What is the association between molecular variations in the fragile X gene and fragile X syndrome?

Fragile X syndrome is caused by a mutation in the FMR1 (fragile X mental retardation 1) gene, which is located on the X chromosome. Specifically, individuals with fragile X syndrome have an expansion of a trinucleotide repeat sequence (CGG) in the FMR1 gene. This expansion leads to a loss of function of the FMR1 protein, which is important for normal brain development and function. The number of CGG repeats in the FMR1 gene can vary between individuals, and this variation is associated with different levels of FMR1 protein expression.

Individuals with fewer than 45 CGG repeats typically have normal FMR1 protein expression, while those with between 45-54 CGG repeats have a premutation and may be at risk for developing fragile X-associated disorders, such as fragile X associated tremor/ataxia syndrome (FXTAS) or fragile X associated primary ovarian insufficiency (FXPOI). Individuals with more than 200 CGG repeats have a full mutation and will typically develop fragile X syndrome. The severity of symptoms in individuals with fragile X syndrome can vary depending on the number of CGG repeats and other factors. Such as sex and genetic background.

Each person is in one of the four groups shown below based on the number of CGG repeats in the person’s FMR1 gene. The number of CGG repeats that a person has can be determined by a blood test ordered by a healthcare provider or genetic counselor. People with different numbers of CGG repeats have different risks of developing fragile X-associated disorders and of having children with FXS. A female has two copies of the FMR1 gene, one on each of her two X chromosomes. The number of CGG repeats on each copy of the FMR1 gene is usually different. For example, a female might have 30 CGG repeats on one copy of her FMR1 gene, but 70 CGG repeats on her other copy. The group a female is in (normal, intermediate, premutation, or full mutation, as shown below) is based on her FMR1 gene copy with the greatest number of CGG repeats.

A male has only one copy of the FMR1 gene on his only X chromosome, so the group a male is in is based on the number of CGG repeats in that one copy. Normal: 5 to 44 Repeats. Most males have about 5 to 44 repeats of the chemical letters, CGG, in their FMR1 gene and most females also have 5 to 44 repeats in each of their FMR1 genes. This is considered a normal number of repeats. People with a normal number of repeats do not have FXS and do not pass a higher chance for having FXS to their children. Intermediate: 45 to 54 Repeats. People who have an intermediate number of repeats (45 to 54) do not have FXS and are not at risk for having children with FXS. However, they may have a slightly higher chance of having some symptoms related to other fragile X-associated disorders and may pass the slightly higher chance of having these disorders to their children. Premutation: 55 to 200 Repeats.

People who have 55 to 200 repeats are said to have a “premutation” in the FMR1 gene. They do not have FXS but they might have, or may later develop, other fragile X-associated disorders. In addition, people with a premutation can have children with a premutation or full mutation (FXS). However, the chances of having a child with a premutation or a full mutation are different for women with a premutation than they are for men with a premutation, as described below.The number of repeats in the egg cells of a woman with a premutation can increase from the premutation range (55 to 200 repeats) to the full mutation range (more than 200 repeats). Therefore, a woman with a premutation can pass on a full mutation.

The more CGG repeats a woman with a premutation has, the more likely her child will inherit an FMR1 gene with a full mutation and, therefore, have FXS. With each pregnancy, a woman with a premutation in one of her FMR1 genes has a 50% chance of passing on either the premutation or a full mutation to her child (daughters or sons), and a 50% chance of not passing on either the premutation or the full mutation. A man with a premutation will pass on his premutation to his daughters, but not to his sons. A man with a premutation will not pass on a full mutation to any of his children. Full Mutation (FXS): More than 200 Repeats. People with a full mutation (more than 200 repeats) have FXS.With each pregnancy, women have a 50% chance of passing fragile X on to their child (sons or daughters).

Best,

Laura Zukerman

Owner and Founder At The Goddess Bibles

A Memoir By Laura Zukerman

Becoming Your Inner Goddess/God

Goddess/God On Fire ❤

Reference for CGG FMRI gene: https://www.cdc.gov/ncbddd/fxs/inherited.html

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