International Fragile X Premutation Registry Aims to Improve, Speed Research
Registry enrolling patients with premutations, family members and at-risk adults
The International Fragile X Premutation Registry (IFXPR) — now enrolling — aims to accelerate research to better understand the impact on health of premutations in the gene associated with fragile X syndrome.
One goal of the IFXPR, launched in the U.S. in 2020 and since going global, is to build community by supporting collaboration among premutation carriers and their families, and researchers and clinicians.
Adults with the premutation, family members without an FMR1 mutation (controls), and untested individuals at risk of carrying the premutation by inheritance can register on the IFXPR webpage after completing an initial survey.
Details of the registry were published in the Journal of Medical Genetics, in a report titled “The International Fragile X Premutation Registry: building a resource for research and clinical trial readiness.”
The FMR1 gene contains repeats of CGG in its DNA sequence, in which C stands for cytosine and G for guanine — two of the four building blocks of DNA.
The number of these CGG repeats normally ranges from 5 to 40. In contrast, people with more than 200 repeats develop fragile X syndrome, marked by delays in intellectual ability, language development, and social awareness.
Investigating the fragile X premutation FMR1 PM
Repeats ranging from 55 to 200 are called the FMR1 premutation — known colloquially as FMR1 PM. Although those who carry the FMR1 PM do not typically develop fragile X, they have an increased risk of late-onset fragile X-associated tremor and ataxia syndrome (FXTAS). In male patients, FXTAS is characterized by cognitive and movement impairment, and in females, by primary ovarian insufficiency (FXPOI).
Beyond motor and reproductive challenges, those with the FMR1 PM present a broad range of other symptoms. These include nerve pain and fibromyalgia, low thyroid hormones, autoimmune disorders, cognitive impairment, and psychiatric problems. Individuals with this fragile X premutation also may have autonomic dysfunction, or impairments related to automatic bodily processes.
However, these broad-ranging additional mental and general health conditions in people with FMR1 PM are not well-characterized. Further, these conditions may fall under umbrella terms common among the general population. As a result, it may be more challenging to confirm a direct connection to FMR1-related disease.
The IFXPR was created to accelerate research to better understand the FMR1 PM and its impact on health. Its key goal is to build community and support collaboration among researchers and clinicians, as well as FMR1 PM carriers and their families. It also will help to identify and characterize diverse groups of clinical trial study participants.
The global registry was built on a partnership between the National Fragile X Foundation (NFXF) in the U.S., the University of California Davis MIND Institute, and members of an international advisory committee. That committee includes four psychologists, four movement disorder neurologists, a geneticist, two general physicians, and five administrators or members of international fragile X associations.
Individuals who register provide basic information regarding FMR1-related genetics, FXTAS and/or FXPOI diagnosis, demographics, and health conditions during the past year.
During registration, participants are presented with an introductory video, frequently asked questions, video instructions, and supporting materials. A legally authorized representative may provide consent and input registrant information for those with impaired mental abilities.
As of January 2022, 747 individuals from 32 countries had registered. Participants range in age from 18 to 90 and, among them, 578 self-identify as FMR1 PM carriers. Of these registrants, 87% are female. CGG repeats ranged from 55 to 200.
The most common reason for FMR1 genetic testing was a positive test for fragile X within a family, whereas 10.2% reported being tested because of a fragile X-related clinical problem. Most (77.9%) were interested in providing biological samples, while about half (50.3%) indicated they had an interest in being a tissue donor after death.
Researchers do not have direct access to registry data or the participants, as privacy controls. However, they may request a summary of registrant statistics and/or numbers of potential participants for their research and, if needed, a letter of support for IFXPR access. The application for researchers is via a web-based form submitted to the NFXF IFXPR webpage.
Because registrants input their own information, local experts cannot contribute data. In the future, the IFXPR will expand to include registrant data through collaborations with fragile X clinics. The registry also will collect laboratory data relevant to risk, progression, and other disease characteristics.
The IFXPR is employing strategies to help increase the ethnic and racial diversity of registrants, as well as improve the proportions of men to women. Family members also are being encouraged to register as controls.
“With larger numbers, increased diversity and potentially the future clinical characterisation of registrants, the IFXPR will contribute to a more comprehensive and accurate understanding of the fragile X premutation in human health and support treatment studies,” the researchers wrote.
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