read the recipe." Imagine reading a cake recipe and you see, "add 1 teaspoon of salt" repeated 50 times. Clearly, a cake with that much salt will not taste right. Likewise, repeating a DNA sequence many times over will cause problems.
How does the change happen? The number of repeats can increase if the gene is passed from parent to child. The body makes a copy of each gene before it is passed on. Changes also can occur when the gene is being copied.
How is the change in the fragile X gene passed along?
The FMR1 gene is on the X chromosome. Males inherit one X chromosome from the mother and one Y chromosome from the father. Females get two X chromosomes, one from each parent. If there is a change in an X chromosome gene that could cause a problem, girls have a second X chromosome that almost always carries a normal version of the gene. Boys, on the other hand, do not have a second X chromosome to fall back on. As a result, a boy with too many repeats in the FMR1 gene will have fragile X. About half of girls with too many repeats in the FMR1 gene have intellectual disability, but their symptoms are often milder than those of boys.
What are the four classes of fragile X repeats?
- Normal: A normal number of repeats ranges from about five to about 40. Within this range, the number of repeats stays the same when the gene is passed on to a child. The child would not have fragile X.
- Intermediate: Between 41 and 58 repeats is a "gray zone." Fragile X genes in this range are less stable. When the gene is passed on, the number of repeats may increase, but usually not enough to cause a problem. The child would not have fragile X.
- Pre-mutation: When the number of repeats ranges from about 59 to about 200, the gene is in a state of "pre-mutation." The person with this many repeats would not have fragile X, but the number of repeats could increase when the gene is passed on to the child. A female who carries a fragile X gene of this size is at higher risk for premature ovarian failure.
- Full mutation: When the number of repeats is greater than 200, the gene cannot work properly. A boy who has a fragile X gene with more than 200 repeats will have fragile X syndrome. A girl with more than 200 repeats may have fragile X, but often with milder symptoms. More than 99% of people with fragile X carry a full mutation. The other 1% probably have another change in the same gene that can’t be detected by routine genetic testing.
Are gene repeats the only change in the gene?
No. There is another change associated with the repeats. When the number of repeats is greater than 200, the gene almost always has another change, called methylation. This means that a chemical group, called a "methyl group," is attached to the gene. With a methyl group attached, the gene cannot work. If the gene is not working in a boy, he will have fragile X. If a girl's FMR1 gene is methylated, she may have fragile X syndrome or she may be protected by a normal FMR1 gene on her other X chromosome.
Methylation causes the most severe symptoms. Knowing the methylation status of the gene helps predict how severe fragile X syndrome will be for a particular person.
A small number of people with fragile X syndrome — less than 1% — do not have a large number of repeats or methylation in the gene. These people have something else wrong with the gene. Routine DNA testing only looks at the number of repeats and methylation. Testing for less common fragile X mutations is offered at a limited number of labs.
Should You Be Tested?
What is my risk of being a fragile X carrier?
About 1 in 200 women is a fragile X carrier. Your chances of being a fragile X carrier may be much higher depending on your family history. If you have a family history of fragile X syndrome or of intellectual disability from an unknown cause, you are more likely to be a fragile X carrier.
Men can also be fragile X carriers, but it's usually only when the woman is the carrier that the children get full fragile X syndrome.
Should you or your future child be tested for fragile X?
If you are pregnant and a fragile X carrier, you may want to have a prenatal test for fragile X syndrome. Fragile X testing also should be considered for anyone who has a chromosome test that shows fragile X. The chromosome test is no longer performed routinely, but if someone in your family was positive for this test in the past, that family member should consider DNA testing to confirm the results.
Should a child with intellectual disability be tested for fragile X?
Fragile X testing should be considered for any child who has been diagnosed with intellectual disability, developmental delay or autism. This is especially true if there is a family history of fragile X or some other form of intellectual disability from an unknown cause, or if the child has any physical features that would suggest fragile X syndrome.
Understanding Test Results and Options
How Do You Make Sense Of The Results?
If I am the mother of a child who has a full mutation in the fragile X gene, does that mean I'm a carrier?
Yes. Every mother of a child with a full mutation in the FMR1 gene is a carrier of a repeat at the pre-mutation or full mutation level.
If I test positive as a carrier, what does that mean for me?
