What is Fragile X Syndrome? Fragile X syndrome (FXS), caused by extra CGG repeats in the FMR1 gene, is a condition that causes a variety of developmental and behavioral problems. Fragile X syndrome is the most common inherited form of intellectual disability. It is the leading single-gene cause of autism spectrum disorders. Fragile X syndrome is inherited in an X-linked manner. This means the condition is typically more severe in individuals assigned male at birth (XY). However, individuals assigned female at birth (XX) may also have symptoms of the condition. Fragile X syndrome typically causes moderate intellectual disability (defined as an IQ below 70). However, the severity of intellectual impairment varies from individual to individual. As infants, children with fragile X syndrome may have weak muscles (hypotonia), stomach acid that comes up into the mouth (gastric reflux), and frequent ear infections. Their motor, mental, and speech milestones tend to be delayed. Children with fragile X syndrome often have behavioral problems such as anxiety, hyperactivity, hand flapping, biting, and temper tantrums. Autism or autism-like behavior is common. Some individuals with the condition have attention deficit disorder and cannot sustain focused attention on a specific task. Individuals with fragile X syndrome may lack impulse control, make poor eye contact, and be easily distracted. Individuals with fragile X syndrome often share characteristic physical features such as a long, narrow face with a prominent jaw and forehead, a large head, flexible joints, and large ears. These features become more apparent with age. Some individuals with fragile X syndrome will experience seizures. While some experience heart murmurs (mitral valve prolapse), it is usually harmless and may not require treatment. Effects of a premutation Individuals with a premutation do not have fragile X syndrome but may experience specific physical symptoms. The main risks for carriers of a premutation are fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated premature ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND). Fragile X-associated tremor/ataxia syndrome (FXTAS): FXTAS causes an inability to coordinate muscle movements that worsens over time (ataxia), tremors, memory loss, impaired ability to think or remember information (dementia), a loss of feeling and weakness in the lower legs, and some mental and behavioral changes. Typically, symptoms of FXTAS begin around age 60 with a tremor, followed several years later by the inability to coordinate muscle movements. Fragile X-associated primary ovarian insufficiency (FXPOI): This condition causes menstrual periods to stop before age 40. Individuals with FXPOI will often have difficulty getting pregnant, and many will not be able to have children. Individuals with a full mutation are not at increased risk for POI. Fragile X-associated neuropsychiatric disorders (FXAND): There is an increased rate of neuropsychiatric conditions among premutation carriers. These include depression, generalized and social anxiety, and attention deficit disorder. How is Fragile X Syndrome inherited? The inheritance of Fragile X is much more complex than many other genetic diseases. A healthcare professional, such as a genetic counselor, can help answer questions about this condition and the risk of transmitting it to the next generation. Fragile X syndrome is caused by changes in the FMR1 gene, which is located on the X-chromosome. This gene contains a segment of DNA called the "CGG repeat." The CGG repeat in the FMR1 gene is a pattern of DNA that repeats itself many times. By counting the number of CGG repeats in the parents, one can determine the likelihood that a child will have fragile X syndrome. The CGG repeat in the FMR1 gene falls into one of the following four categories: Category FMR1 CGG repeat size Normal 5 to 44 repeats Intermediate 45 to 54 repeats Premutation 55 to 200 repeats Full mutation More than 200 repeats Normal An FMR1 gene with 5 to 44 CGG repeats is considered normal. Individuals with this number of FMR1 CGG repeats do not have an increased chance of having a child with fragile X syndrome. CGG repeats in this range are considered stable because they usually pass from parent to child with the same number of repeats. For example, if a parent's gene has 30 CGG repeats, their child will likely have a gene with 30 CGG repeats. Intermediate An individual with 45 to 54 repeats is not expected to have an increased chance of passing on fragile X syndrome to their child, but the number of repeats transmitted to the next generation may increase slightly. Premutation Individuals with 55 to 200 CGG repeats have a premutation. They do not have symptoms of