What does it mean to be a carrier for fragile X syndrome?
October 15, 2024
One of the genetic carrier screenings available to pregnant patients tests for fragile X syndrome, the most common inherited cause of intellectual disability.
Triggered by a mutation in the FMR1 gene on the X chromosome, fragile X syndrome affects about 1 in 7,000 males and about 1 in 11,000 females. These individuals may have delayed speech and motor skills, hyperactivity, and social and emotional challenges. Fragile X syndrome is also associated with 1%-6% of cases of autism spectrum disorder.
While having fragile X syndrome is not particularly common, it is far more common to be a carrier – a person with an altered version of the FMR1 gene who does not show any symptoms of the syndrome.
About 1 in 150-300 women and 1 in 400-850 men are believed to be carriers of an FMR1 premutation, meaning the gene is changed enough to be passed on during pregnancy but not enough to cause the full syndrome in the parent. Most women who are carriers for fragile X syndrome will have a healthy pregnancy, though there are some considerations to keep in mind.
Carriers of fragile X mutations are at increased risk of certain conditions, such as early menopause or a movement disorder called fragile X-associated tremor/ataxia syndrome. Many carriers of fragile X syndrome have no associated health conditions.
You may not have heard of fragile X syndrome. The American College of Obstetrics and Gynecology currently recommends offering people who are considering pregnancy or who are pregnant carrier screening for cystic fibrosis, spinal muscular atrophy, and hemoglobinopathies (with other offerings based on ethnicity or family history). However, the American College of Medical Genetics advocates for offering carrier screening for conditions with at least a 1 in 200 carrier frequency, which does include fragile X syndrome.
Let’s dive into the science of fragile X syndrome and what it means to be a carrier of this genetic mutation.
How the fragile X mutation works
All genes are made of DNA, which is in turn made of nucleotides. Think of nucleotides as the building blocks of DNA. There are four types of nucleotides, commonly referred to by their first letter: A, C, G, and T. These appear in unique combinations in DNA. Depending on the order and number of these nucleotides, your genes provide the instructions for body processes, from building proteins to regulating growth.
There’s a portion of the FMR1 gene, which is located on the X chromosome, where the nucleotides repeat as CGG, CGG, CGG. Less than 45 repeats is considered in the normal range. For people with fragile X syndrome, this portion repeats over 200 times, making the gene not work normally. People with between 45 and 200 repeats don’t have fragile X syndrome but are considered carriers of the mutation. As the repeat number increases over 45, the gene becomes less stable as it is transmitted from generation to generation. The number of repeats you have matters:
- If you have between 45 and 54 repeats, this is referred to as being an “intermediate carrier.” This repeat range has never been reported to expand to over 200 in one generation.
- If you have between 55 and 200 repeats, this is referred to as being a “premutation carrier.” If you pass down the gene in the premutation range in an egg, there is a possibility of the gene expanding to have more than 200 repeats in your child and therefore to have a child with fragile X syndrome – the larger the premutation repeat number, the higher the likelihood. Premutation carriers also typically have a second copy of the FMR1 gene with a normal repeat number on their second X chromosome and a 50% chance to transmit this normal range repeat number to each of their children.
Testing for fragile X status during pregnancy
A test for fragile X carrier status in the parents is a simple blood draw and can be easily done before, during, or after pregnancy.
Among those with no symptoms, we typically test only women for carrier status. That's because the expansion of the FMR1 gene only tends to happen in eggs, not in sperm. This means that unless a man is affected with fragile X syndrome himself, he is not at risk to transmit fragile X syndrome to a child.
Patients with a personal or family history of fragile X syndrome symptoms may wish to pursue testing as well. Symptoms of fragile X syndrome can include:
- Developmental delays: Significant delays are found in reaching milestones such as walking, talking, or motor skills.
- Intellectual disabilities: Difficulties with cognitive functions affect learning, problem-solving, and understanding.
- Learning disabilities: Challenges in acquiring and applying academic skills, such as reading, writing, or math, occur.
- Attention-deficient/hyperactivity disorder (ADHD): Persistent patterns of inattention, hyperactivity, and impulsivity affect functioning and development.
- Certain physical features: Common features include a prominent jaw and forehead, unusually flexible fingers, long and narrow facial features, flat feet, or large ears.
Health conditions associated with fragile X premutation carriers (but not associated with intermediate carrier range genes) include:
- Tremor/ataxia syndrome: Symptoms affect movement and thinking ability, including tremors, balance problems, memory loss, difficulty with coordination, and cognitive decline. This condition occurs in 40% of men and 16% of women who are fragile X carriers and usually develops after age 60.
- Early menopause in women: Menopause prior to age 40 is seen in 20% of women who are premutation carrier
I’m a carrier for fragile X: What now?
Before pregnancy
Because some women who are carriers of fragile X experience early menopause, an egg retrieval may be considered to collect eggs from a woman’s ovaries to store for future pregnancy. Additionally, if a woman who desires to carry a pregnancy is found to have a premutation, she may also consider pursuing alternatives to spontaneous conception such as IVF with an egg donor who is not a premutation carrier, or embryo adoption from a similarly tested family, or IVF with preimplantation genetic testing in an effort to choose an embryo for transfer that does not have over 200 repeats.
During pregnancy
Chorionic villus sampling (CVS) or amniocentesis can help determine whether the baby has fragile X syndrome by analyzing the placental or fetal genetic material. This allows for early diagnosis and helps you prepare. Fragile X status generally does not complicate pregnancy or delivery and does not have findings amenable to ultrasound diagnosis.
After pregnancy
If your child has fragile X syndrome, talk with your pediatrician to create a treatment plan tailored to your child's needs. This may involve managing symptoms through medication for issues such as anxiety, ADHD, or seizures, along with therapies that address specific challenges in communication and behavior. Specialists including behavioral pediatricians and speech, occupational, or ABA therapists, as well as other educational resources, are available to help your child.
Genetic testing is a personal choice that some people pursue to better understand their risk factors. If you decide to pursue genetic testing before or during pregnancy, a genetic counselor can help you decide whether to test for fragile X syndrome and offer support if necessary. If you discover that you’re a carrier for fragile X syndrome, your team will help you understand your risks and manage them with respect to pregnancy as well as your future health.
To talk with an expert about genetic counseling before or during pregnancy, call 214-645-8300 or request an appointment online.