A man or a woman who carries a fragile X pre-mutation will generally have normal intellectual abilities and a normal appearance, but a carrier of an FMR1 repeat is at risk of having some symptoms of fragile X syndrome. For example, among pre-mutation carriers:
- 21% of females experience premature ovarian failure (POI), which can lead to infertility and a lack of normal female hormones.
- Men and women who are premutation carriers can develop tremors and an unsteady gait as older adults. This is known as fragile X Tremor-Ataxia Syndrome (FXTAS).
- Some people develop a mild learning disability. This would be someone with normal intelligence who has problems in a certain area, such as math or reading. They may need extra help in school.
How does being a fragile X carrier affect my family?
A woman who is a fragile X pre-mutation carrier has a 50% chance of passing the gene on to her children. When the gene is passed on, the number of repeats in the gene could stay the same or could increase.
A man who is a pre-mutation carrier has a 100% chance of passing the gene on to his daughters (because they always get his X chromosome) and no chance of passing the gene on to his sons (because they always get his Y chromosome, never his X). It is rare for the number of repeats to increase significantly when passed down from the father.
If the number of repeats stays the same, the child will be a pre-mutation carrier. If the number of repeats increases to more than 200, the child will have a full mutation. A boy who inherits a full mutation will have fragile X. A girl who inherits a full mutation will have fragile X about half of the time, but her symptoms will typically be milder.
Family members of a carrier are also at risk of having fragile X syndrome or passing it on to their future children.
- If your father was a pre-mutation carrier, you cannot inherit the gene from him because the father only gives his X chromosome to his daughters.
- If your mother was a pre-mutation carrier, you have a 50% chance of being a pre-mutation carrier (if you are not already affected).
- If your daughter had a child with fragile X syndrome, you are almost certainly a pre-mutation carrier and at risk for developing fragile X Tremor-Ataxia Syndrome, the symptoms of which are tremors and an unsteady gait.
- If your father was a pre-mutation carrier, you have inherited his affected gene. It is rare for the number of repeats to increase when passed down from the father, so you will most likely be a pre-mutation carrier also.
- If your mother was a pre-mutation carrier, you have a 50% chance of being a pre-mutation carrier (if you are not already affected).
- If your sister was a pre-mutation carrier, you have a 50% chance of being a pre-mutation carrier.
Could I get a positive test result, but not carry the disease gene (a false positive)?
The test for fragile X is highly accurate for the full mutation. False positives for a full mutation are unlikely. If the number of repeats ranges between intermediate and pre-mutation, it may be difficult to determine whether someone is a carrier. Each case must be interpreted individually.
Could I get a negative test result, but have a change in the gene that I could pass on to my children (a false negative)?
False-negative test results can occur if:
- Only one DNA testing method (polymerase chain reaction [PCR] or Southern Blot) is used. On rare occasions, a person may appear to have a normal number of repeats according to the PCR test when they actually have an abnormal gene. The Southern blot test, however, will find the abnormal gene.
- The number of repeats lies in the intermediate range. A lab cannot always provide a guaranteed interpretation for results that fall in the "gray zone" between normal and pre-mutation.
If I have the fragile X gene, can I have children who don't have it?
If you are a woman carrying a fragile X pre-mutation, you have a 50% chance of passing on the affected gene to each child you have. If you are a man with a pre-mutation, you will pass it on to your daughters, but not your sons. In the unlikely event that both parents carry a pre-mutation, the chances of getting a changed gene are 100% for their daughters and 50% for their sons.
While I'm pregnant, can I determine the risk my baby has of developing fragile X?
To discover whether your unborn child has inherited changes in the fragile X gene, you and your partner can get prenatal testing. Prenatal DNA testing is available if you have a family history of fragile X or of unexplained intellectual disability. There are two common ways of obtaining DNA from fetal cells:
- Chorionic villus sampling is performed early in the pregnancy — between 10 and 13 weeks. A physician takes a sample of chorionic villus cells from part of the placenta that contains fetal cells.
- Amniocentesis is performed after 15 weeks. The physician obtains fetal cells from the amniotic fluid that surrounds the fetus.
You can also get tested before a pregnancy using preimplantation genetic diagnosis (PGD). PGD is done by in vitro fertilization (IVF). Each fertilized embryo is tested to see if it has the fragile X mutation. Only the embryos without a mutation are implanted into the mother.
Talk with your obstetrician or a genetic counselor about your options.
If I am a fragile X carrier, could I give birth to a girl with the disease?