fragile X syndrome. However, they are at increased risk for FXTAS, FXPOI, and FXAND. Depending on which parent has the premutation, future children may be at risk of having fragile X syndrome. Full mutation Individuals with more than 200 CGG repeats have a non-functioning FMR1 gene (also known as a full mutation). Individuals with more than 200 CGG repeats usually have symptoms of fragile X syndrome. What does it mean to have an intermediate result? An FMR1 gene that has 45-54 repeats is considered intermediate. The number of CGG repeats is higher than normal but not large enough to be considered a premutation. Individuals with an intermediate repeat do not have an increased chance of having a child with fragile X syndrome. Most intermediate genes are stable and do not significantly expand when passed on. However, repeats in the intermediate range may slightly expand when passed on to the next generation in some cases. Children of individuals with an intermediate result may consider fragile X testing to determine their CGG repeat sizes once they are adults for reproductive planning purposes. Approximately 3% of patients undergoing fragile X carrier screening will have an intermediate result. Individuals with an intermediate repeat do NOT have an increased chance of having the physical symptoms affecting premutation carriers such as FXTAS, FXPOI, and FXAND. What does it mean to have a premutation or full mutation? Individuals with a full mutation have a 50% chance of having a child with fragile X syndrome with each pregnancy. Premutations are more complicated. The risk of having a child with fragile X syndrome depends on multiple factors including which parent has the premutation, whether the child will inherit the premutation, and whether the premutation will expand to a full mutation. Premutations are known to expand in a single generation, therefore the children of premutation carriers may be at risk for FXAND, FXTAS, FXPOI or fragile X syndrome. This risk for expansion can be modified by AGG interruptions, which reduce the likelihood of expansion. Rarely, a CGG repeat may contract (or reduce in number). Therefore, there is a small possibility that a premutation could be passed on as an intermediate or normal repeat to the child. The greater the number of CGG repeats an individuals has, the more unstable the gene is and the more likely it will expand to a full mutation in their children. The smallest premutation observed to expand to a full mutation in a single generation is 56 repeats. Number of Maternal Premutation CGG Repeats Percentage (# of individuals) Which Expanded to Full Mutations 55-59 <1% (1/197) 60-64 2% (2/115) 65-69 7% (6/85) 70-74 21% (18/84) 75-79 47% (47/99) 80-84 62% (60/96) 85-90 81% (34/42) More than 94% of genes with >90 CGGs expand to a full mutation. Adapted from Nolin et al. (2015) and Nolin et al. (2011). These percentages typically exclude families with a family history of fragile X syndrome. Given how complex the inheritance for fragile X syndrome is, all carriers of a premutation or full mutation are recommended to have genetic counseling to discuss their exact risks. How common is Fragile X Syndrome? The incidence of fragile X syndrome is estimated to be 1 in 4,000 XY individuals and 1 in 8,000 XX individuals. How is Fragile X Syndrome treated? There is no cure for fragile X syndrome, but children with the condition can be treated and supported in many ways depending on their particular symptoms and the severity of those symptoms. They may benefit from educational support like early developmental intervention, special education classes in school, speech therapy, occupational therapy, and behavioral therapies. A physician may prescribe medication for behavioral issues such as aggression, anxiety, or hyperactivity. A small number of these children experience seizures which can be controlled with medication. While some have a heart murmur, it is usually harmless and may not require treatment. What is the prognosis for an individual with Fragile X Syndrome? While many of the children with fragile X syndrome have learning and behavioral problems, they generally do not have major medical problems and can live a normal lifespan. Other names forfragile X syndrome FXS References Hunter et al., 2019, https://www.ncbi.nlm.nih.gov/books/NBK1384/ Mila et al., 2018, Clin Genet, 93(2):197-205, PMID: 28617938 Nolin et al., 2003, Am Journ Hum Genet, 72(2):454-64, PMID: 12529854 Nolin et al., 2011, Prenat Diagn, 31(10):925-31, PMID: 21717484 Nolin, et al., 2015, Genet. Med. 17: 358–364, PMID: 25210937 OMIM: Online Mendelian Inheritance in Man, OMIM [300624], 2016, http://www.omim.org/300624 Raspa et al., 2017, Pediatrics, 139(Suppl 3):S153-S171, PMID: 28814537