Fragile X Syndrome and premutation-associated disorders
What is fragile X syndrome?
Fragile X syndrome is an inherited, genetic disorder associated with a wide range of symptoms, including learning and behavior challenges. Children and adults with fragile X syndrome may also have autism spectrum disorder or autistic-like behaviors such as anxiety, attention-deficit disorder (ADD), and attention-deficit hyperactivity disorder (ADHD). Autism is complex, and people with autism may have difficulty with communication and relating to others. The mildness or severity of learning and behavior issues vary with each person. A person with fragile X syndrome can face challenges in learning, health, and behavior throughout their lifetime, but each person faces their own journey that is not predetermined.
Fragile X syndrome is usually inherited from people who do not have fragile X syndrome, so people who are thinking about starting a family should know their carrier status before getting pregnant.
FX-associated primary ovarian insufficiency (FXPOI)
Women who have a premutation are at risk for FX-associated primary ovarian insufficiency (FXPOI). Common symptoms of FXPOI include irregular menstrual cycles and early menopause by the time they reach 40 years of age. Some women may become infertile, while others who have FXPOI can still get pregnant. FXPOI is common in women with premutations, with 20-25% of these individuals experiencing symptoms.
FX-associated tremor ataxia syndrome (FXTAS)
Men and women who have a premutation are at risk for symptoms from FX-associated tremor ataxia syndrome (FXTAS). Symptoms of FXTAS only appear after a person is an adult. Some people with premutations are also at risk for learning difficulty, autism spectrum features, attention deficits, and depression or anxiety disorders.
FXTAS occurs more often in men than women. The reason is because fragile X gene is on the X chromosome. Women have a two X chromosomes and often one of the X chromosomes has a gene that is normal and can compensate for the gene that is not functioning.
What does it mean to be a carrier?
A person is a carrier if they have a premutation in the fragile X (FMR1) gene, and this can only be determined by genetic testing. People who are carriers have a fragile X premutation and they do not have fragile X syndrome, but their child may be at risk of having fragile X syndrome. If a person is a carrier, genetic testing can also determine if the risk is high or low for having a child with fragile X syndrome.
What is the risk of being a carrier?
Genetic testing and risk assessment
Why is testing important and when testing is appropriate?
People who are thinking about starting a family or getting pregnant can be empowered by knowing if they are a fragile X carrier and have a high or low risk of having a child with fragile X syndrome. Genetic testing for carrier status is best performed before pregnancy because this enables couples to learn about the risk of having a child with fragile X syndrome and to consider a range of reproductive options. Healthcare providers or genetic counselors can provide information to support the family planning options that are right for your family.
Fragile X syndrome has a genetic basis and can run in families ─ relatives may also have irregularities in their fragile X gene (either a full mutation or premutation). Although a person who is a carrier may not have any symptoms, there are a broad range of symptoms associated with full mutations and premutations.
Fragile X syndrome is caused by a unique sequence of DNA in the fragile X gene called a full mutation. This genetic sequence is actually made up of a short sequence of DNA (also known as a “CGG triplet”) that can be repeated hundreds of times. Genetic testing can determine the size of the DNA sequence. If a person has a full mutation, the CGG triplet is repeated more than 200 times and the person is determined to have fragile X syndrome. If the individual has between 55 and 200 CGG triplets, the person is designated as having a premutation. People with premutations do not have fragile X syndrome but they may present with milder symptoms especially as they get older, however, they may be at increased risk for passing along fragile X syndrome to their children.
A full mutation is inherited; therefore, prospective parents should be tested for their carrier status. Genetic testing will identify individuals who are carriers and have a premutation in the fragile X gene and who may be at risk of having a child with fragile X syndrome. People with premutations may not have any noticeable symptoms, but the instability of the gene can be increased in future generations. Therefore, women who are premutation carriers can pass a full mutation to their son or daughter and men who are premutation carriers can pass the premutation to their daughters, but not their sons.
Genetic testing for fragile X carrier status is routine and can improve an understanding of the risk of repeat expansion from parent to child. For women who are fragile X carriers, an additional genetic test can detect small genetic sequences called AGG interruptions in the fragile X premutation. The AGG interruptions make the fragile X gene more stable by interrupting the repetitive CGG sequence. In general, the more interruptions, the more stable the gene and the lower the risk of passing along a full mutation; however, this also depends on the number of repeats in the premutation, so carrier testing is required before determining risk based on the presence of AGG interruptions. Not all women with premutations require AGG interruption testing.
A small amount of blood is needed for genetic testing to determine if someone has a fragile X premutation and for AGG interruption testing. Xpansion Interpreter®, a testing service developed and offered by Asuragen, is available for women of a select premutation range to refine their risk of transmission. To find out more about FDA-cleared fragile X carrier testing options follow this link. For more information on AGG interruption testing and the Xpansion Interpreter® service follow this link.
Is carrier testing available?
Yes, genetic testing is available for fragile X syndrome and fragile X associated-disorders, and carrier screening. In February of 2020, the first laboratory test to aid in the diagnosis of fragile X syndrome and premutation-associated disorders, as well as for fragile X carrier screening, was cleared by the United States Food and Drug Administration (FDA). The test is called AmplideX® Fragile X Dx & Carrier Screen Kit and was developed by Asuragen, Inc.
Discuss testing options with your healthcare providers and ask if they are aware of the AmplideX test.
What do the carrier screening results mean?
