What is fragile X syndrome?
Fragile X syndrome is the most common inherited cause of intellectual disability and autism. The gene that causes fragile X syndrome helps in the development of neuronal synapses. Therefore, mutations in this gene lead to delayed developmental milestones, a moderately low IQ, and atypical behavior. Individuals with fragile X syndrome often have characteristic physical traits, such as large ears, a long face, and large testicles. Some may have medical problems including joint flexibility, low muscle tone, mitral valve prolapse, seizures, and eye problems.
Preimplantation genetic testing (PGT) may offer families with a risk for fragile X syndrome the option of conceiving without the concern of passing the condition on to a future generation.
How is fragile X syndrome inherited?
Fragile X syndrome is an X-linked condition and is caused by a mutation in a gene called FMR1, which is located on the X chromosome. Males typically have only one X chromosome and therefore experience the disease-causing effects of the mutation with greater severity and frequency. Since females have two X chromosomes, they generally experience less severe symptoms, or no symptoms at all.
What does it mean to be a carrier of fragile X syndrome?
Fragile X syndrome is a unique X-linked condition. The mutation on the FMR1 gene is called a trinucleotide repeat expansion, which is a sequence of three DNA nucleotides that is repeated many times. DNA segments with these repeats are called alleles. Large alleles are unstable, or “fragile,” and so the number of repeats can change as the gene is passed from generation to generation. In this way, some carriers of the FMR1 mutation can have no symptoms, but if the repeat size of their mutation increases to a critical point when passed to their child, then the child may be symptomatic. As the expansion continues to grow from one generation to the next, symptoms can become more and more severe. This process is called anticipation.
There are four categories of FMR1 alleles:
- Normal allele: less than 45 repeats
Generally stable. These individuals do not have symptoms.
- Intermediate, “grey zone,” or “borderline” alleles: 45 to 54 repeats
Some alleles in this category are unstable and can become larger when passed to a child. However, they will not expand to a full mutation. So, children of carriers of intermediate alleles are not at risk of fragile X syndrome.
- Premutation alleles: 55-200 repeats
Many alleles of this size are unstable and can expand to a full mutation. Carriers of a premutation allele can have a child with fragile X syndrome, although this risk depends on their specific allele size.
- Full mutation allele: greater than 200 repeats
Alleles of this size are unstable. Carriers of a full mutation allele can have an affected child. Also, about half of female carriers of a full mutation allele have symptoms of fragile X syndrome and are considered to be affected.
- Normal allele: less than 45 repeats
A genetic counselor can help you better understand your allele status and your risk to have a child with fragile X syndrome, which may help guide your decision about whether PGT is a good option for you.
Do carriers of fragile X syndrome have any health risks?
Carriers of intermediate alleles are not expected to have any health problems related to their fragile X syndrome carrier status. Carriers of premutation and full mutation alleles can experience FMR1-related disorders:
- Both male and female carriers of premutation alleles are at risk for fragile X-associated tremor/ataxia syndrome, or FXTAS. FXTAS causes tremor, balance problems, memory loss, and trouble with problem-solving. A premutation carrier’s risk of FXTAS increases with age. Sometimes FXTAS is confused with Parkinson’s disease.
- Female carriers of premutation alleles are also at an increased risk of fragile X-associated primary ovarian insufficiency, or POI. POI causes women to enter menopause earlier than average, usually before the age of 40. As such, premutation allele carriers are at risk of infertility due to POI. Female carriers of full mutation alleles are not at an increased risk of POI.
How is fragile X syndrome treated?
Both males and females with intellectual disabilities and behavioral challenges can benefit from early educational interventions. Boys with fragile X should be monitored for muscle or joint problems, eye problems, heart problems, or seizures. Adults with FXTAS may need support for their tremor and balance problems. Women with POI may benefit from an early conversation with a reproductive fertility expert.
What is preimplantation genetic testing and is it available for fragile X syndrome?
Preimplantation genetic testing (PGT), also historically referred to as preimplantation genetic diagnosis or PGD, is a technique used to screen embryos for specific genetic diseases. Because the condition is so common, many women seek IVF with PGT for fragile X syndrome. PGT for fragile X syndrome can be challenging because of POI in premutation allele carriers and technical challenges with the FMR1 gene. Scientists are working to improve this technology for fragile X syndrome. If a family is at risk of having a child with fragile X syndrome, it is important to speak with a fertility expert familiar with PGT and fragile X syndrome. The option of IVF with PGT provides an alternative route to conception that may help reduce stress and anxiety for families at risk for the condition.
Elysia is a board-certified Reproductive Genetic Counselor and Clinical Instructor at the University of North Carolina in Chapel Hill. She received her Bachelor’s in Science at the University of Maryland in College Park and her Master’s in Genetic Counseling from the University of Maryland in Baltimore. In her role as educator, Elysia is involved in didactic and clinical teaching of a variety of learners, including medical students, residents, and fellows, as well as genetic counseling students. As a clinician, Elysia provides genetic counseling services for patients considering pregnancy and who are currently pregnant. Elysia has enjoyed a number of leadership roles in professional committees with the National Society of Genetic Counselors, the American Board of Genetic Counseling, and the Accreditation Council for Genetic Counseling.