There is a 100% chance a male pre-mutation carrier would pass on the gene, but his daughter would only be a carrier and not have the disease. There is a 50% chance that a female pre-mutation carrier will pass the expanded gene on to her daughter. If the number of repeats stays the same, the daughter also will be a pre-mutation carrier. If the number of repeats increases to the more than 200, then the daughter might be affected. Also, a girl with a full mutation might have symptoms of fragile X, including intellectual disability, but symptoms are less severe in girls because they have an extra X chromosome to fall back on.
If I DON'T have the fragile X gene, can I have children who DO have the gene?
If you're not a carrier, then your children cannot inherit the gene from you. But there is always the possibility that the number of repeats in the gene could increase from one generation to the next. We all have some repeats in the FMR1 gene. It would be very unusual, however, for the gene to expand from a normal number of repeats to a full mutation in one generation.
Is there any harm in finding out if I am a carrier?
Possibly. You may feel upset if you learn that you carry a gene that could potentially cause intellectual disability in your future children. However, it is important to note that carriers generally have normal intellectual abilities and normal appearance.
How does the test work?
There are three tests for fragile X syndrome:
- Repeat number testing looks for repeats in the gene. There are two methods for "counting" repeats:
- The lab can estimate the number of repeats using a method called Southern blotting, which breaks up the DNA with enzymes. The lab checks the size of a piece of DNA that contains the repeat section. If the piece is over a certain size, the lab concludes that there are too many repeats in the FMR1 gene. This test only gives an estimate of the number of repeats.
- The lab can also count the number of repeats by using a method called polymerase chain reaction (PCR). This method is better than Southern blotting for estimating the number of repeats. However, it will not work as well when the number of repeats in the gene is very large, because the PCR test has a higher chance of a false negative when the gene has more than 200 repeats. With a large number of repeats, the PCR may give a false-negative result. There is no exact number of repeats where this will definitely happen, but the risk of a false negative increases with the number of repeats. Some of the newer methods of PCR are able to detect a full mutation, so a Southern blot is not always necessary.
- Methylation testing detects the presence of a methyl group on the gene. There are two ways to look for methyl groups:
- When the lab uses Southern blotting for checking the number of repeats, they also check for methyl groups. The lab chooses appropriate enzymes to break up the DNA. Some of these enzymes cannot break up DNA that has methyl groups attached. The pattern of DNA pieces remaining after enzyme treatment tells the lab if methyl groups are present.
- When the lab uses PCR testing, it can check for methyl groups using a test that is sensitive to the presence of methyl groups. This PCR test is not yet used routinely for clinical testing, however.
- DNA sequence analysis can be done if the person seems to have symptoms of fragile X, but testing for repeat number and methylation are normal. DNA sequence analysis became available in late 2005. It is estimated that up to 1% of people with fragile X could have a change detectable by sequence analysis (and that would not be detected by the routine test).
What do the tests cost?
Cost varies depending upon which lab does the testing, but is generally about $500 total for both mutation and methylation testing. Sequence costs about $2,200.
Does insurance pay for the test?
Most health-insurance companies pay 80% or more of the cost. Some companies pay all the cost; others won't pay any portion. If you are considering this test, call your insurance company and ask about its coverage.
How long does it take to get results?
Once you have blood drawn for the test, results should be available in two to three weeks. The test results will not be reported directly to you. Instead, the laboratory provides the results to the medical center that ordered the test. You would then return to the center for another appointment to discuss the results.
Can a health-insurance company raise my rates or drop me from coverage if I test positive?
In 2008, the U.S. government passed a law called GINA (Genetic Information Nondiscrimination Act). This law prohibits discrimination by health insurers and employers on the basis of genetic information. Learn more here.
Also, the Federal Health Insurance Portability and Accountability Act (HIPAA) of 1996 prohibits health insurance discrimination based on any "health status-related factor" (including genetic information) by group health plans. People with group insurance are usually covered by HIPAA, while people who are self-employed are covered only by state laws.
Some states have enacted legislation to cover the gaps. Thirty-four states prohibit health-insurance companies from using genetic information to deny coverage. Other states require specific justification for the use of genetic information in denying a claim.
Life insurance, long-term care and disability insurance are generally not covered by these laws. People with life and disability coverage provided by their employers are unlikely to have this insurance affected by a genetic test result.
For information about laws in individual states, click on the following links:
Learn more about life insurance, disability insurance, and long-term care insurance laws.
Learn more about health insurance laws.