• Elizabeth Kearney

What People Planning for Pregnancy Should Know About Genetic Testing for Fragile X Syndrome

Many people who are considering pregnancy have healthy family members with normal development. Other people may have a family member, such as a cousin, aunt, or uncle, who had severe learning problems, perhaps severe enough that they had special education services or needed to live with family or in a group home as adults. There are many possible causes of those types of learning problems. Most of the time, relatives of the individual with learning problems will have healthy families with typical abilities to learn. However, some causes of severe learning problems may be inherited conditions that can affect family members.

Fragile X syndrome is one of the more common inherited causes of autism and severe learning problems. Therefore, the American College of Obstetricians and Gynecologists (ACOG) recommends that women who are pregnant or planning a pregnancy with a family medical history of autism or severe learning problems consider carrier testing for Fragile X. ACOG also supports a range of carrier testing, including Fragile X, for any woman, regardless of her family medical history, prior to pregnancy. It is important that all women are aware of these chances and recommendations when planning a family.

What is Fragile X syndrome?

Fragile X syndrome is the most common known inherited cause of autism and intellectual disability, or severe learning problems. (Autism is a disorder that can cause differences in a person’s communication and learning skills, social interactions and behaviors.)

Fragile X syndrome is a highly variable inherited disorder, which means that there is a wide range of possible symptoms and each person has their own, unique set of characteristics.

Some of the common characteristics of people with Fragile X include delayed childhood development, autism, learning differences, intellectual disability ranging from mild to severe, behavioral issues, and ADHD (attention deficit hyperactivity disorder). Many individuals with Fragile X have characteristic facial features such as a long face, large forehead and large ears. People with Fragile X may share these features, but each person also shares resemblance with their family members. Some individuals with Fragile X may also have health problems, such as muscle problems, unusually flexible joints, seizures, heart issues, flat feet, and curvature of the spine. Many of these problems can be treated with medications or surgery.

Fragile X syndrome is more common in males than in females; however, females with Fragile X syndrome can have the same symptoms as males, ranging from mild (only some symptoms) to severe (all or most of the reported symptoms).

Although Fragile X syndrome can cause a combination of developmental and medical challenges, it does not affect a person’s ability to lead a long and fulfilling life.

How did Fragile X get its name?

Fragile X syndrome got its name from a laboratory test performed many years ago. As explained below, Fragile X involves the X chromosome. Under certain laboratory conditions, the X chromosome appeared to “fracture” in a certain location in people with Fragile X. That form of testing is no longer used today.

How common is Fragile X syndrome?

Fragile X is one of the most common inherited genetic disorders. Fragile X syndrome affects approximately 1 in 4,000 to 1 in 7,000 males and 1 in 6,000 to 1 in 11,000 females. According to specialists, 2-3% of people with autism have Fragile X syndrome.

According to the Center for Disease Control, studies show that between 1 in 148 and 1 in 291 women in the United States have an increased chance to have a child with Fragile X syndrome.

Many of those women will have healthy children, but they may want to know about genetic testing. Those women are also more likely to have health issues that may affect their fertility and future family planning.

What causes Fragile X syndrome?

Fragile X is an inherited condition that is passed from one generation to the next through a gene called FMR1. Genes are segments of our genetic blueprint called DNA. Each gene in the body plays an important role because it provides specific instructions for various functions inside our cells. It is therefore very important for typical growth and development that there are no alterations or disruptions, called variants, within genes. A gene that is not working properly can cause an inherited disorder.

Fragile X is inherited in an X-linked manner. This means that the FMR1 gene is located on the X chromosome. A typical male has one copy of the X chromosome and one copy of the Y chromosome, whereas a typical female has two copies of the X chromosome. Individuals with Fragile X syndrome have a variation, or difference, within the FMR1 gene. The nature of this difference is important for genetic testing for Fragile X because it predicts the chances for features of Fragile X syndrome.

