Last updated:
3/31/2026
Years published: 1988, 1989, 1990, 1991, 1994, 1995, 1997, 1998, 1999, 2006, 2010, 2017, 2026
NORD gratefully acknowledges Anthony DeSano, Ryan McLaughlin and Daniella Fonseca, Editorial interns from the University of Notre Dame, and Elizabeth Berry-Kravis, MD PhD, pediatric neurologist, Rush University Medical Center, Chicago, IL for their assistance in the preparation of this report.
Fragile X syndrome is characterized by mild to severe intellectual disability. It primarily affects males, but females can also be affected, with symptoms ranging from no intellectual disability to severe impairment..1 Distinctive physical features are variably present in affected males including a large head, long face, prominent forehead and chin, protruding ears, loose joints and large testes, but these features develop over time and may not be obvious until puberty.2 Motor and language delays are usually present but also become more apparent over time.3 Behavioral differences including autistic behaviors are common.4
Fragile X syndrome is caused by expansion of a CGG repeat sequence in the promoter region of the FMR1 gene.5 FMR1 is located on the X chromosome and produces a protein called FMRP needed for proper cellular function.6 Inheritance is X-linked with variable expression, and it is often more severe in males.
The syndrome became known as the “Fragile X syndrome” because individuals with the disorder were found to have a segment of their X chromosome that appeared to be broken or fragile (although not completely disconnected) when their cells were grown in folate-deficient media.7 Later it was learned that the FMR1 gene is located precisely where the X chromosome appears to be “fragile” in affected individuals and the expanded CGG repeat sequence is what causes the fragile appearance.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. The FMR1 gene is located at “chromosome Xq27.3” which refers to band 27.3 on the long arm (q) of the X chromosome where the FMR1 gene is located.8,9 The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The FMR1 gene produces a protein known as FMRP. The absence or reduction of the FMRP protein causes fragile X syndrome.10. Nearly all affected individuals have an instability within the gene leading to an increased number of copies of a portion of the gene called the CGG repeat region (also sometimes called “trinucleotide” or “triplet” repeat region).11 When the number of CGG repeats exceeds 200, abnormal chemical changes occur in the promoter region of the FMR1 gene, which acts as an on-off switch controlling gene activity. This process, called methylation, turns the gene off. The expansion to more than 200 repeats is known as a “full mutation” and is typically accompanied by methylation, which prevents the production of the FMRP protein and leads to fragile X syndrome.
However, partial methylation of FMR1 gene may lead to some (variable) production of the FMRP protein which can result in an atypical presentation in which affected individuals may be higher functioning with an IQ score in the borderline (70-85) or even normal (>85) range.12
Variants in theFMR1 gene are unusual when compared to variants found in other genes. Some individuals carry between 55 – 200 CGG repeats called a “premutation,” which has been typically thought to present without any symptoms of fragile X. However, research has shown that some individuals with the premutation may have some symptoms associated with fragile X, such as facial features, behavioral abnormalities like ADHD and anxiety, as well as other health issues.13 Furthermore, these individuals are at risk for having children or grandchildren with fragile X syndrome, and also at risk for two adult onset disorders, fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). The conditions have been termed FMR1-Related Disorders.
Fragile X syndrome causes mild to severe intellectual disability in males, while females show a wider range of effects, from no intellectual disability to severe impairment, due to the variable nature of the condition. The physical features in affected males are variable and may not be obvious until puberty. These symptoms can include a large head, long face, prominent forehead and chin, protruding ears, loose joints and large testes.14 Other symptoms can include:12
Other problems may include motor delay, delayed language development, hyperactivity, and behavior problems. Autism spectrum disorder (ASD) is present in about 50%-70% of the affected people.12 Autistic behaviors such as poor eye contact, hand flapping, and/or self-stimulating behaviors are also common. Motor and language delays are usually present but become more apparent over time.
As mentioned above, fragile X syndrome is caused by a change (variant or mutation) in the FMR1 gene located on the X chromosome at position Xq27.3. Individuals with fragile X syndrome, in more than 99% of cases, have a completely altered (full mutation) FMR1 gene, meaning that they have over 200 CGG repeats, and abnormal methylation of the gene. Methylation is a process by which a chemical methyl group is added to the DNA. The abnormal methylation of the FMR1 gene, which is associated with fragile X syndrome, prevents the production of the FMRP protein needed for typical development.
On rare occasions some people with fragile X syndrome have a partial or complete loss of the FMR1 gene due to a deletion of the region of the DNA on the X chromosome where FMR1 is located and have the syndrome because their cells do not produce FMRP. Very rarely, some people with fragile X syndrome have a variation in a single DNA base (called point mutations) resulting in absent or defective FMRP.15 FMRP is involved in making connections between neurons (nerve cells) in the brain.16 The absence or severe reduction of this protein leads to the symptoms of fragile X syndrome.
