Human DNA contains small, repeating sequences. One is the CGG trinucleotide repeat—composed of cytosine, guanine, and guanine—which appears multiple times in a row. These repeats are a normal feature of everyone’s genetic code, but the number of repetitions differs from person to person. When the number of CGG repeats surpasses a typical range, it can disrupt genetic function and lead to specific health conditions.
The FMR1 Gene and Its Function
The CGG trinucleotide repeat is located within the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, which resides on the X chromosome. This gene holds the instructions for creating a protein called FMRP. This protein is produced in many cells, including in the brain, testes, and ovaries, though its role in the brain is the most well-understood.
In the brain, FMRP helps regulate synapses, the connections between nerve cells that enable communication. FMRP is involved in synaptic plasticity, a process where synapses adapt based on experience, which is important for learning and memory. It manages this by transporting messenger RNA (mRNA) molecules and controlling when they are used to build proteins. A disruption in FMRP production can interfere with normal brain development.
Understanding CGG Repeat Count Categories
Genetic testing can determine the exact number of CGG repeats within the FMR1 gene, which is then classified into one of four categories. These classifications help to predict the gene’s stability and potential health implications for an individual and their future children. The number of repeats directly influences how the FMR1 gene functions.
The majority of people have a normal repeat count, which ranges from 5 to 44 CGG repeats. In this range, the FMR1 gene functions as expected, producing adequate amounts of FMRP. The gene is stable, meaning the number of repeats is not likely to change when passed to the next generation. Individuals in this category are not at risk for health conditions associated with an altered FMR1 gene.
An intermediate result, sometimes called the “gray zone,” falls between 45 and 54 repeats. For individuals with a repeat count in this range, the FMR1 gene functions correctly, and they are not expected to experience direct health consequences. However, the gene shows a slight instability, and there is a small possibility that the number of repeats could expand when passed to offspring.
A premutation is diagnosed when a person has between 55 and 200 CGG repeats. While individuals with a premutation do not have Fragile X syndrome, the gene is considered unstable. They are at an increased risk for developing other specific health conditions later in life, and the gene is very likely to expand further when passed from a mother to her children.
A full mutation is characterized by having more than 200 CGG repeats. This large expansion makes the gene region unstable and triggers a cellular mechanism called methylation. Methylation effectively “turns off” or silences the FMR1 gene, preventing it from producing any functional FMRP. This absence of FMRP leads to the challenges characteristic of Fragile X syndrome.
Health Conditions Linked to CGG Expansion
The expansion of the CGG repeat sequence within the FMR1 gene is linked to a spectrum of medical conditions. The specific diagnosis depends on the number of repeats—whether in the premutation or full mutation range—and the resulting molecular changes. These changes lead to a range of neurological, reproductive, and developmental disorders.
Fragile X Syndrome (FXS)
Fragile X Syndrome (FXS) is the condition caused by a full mutation of more than 200 CGG repeats. The silencing of the FMR1 gene halts the production of its protein, FMRP. The resulting loss of FMRP disrupts the normal development of the nervous system. This leads to the primary characteristics of FXS, which include intellectual disability, developmental delays, and distinct physical and behavioral features.
Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)
FXTAS affects some individuals who carry a premutation (55 to 200 repeats), emerging later in life. Unlike FXS, which is caused by a lack of FMRP, FXTAS is believed to result from a “toxic gain-of-function” mechanism. In this case, the FMR1 gene is overactive, producing excessive amounts of its messenger RNA (mRNA). This surplus mRNA is harmful to nerve cells, and the primary symptoms include problems with movement and balance (ataxia), tremors, and cognitive decline.
Fragile X-associated Primary Ovarian Insufficiency (FXPOI)
FXPOI is another condition that can affect women who carry an FMR1 premutation. It is characterized by reduced function of the ovaries before the age of 40, which can lead to irregular menstrual cycles, infertility, and early menopause. The mechanism is thought to be related to the same RNA toxicity that contributes to FXTAS, affecting the health of the ovaries.
Inheritance and Genetic Instability
The inheritance pattern of the CGG repeat is unique due to its instability, particularly in the premutation range. This instability gives rise to a phenomenon known as anticipation, where the number of repeats increases as the gene is passed to the next generation. This expansion is almost exclusively observed when the premutation is inherited from the mother.
When a mother with a premutation passes the FMR1 gene to her children, the repeat sequence is prone to expansion. The larger a mother’s premutation, the higher the likelihood that it will expand to a full mutation in her child. This explains why a person can have a more severe condition than their parent.
The inheritance pattern differs when the father carries the premutation. A father will pass his X chromosome, and therefore his FMR1 premutation, to all of his daughters but to none of his sons. For reasons not fully understood, the CGG repeat sequence remains stable and does not typically expand when passed from a father. His daughters will be premutation carriers like him but will not have Fragile X syndrome, though they face the risk of the repeat expanding if they have children.