Is there genetic testing for Fragile X syndrome for people planning for pregnancy?

Genetic testing for Fragile X syndrome is available to people who are planning for pregnancy, regardless of having a family member with Fragile X syndrome. Genetic testing offered to healthy people when they are considering pregnancy is often referred to as carrier testing. Results of carrier testing can help women understand their chances of having a child with Fragile X syndrome, in addition to their own chances of developing some health issues sometimes seen in Fragile X carriers, like fertility issues and movement problems in adulthood. (These are described in more detail below.)

Studies show that as many as 1 in 148 women are carriers of Fragile X syndrome.

Women who are carriers are usually healthy themselves, and many do not have children or other known relatives with Fragile X syndrome. This means that a woman can be a carrier without having any prior health problems and without any family medical history of Fragile X or features of Fragile X.

What does a person planning for pregnancy learn from genetic testing (called carrier testing) for Fragile X syndrome?

Carrier testing for Fragile X syndrome will give more information than just saying whether the person is a Fragile X carrier or not. A portion of the FMR1 gene contains a repeated DNA sequence, called CGG repeats. This means that these three letters are repeated many times within a part of the gene. The number of CGG repeats falls into one of four categories. (The language used to describe gene variations has changed. The term “mutation” is not used as often as it used to be. In Fragile X syndrome, the term “mutation” was use to describe these categories and is still therefore used today.)

Normal repeat length:

A normal FMR1 gene has anywhere between 10 and 44 CGG repeats with most people having around 29-31 repeats.

Intermediate repeat length:

Individuals with the intermediate number of CGG repeats are not at risk to have symptoms of Fragile X. However, these repeat sizes can increase when they are passed down to future generations. A woman with an intermediate repeat length has an increased chance to have a child with a premutation. According to the National Fragile X Foundation, 1 in 3 people in the general population have an intermediate repeat size.

“Premutation” repeat length:

Individuals with the premutation number of CGG repeats are not at risk to have symptoms of Fragile X syndrome. However, these repeat sizes can increase when they are passed down to future generations. This means that a woman with a premutation has an increased chance to have a child with a full mutation. A person with a premutation is also called a Fragile X carrier. Some people with premutation repeat length have some health issues themselves. See below for more information.

“Full Mutation” Repeat Length:

Individuals with Fragile X syndrome have greater than 200 CGG repeats in the FMR1 gene. Typically, this large number of repeats is inherited from the individual’s mother, who has the FMR1 premutation (55-200 CGG repeats). In a woman’s eggs, the premutation can expand to a larger number of repeats, so the child may have over 200 CGG repeats, resulting in Fragile X syndrome. Typically, the larger the number of CGG repeats in the mother, the higher the likelihood that it will expand to a full mutation in their child.

If someone is a carrier for Fragile X, what are the chances to have a child with Fragile X syndrome?

A woman who is a carrier of Fragile X has a 50% chance of passing down her copy of the FMR1 premutation to her children with the added risk that the premutation will expand to a full mutation in the child. Both females and males can inherit the premutation from their mothers. However, because females have two copies of the FMR1 gene, they are less likely to have full symptoms of the disorder.

A woman who is a carrier of Fragile X has a 1 in 2 chance to give the expanded gene to her child, but the chances of the child having Fragile X syndrome depends on the type of carrier she is and whether the child is a boy or girl.

This is partly because a female with over 200 CGG repeats will have another copy of the FMR1 gene with the typical number of repeats, meaning that she will have at least one working copy of the gene. The female body typically does not use both of its X chromosomes and will selectively turn one off in each cell. This process can sometimes lead to most cells leaving on the typical copy of the FMR1 gene, which results in fewer symptoms. This is not always the case; in some females, the expanded copy of the gene is turned on and that can lead to the same symptoms as those seen in males with Fragile X syndrome.

A woman with a number of CGG repeats in the intermediate range does not have an increased chance of having a child with Fragile X syndrome. However, in some instances, the intermediate number of repeats can expand to the premutation range when passed on to a child, who would then be a Fragile X premutation carrier.