The fragile X test results will identify if a person has a full mutation or premutation in the fragile X gene. People who have a premutation are fragile X carriers. For select women who are premutation carriers, a healthcare provider may recommend additional AGG interruption testing to refine the risk of having a child with fragile X syndrome. Discuss the test results with your healthcare provider and/or genetic counselor, and they can answer questions or concerns that you may have.
Assay results are solely intended to be interpreted by healthcare professionals who are board certified in molecular genetics and to be used in conjunction with other clinical and diagnostic findings, consistent with professional standards of practice. Reflex testing, clinical genetic evaluation, and genetic counseling should be offered as appropriate..
After a person is diagnosed with fragile X syndrome or premutation-associated disorders, specific intervention strategies may be recommended to overcome challenges and improve outcomes. There is currently no cure for fragile X syndrome or premutation-associated disorders, but researchers are making advances in behavioral strategies and treatments that may be recommended for future management of the condition.
How can I be tested for AGG interruptions?
For women who are fragile X carriers, there is a risk that the premutation will expand to a full mutation in their child and their child will have fragile X syndrome. A fragile X test identifies the size of the fragile X premutation, and this is important because the risk may be higher or lower depending on the size of the premutation. For select fragile X carriers who have premutations of select lengths, additional genetic testing for AGG interruptions may be recommended to further refine the risk of having a child with fragile X syndrome. In conjunction with our partner laboratories, Asuragen, Inc. offers a unique and proprietary laboratory testing service available for AGG interruption testing. More information can be found here.
Do professional medical guidelines recommend carrier screening?
The American College of Obstetrics and Gynecology (ACOG) recommends Fragile X premutation carrier screening for women with a family history of fragile X-related disorders or intellectual disability suggestive of fragile X syndrome and who are considering pregnancy or are currently pregnant. If a woman has unexplained ovarian insufficiency or failure or an elevated follicle-stimulating hormone level before age 40 years, fragile X carrier screening is recommended to determine whether she has an FMR1 premutation. Although following these guidelines will not detect most premutation carriers in the population, the guidelines do target a higher prevalence group based on current data with regard to carrier frequency. If a patient with no family history requests fragile X screening, it is reasonable to offer screening after informed consent. All identified individuals with intermediate results and carriers of a fragile X premutation or full mutation should be provided follow-up genetic counseling to discuss the risk to their offspring of inheriting an expanded full-mutation fragile X allele and to discuss fragile X-associated disorders (premature ovarian insufficiency and fragile X tremor/ataxia syndrome).
Who is at greatest risk of being a fragile X carrier?
You are at greater risk if you have:
- A family history of fragile X syndrome
- A family history of mental retardation, developmental delay or autism of unknown cause
- Infertility problems associated with elevated follicle stimulating hormone (FSH) levels or premature ovarian failure (POF)
- A family history of adult onset ataxia and/or tremors
Can I tell if I am a carrier by my symptoms?
People with premutations may not have any noticeable symptoms. The only way to know if you are a fragile X carrier is to have a genetic test for fragile X.
My mother went through menopause when she was 39 years old, and my grandfather has trouble with balance and walking, does this mean I am a carrier?
The only way to know if you are a fragile X carrier is to have a genetic test for fragile X.
How many women in the United States are fragile X carriers?
One in 150 women, and one in 470 men* are fragile X carriers.
If I am a carrier, what is my risk of having a child with fragile X syndrome?
Genetic testing can assess your risk of having a child with fragile X syndrome.
How can I be tested?
For testing, follow up with your healthcare provider, physician, obstetrician, gynecologist, and/or genetic counselor.
How is fragile X inherited?
Fragile X is inherited from a parent who has a premutation in the fragile X gene. Women who are carriers can pass a full mutation to their son or daughter, and men who are premutation carriers can pass the premutation to their daughters and not to their sons.
I am a fragile X carrier and pregnant. Can I know if I am having a child with fragile X syndrome?
Prenatal testing, which are conducted on CVS (chorionic villi sampling) or amniocentesis samples, is available to test whether or not your child will develop fragile X, be a carrier, or neither. Discuss the testing options with your healthcare provider, obstetrician, and/or genetic counselor.
What are CGG repeats and AGG interruptions?
CGG is the abbreviation for the short DNA sequence made up of three nucleotides: cytosine-guanine-guanine (CGG), and this short sequence of DNA is repeated multiple times in the fragile X gene. When the CGG sequence is repeated more than 200 times, it is called a full mutations (associated with fragile X syndrome); if it is repeated between 55 to 200 times it is called a premutation. Carriers have premutations.
AGG is the abbreviation for a DNA sequence: adenosine-guanine-guanine. Sometimes in the CGG repeat an adenosine takes the place of a cytosine, so the DNA repeat sequence will have an AGG interruption. The AGG interruptions make the fragile X gene more stable by interrupting the repetitive CGG sequence. In general, the more interruptions, the more stable the gene and the lower the risk of passing along a full mutation; however, this also depends on the number of repeats in the premutation, so carrier testing is required before determining risk based on the presence of AGG interruptions. Not all women with premutations will require AGG interruption testing.
Where can I find out more information?
Fragile X Clinical and Research Consortium | https://fragilex.org/research/
Genetic and Rare Diseases Information Center | www.rarediseases.info.nih.gov/gard
P.O. Box 8126
Gaithersburg, MD 20898-8126