Science Update: Fragile X carriers may be at higher risk for several health conditions, NIH-funded study suggests

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Carriers of the FMR1 premutation—a mutation in the gene associated with the developmental disorder Fragile X syndrome—may have a higher risk for several health conditions, according to an analysis funded by the National Institutes of Health.

Researchers compared genetic data to an extensive database of health care records and found that people with the premutation may be at higher risk for such conditions as depression, anxiety, mood disorders, sleep apnea, respiratory and stomach problems, and bone fractures. Previously, people with the premutation were thought to be at higher risk only for a form of early menopause and for a neurological condition occurring after age 50.

The study was led by Marsha Mailick, Ph.D., of the University of Wisconsin-Madison and appears in Science Advances. Funding was provided by the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, and National Center for Advancing Translational Sciences.


Fragile X syndrome is a genetic disorder associated with intellectual disabilities, autism, anxiety, and sensory disorders. The condition results from a mutation in the FMR1 gene on the X chromosome. People with Fragile X syndrome have 200 or more duplications, or repeats, of a specific sequence of DNA bases in a specific region of the gene. In most people, the region has from 24 to 40 repeats, and they are passed on from parent to child in a stable manner. The FMR1 premutation consists of between 55 to 200 repeats, and the number of repeats often increases between generations. The premutation does not cause developmental disabilities, but does increase the risk for two conditions: Fragile X-Associated Primary Ovarian Insufficiency, a form of early menopause, and Fragile X Associated/Tremor and Ataxia Syndrome, which results in problems with movement and thinking ability in people over 50.

Some studies have suggested that premutation carriers also may be at risk for other conditions, such as disorders of the immune system, migraines, fibromyalgia (generalized muscle and skeletal pain), neuropathy (weakness, numbness, and pain), infertility, depression, and anxiety. However, researchers have been unable to determine whether these symptoms are the direct result of having the FMR1 premutation. One alternative explanation is that after their diagnosis, patients and their physicians may be more likely to notice health problems and attribute them to the premutation. Another alternative explanation is that the symptoms of carriers result from the stress of caring for a child with Fragile X syndrome. The researchers sought to distinguish between these possible explanations.


The researchers used an artificial intelligence program to analyze 40 years of health records and DNA samples of nearly 20,000 patients in a Wisconsin-based health care system. The search identified 98 premutation carriers (72 females and 26 males). The researchers compared the premutation carriers to 1,000 people without the premutation, roughly 500 males and 500 females. Premutation carriers were matched to noncarriers of the same age and who had been members of the healthcare system a similar length of time. Carriers and noncarriers also had a similar likelihood of parenting a child with a disability.

The researchers found that female carriers were more likely than noncarriers to have mental disorders like agoraphobia (fear of any place or situation where escape might be difficult), social phobia, and panic disorder. They were also more likely to have reproductive system problems, such as infertility and endometriosis, as well as injuries such as sprains and bone fractures. Other health issues that occurred more frequently in female carriers were sleep apnea; circulatory system problems; skin conditions such as acne, cellulitis, and skin ulcers; and muscle pain and inflammation.

Male carriers were more likely than noncarriers to have mental disorders, such as depression and mood disorder; respiratory symptoms, like chronic sinusitis and shortness of breath; and urinary incontinence.


These findings suggest that the FMR1 premutation is associated with a wider range of symptoms and health effects than was previously known. Knowledge of these effects may inform the health care of FMR1 premutation carriers.


Movaghar A, et al. Data-driven phenotype discovery of FMR1 premutation carriers in a population-based sample. Science Advances. DOI: 10.1126/sciadv.aaw7195.

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