All daughters of a father with a Fragile X premutation will be Fragile X carriers because he will pass down his X chromosome to them.

Men can also be carriers of a premutation and can pass it to their daughters. However, the number of repeats does not expand in sperm, so their daughters will be carriers but not expected to have Fragile X syndrome. Because a father passes on his Y chromosome to a son, he cannot pass on the premutation to his sons.

Can genetic testing for Fragile X give any information about the person’s own health?

For many inherited diseases, carriers do not have features of the disease and do not have any other health issues related to being a carrier. However, some Fragile X carriers have some health features unrelated to their learning ability, so it is important to realize that genetic testing may provide some health information.

Individuals with the FMR1 premutation are not at risk to have Fragile X syndrome themselves, but they have an increased chance to develop certain health problems.

Women with the premutation have an increased chance to develop Fragile X-associated primary ovarian insufficiency, called FXPOI. Ovarian insufficiency can cause fertility issues and hormonal changes similar to menopause. This can have long term health consequences that can affect heart and thyroid health, as well as bone density. Studies show that about 20% of women with a premutation develop FXPOI, which means that many women with a premutation do not have any issues. Because FXPOI is thought to be one of the most common inherited causes of premature ovarian failure, ACOG recommends genetic testing for any woman who has this diagnosis or any symptoms of premature ovarian failure before age 40.

In addition to FXPOI, premutation carriers have an increased chance to have Fragile X-associated Tremor and Ataxia syndrome, called FXTAS. This means that premutation carriers are at an increased risk to develop movement issues as they get older. This can affect both males and females. Symptoms of FXTAS include tremors, changes in how they walk and stand, muscle weakness, behavioral changes (such as irritability and anger outbursts), difficulty with decision-making and learning new things, and memory issues. These symptoms usually start after the age of 60.

Is there treatment for Fragile X syndrome?

Although there is no cure for Fragile X syndrome, there are many areas where medical care can be helpful in improving the quality of life for a person with Fragile X syndrome.

For example, early diagnosis can lead to early intervention and access to special education services, which can help a child with Fragile X reach their greatest potential. Because features of Fragile X syndrome can look like other conditions, a diagnosis may not be made right away. However, if the parents had genetic testing prior to having children, they would know they had a chance to have a child with Fragile X, which would likely lead to an earlier diagnosis.

A number of different treatment options exist to help treat other symptoms of Fragile X, including FXTAS and FXPOI. If a woman is found to have the Fragile X premutation, she may use this information for family planning purposes. Some women with an increased chance for FXPOI may decide to expedite their plans to get pregnant, while others may choose to freeze their eggs or go through IVF earlier and freeze embryos to use later.

There are specialty clinics around the country that specialize in providing patients with Fragile X individualized care based on research and experience.

Is genetic testing for Fragile X used for people who have symptoms of Fragile X syndrome?

Genetic testing for Fragile X syndrome is available for any person with autism or developmental delay. The goal of testing is to provide an accurate diagnosis and good medical management. Results of testing will also provide parents and family members information for family planning.

Why consider genetic testing for Fragile X prior to pregnancy instead of waiting until pregnancy?

Genetic testing for Fragile X is a very personal decision. Some women choose to have Fragile X carrier testing to better understand their chances of having a child with Fragile X syndrome. If a woman finds out that she is a Fragile X carrier before pregnancy, she and her partner have more family planning options. For example, many couples don’t realize that even if they have normal fertility, they could use in vitro fertilization (IVF) and genetic testing on embryos or use an egg donor who is not a Fragile X carrier. Others may decide to get pregnant naturally and have genetic testing on the fetus during pregnancy. If the baby has Fragile X syndrome, some may decide not to continue the pregnancy, while others may use the information to better plan for the baby’s arrival and long-term care. There are also some women that may choose not to have children at all or consider adoption.