The “premutation” refers to having 55–200 CGG repeats and it is considered unstable. People with a premutation do not have fragile X syndrome, but they are at risk of developing adult-onset conditions such as FXTAS and FXPOI. In some cases, especially with larger premutations, the expanded repeat can interfere with normal protein production, leading to reduced levels of FMRP and the development of certain features associated with fragile X. 13
When passed from generation to generation the premutation may be unstable and become a full mutation, but the risk for instability is different depending upon whether a female or male is transmitting the premutation.17 Females with a premutation of the FMR1 gene are at risk to have children with fragile X syndrome because the number of CGG repeats can increase to over 200 when the gene is passed into the next generation. The greater the number of copies of CGG in a premutation, the more likely these will increase to become a full mutation causing fragile X syndrome in offspring. In normal and stable alleles, the CGG region is interrupted by an AGG triple every 9-10 nucleotide bases. AGG genotyping can also be performed to locate these interruptions as the number of AGGs in a premutation is linked to a reduced risk of expansion to a full mutation.22
When males with a premutation reproduce, their male offspring have no risk to inherit the premutation because fathers do not contribute an X chromosome to their sons. In contrast, female offspring whose fathers have a premutation always inherit the premutation and thus grandchildren of males with the premutation are at risk to have fragile X syndrome. Because the premutation does not expand above 200 repeats when transmitted from father to daughter, the daughters are never affected with fragile X syndrome. However, their children are at increased risk because the premutation may be unstable when transmitted to the next generation.
Normal FMR1 genes have approximately 5-44 CGG repeats and this number remains stable from generation to generation. Occasionally, in some individuals with 45-54 repeats there will be some minor instability such that these individuals will have several more (or less) repeats than their parents. An FMR1 repeat number between 45 and 54 is called “intermediate” or “gray zone”, but this minor instability does not lead to any symptoms of fragile X syndrome or the FMR1-related disorders.
The exact number of patients with Fragile X syndrome is unknown; however, current estimates indicate that about 1 in 7,000 males and 1 in 11,000 females in the United States are affected.19 However, about four times as many females appear to be carriers of the altered gene as do males (1:250 females and 1:1000 males). Fragile X syndrome has been found in all major ethnic groups and races.20
Over 99% of individuals with Fragile X syndrome have a full mutation (over 200 CGG repeats and abnormal methylation) in the FMR1 gene. Diagnosis of FXS is made through specialized molecular genetic testing. A definitive diagnosis typically requires more than 200 CGG repeats. In contrast, FXTAS and FXPOI are usually associated with repeat sizes ranging from 50 to 200 CGG repeats. Molecular genetic testing is used to determine the number of CGG repeats in the FMR1 gene and testing to determine methylation status of the FMR1 gene is often used to follow up a finding of an expanded CGG region.23 When no expansion of the CGG repeat sequence is detected, but FXS is still suspected, then multigene panels, whole exome sequencing or whole genome sequencing might be useful for diagnosis.
Chromosome analysis using special techniques to induce fragile sites in chromosomes was once used to diagnose fragile X syndrome, but this technique is no longer used in the diagnosis of this syndrome because it is both less accurate and costlier than are molecular techniques.
Treatment
Treatment options for fragile X syndrome focuses on improving the lives of affected individuals and their families.24 These include special education, speech, occupational, and sensory integration training, individualized educational support, and behavior modification programs.22,25 With educational efforts, therapy, and support, all individuals with fragile X syndrome can make progress. It is suggested that these therapies are used in conjunction with psychopharmocologic treatments when behavior limits functioning.22 Other treatments may depend on an affected individual’s specific symptoms. Genetic counseling is recommended for affected individuals and their families.
There are certain agents that affected individuals should avoid. For FXTAS affected individuals, they should avoid anticholinergic agents (medicines that block certain nerve signals to help relax muscles) due to worsening of cognitive effects, excessive use of alcohol due to potential postural instabilities and cerebellar dysfunctions (trouble with balance, movement, or coordination), and drugs that might have cerebellar toxicity side effects. For people with FXPOI, use of tobacco products might result in lowering of ovarian reserve and age on FXPOI onset.22
There are numerous fragile X Clinics in the US and throughout the world. These clinics specialize in treatments, therapies, and support for individuals with Fragile X syndrome and can guide parents to medication options to address specific symptoms. New medications are likely to become available to treat affected individuals and the specialty clinics can assist parents with current information.26
For a detailed discussion of the treatment options and available Interventions please go to the National fragile X Foundation website ( https://fragilex.org/learn/treatment-and-intervention/).
In determining the phenotypic outcomes (physical manifestations) of females with fragile X, the activation ratio (AR) is currently being investigated through case studies.27 AR is only in females. The AR is the fraction of the normal allele carried on the active X chromosome. Case studies have determined that lower ARs correspond to worse performance in most cognitive, mathematical, behavioral, and social skills. However, some considered areas such as time perception and gait analysis do not show worse performance.
There are many researchers who are actively working on treatments for Fragile X syndrome. In May 2024, the FDA granted Fast Track designation to SPG601, a potential FXS treatment from Spingogenix.29 Trials with SPG601 have provided promising preliminary data, showing that it could address underlying synaptic deficits in patients. Another company, Tetra Therapeutics has ongoing trials for its advanced PDE 4D inhibitor called zatolmilast, which has shown promising data in both animal and phase 2 human trials.30 Data from these trials have shown statistically significant improvement in patients with FXS: behavior, quality of life, electrophysiology (how electrical signals work in the body), and cognition all improved.
Information on current clinical trials is posted on www.clinicaltrials.gov.
All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View reportGeneReviews has an article on this condition covering diagnosis, management, and inheritance. Each article is written by one or more experts on the specific disease and is reviewed by other specialists. The article contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. The GeneReviews database is managed by the University of Washington.
View reportPlease complete this form to access the requested resource.
