The clinical profile of FMR1 premutation carriers — individuals who have 55 to 200 CGG repeats in their fragile X mental retardation 1 gene sequence instead of the normal 24 to 40 — is markedly different from that of healthy people, a study found.
Individuals with that profile may have an increased risk toward certain mental health disorders, which should be taken into consideration by their healthcare providers, the investigators say.
The study, “Data-driven phenotype discovery of FMR1 premutation carriers in a population-based sample,” was published in Science Advances.
Fragile X syndrome (FXS) is the most frequent single genetic cause of autism spectrum disorder (ASD). It is caused by the expansion of CGG repeats in the FMR1 gene, which provides instructions for making a protein called fragile X mental retardation protein (FMRP). Full mutation carriers — those usually diagnosed with fragile X syndrome — typically have more than 200 CGG repeats.
Those who are premutation carriers, who have between 55 and 200 CGG repeats, do not have fragile X syndrome. However, they might have an associated disorder, such as fragile X-associated primary ovarian insufficiency (FXPOI), or fragile X-associated tremor/ataxia syndrome (FXTAS). FXPOI compromises a woman’s ovary function and can lead to infertility and early menopause. Primarily affecting older patients, FXTAS is a condition characterized by motor and cognitive impairments.
Researchers note that there is still considerable controversy in the medical community regarding the impact of FMR1 premutations on the overall health of individuals who carry them. One of the most basic, yet still unanswered questions, is whether these premutations are truly linked to the clinical symptoms these patients experience.
However, so far, studies focused on exploring the interaction between premutation carriers’ genetic backgrounds and clinical signs have failed to do so in a systematic and unbiased manner. That, the investigators say, “could lead to invalid research conclusions and negatively affect clinical practice.”
In this study, researchers from the University of Wisconsin–Madison and their collaborators sought to create the first U.S. population-based FMR1-informed biobank. Their goal was to compare — in a systematic and unbiased way — health characteristics of premutation carriers with those of individuals who had a normal number of CGG repeats in FMR1 (controls).
Researchers created the biobank by connecting clinical information found on the electronic health records (EHRs) of 19,996 adults to their FMR1 genetic data.
“The approach we used was double blind, as neither the patient nor the provider was aware of the individual’s FMR1 status, and so expectancy of associated conditions cannot account for the patterns,” they said.
From the 19,996 individuals included in the biobank, a total 98 people — 72 females and 26 males — were considered premutation carriers based on their genetic profile. These were the individuals selected for inclusion in the study. As a reference for comparison, a subgroup of 1,001 individuals carrying 24 to 40 CGG repeats in FMR1 (normal range), matched for birth year and time of clinic healthcare, also were included in the study.
Using a machine-learning approach to extract information from the electronic health records, researchers managed to distinguish and characterize premutation carriers from controls.
Analyses revealed that premutation carriers had higher rates of injuries and bone fractures compared with controls. In addition, certain mental disorders, including anxiety, depression and panic disorder, tended to be more prevalent and severe among premutation carriers than controls.
“Psychiatric counseling, therapeutic intervention, [specific instructions about avoiding certain risky behaviors] and proper medication will be helpful in improving these conditions” in premutation carriers, the researchers said.
There were no significant differences in the number of annual clinic visits between premutation carriers and controls. However, the team found that for the medical conditions identified as being more prevalent in premutation carriers, the number of medical visits was higher for the premutation carriers than for the controls.
“In other words, the premutation is associated with a unique pattern of health conditions,” the investigators said.
Moreover, for these specific health conditions, the researchers found that premutation carriers tended to be diagnosed at a much younger age compared with controls.
“Our [study] shows that premutation carriers experience a clinical profile that is significantly different from controls and is evident throughout adulthood. Comprehensive understanding of the clinical risk associated with this genetic variant is critical for premutation carriers, their families, and clinicians and has important implications for public health,” they said.