There is no right or wrong decision when it comes to family planning. It is important for women to understand their options and have the support to make a choice that is right for them.

Does family medical history matter for Fragile X genetic testing?

Family medical history is an important part of the discussion when considering genetic testing for Fragile X syndrome. Because Fragile X syndrome is the most common inherited form of autism, some people have more than one family member with this disorder.

Because not all people have access to genetic testing, there are some individuals who have Fragile X syndrome, but were never accurately diagnosed. This means that there may be an undetected inherited condition running in the family that can impact the health and reproductive chances of many family members.

In thinking about family medical history, it is helpful to consider if there are individuals with autism, intellectual disability, learning issues, neurological problems (like seizures or tremors), or women with premature ovarian failure.

Family medical history can be a sensitive topic and it may be difficult for relatives to ask these questions. However, having access to family medical history information can be very helpful when making decisions about genetic testing and family planning. Mainstream Genomics’ Family Screens can help guide collection of family medical history and allow review by a licensed genetic counselor.

Collecting your family medical history and reviewing it with a genetic counselor will ensure that you are offered access to the right information and can make an informed decision when it comes to your own health and genetic testing options. If a person is adopted or separated from biological family, there are still genetic testing options, like Fragile X carrier testing, available to them that can be discussed with a genetic counselor.

Why should someone planning for pregnancy meet with a genetic counselor instead of talking with their regular care provider?

A genetic counselor is a healthcare professional specially trained in genetic and inherited diseases. A genetic counselor is an expert in reviewing family medical history to decide if there are chances for genetic or inherited diseases in a family. A genetic counselor can also help people decide if genetic testing is right for them based on their health needs, family medical history, and individual values. Although other healthcare providers like physicians are experts in medical care, studies have shown the genetics professionals like genetic counselors are better at assessing genetic risk and choosing the right genetic tests. In fact, over 10% of pregnancies evaluated by a genetics professional have a genetic risk that was not identified through routine prenatal care.

Is genetic counseling the same thing as genetic testing?

Genetic counseling is a process of meeting with a genetic counselor to review health and family medical history and discuss available genetic testing options. As part of this process, a genetic counselor can help a person make a decision on what, if any, testing options are right for them. They will work with that person and support them throughout the decision-making process. If a person chooses to have genetic testing, the genetic counselor will help them order testing and provide guidance every step of the way.

In summary, women and couples planning a family should have access to information about Fragile X syndrome and the available genetic testing options. Because Fragile X syndrome is a common genetic disorder with complex inheritance, genetic testing can have many implications for the whole family, starting with the people planning a pregnancy, to their future children and extended family members, like grandparents, aunts and uncles. The Mainstream Genomics’ Family Screens are a good way to connect with a genetic counselor’s expertise to learn whether Fragile X carrier testing or any other genetic testing.


Sources and Resources:

1. National Fragile X Foundation accessed 2/11/2021.

2. Fragile X Info Series, Fragile X Testing, National Fragile X Foundation, accessed 2/11/2021.

3. Hunter et al, FMR1 Disorders. GeneReviews, National Institutes of Health. Accessed 2/11/2021.

4. Center for Disease Control. What is Fragile X Syndrome? Accessed 2/11/2021.

5. What is autism? Autism speaks. Accessed 2/11/2021.

6. , UCSF Health, Carrier Testing for Fragile X Syndrome. Accessed 2/11/2021.

7. The Oncofertility Consortium, Fragile X-Associated Primary Ovarian Insufficiency. Accessed 2/11/2021.

8. Fragile X Foundation, Fragile X Clinics. Accessed 2/10/2021.

9. Meschede, SD and Horst, J. The practical importance of pedigree analysis in women considering invasive prenatal diagnosis for advanced maternal age or serum screening. Prenatal Diagnosis 2000.

10. Chapman et al. The genetics of premature ovarian failure: current perspectives. Int J Womens Health. 2015; 7: 799–810.

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