A premutation is a specific type of change within a person’s genetic code that represents an intermediate state. While it does not cause a fully expressed genetic disorder, it can be associated with its own set of health considerations for the carrier. This genetic alteration is also unstable as it is passed from one generation to the next. This instability means the premutation can expand into a more significant mutation in a person’s children, which carries different implications.
Defining a Premutation
A premutation is defined by a change in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, on the X chromosome. This gene contains a repeating DNA pattern known as a CGG triplet repeat. In most people, the FMR1 gene has between 5 and 44 repeats. A premutation is characterized by having an intermediate number, in the range of 55 to 200. This is distinct from a full mutation, where the number of repeats exceeds 200 and often leads to the silencing of the FMR1 gene.
The genetic sequence in the premutation range is considered unstable, primarily relating to its transmission to offspring where the number of CGG repeats can increase. While the FMR1 gene in a person with a premutation is still active, it produces elevated levels of messenger RNA (mRNA). This overproduction, rather than a lack of the gene’s protein product, is believed to cause the health conditions associated with being a carrier.
The stability of the CGG repeat sequence is influenced by adenine-guanine-guanine (AGG) interruptions. These AGG sequences act as stabilizing anchors within the gene. The number and placement of these interruptions affect the likelihood of the premutation expanding when passed to the next generation, with fewer AGGs increasing the risk of expansion.
Associated Health Conditions
Individuals who carry an FMR1 premutation are at risk for developing specific health conditions, distinct from the syndrome caused by the full mutation. The two most well-documented are Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) and Fragile X-associated Primary Ovarian Insufficiency (FXPOI). These conditions arise from the effects of the premutation itself, not the absence of the FMR1 protein.
FXTAS is a neurodegenerative disorder affecting carriers in later life, with onset between 60 and 65 years of age. Symptoms include intention tremor (shaking during purposeful movements) and gait ataxia (problems with balance and coordination), along with potential cognitive decline. FXTAS is more common in male carriers, affecting about 40%, compared to 16-20% of female carriers.
FXPOI affects female carriers and is characterized by reduced ovarian function, leading to irregular menstrual cycles, infertility, and early menopause (before age 40). About 20% of women with a premutation develop FXPOI, compared to 1% in the general population. Beyond these conditions, carriers may have an increased risk for other issues, including:
- Anxiety
- Depression
- Autoimmune disorders
- Migraines
Inheritance Patterns and Family Planning
The inheritance of an FMR1 premutation follows an X-linked pattern with unique considerations due to its instability. A male carrier will pass the premutation to all of his daughters but none of his sons. The CGG repeat number tends to remain stable when passed from a father, so his daughters inherit the premutation, not a full mutation.
For a female carrier, the situation is different. A woman with a premutation has a 50% chance of passing the altered FMR1 gene to each of her children. When a mother passes on the premutation, the CGG repeat sequence is prone to expansion, a phenomenon known as maternal expansion. This can cause the premutation to enlarge into a full mutation in her offspring, which causes Fragile X syndrome.
The likelihood of expansion is related to the size of the mother’s premutation, with a larger number of CGG repeats increasing the risk. For example, women with over 100 repeats face a much greater risk than women with smaller premutations. These complexities make genetic counseling a valuable resource for carriers or those with a family history of Fragile X-related disorders who are planning a family.
Diagnosis and Monitoring
Identifying an FMR1 premutation is done through a DNA blood test. The most common methods are polymerase chain reaction (PCR) and Southern blot analysis. PCR can accurately determine the number of CGG repeats in the FMR1 gene, identifying whether an individual has a normal, intermediate, premutation, or full mutation allele. For larger expansions, Southern blot analysis is often used to confirm the size and assess if the gene has been turned off.
Testing is recommended for individuals with a family history of Fragile X syndrome, FXTAS, or FXPOI, or for those with consistent symptoms. This includes women with primary ovarian insufficiency or older adults with tremor and balance problems. Prenatal testing can also be offered during pregnancy to known carriers.
Once identified, a premutation carrier’s long-term health management includes monitoring for symptoms of associated conditions. For instance, a female carrier might be monitored for signs of early menopause, while an aging male carrier is observed for neurological symptoms. If symptoms arise, management focuses on specific issues, such as medication for tremor or hormone therapy for ovarian insufficiency.