FMR1 mutation testing is used to assess the FMR1 gene in a person. The FMR1 gene is carried on the X chromosome. Males have only one X chromosome (and one Y chromosome). Therefore they have only one copy of the FMR1 gene in each cell in their bodies. Women, have two X chromosomes, and therefore have two copies of the gene in each cell. In women one of the X chromosomes in each cell is randomly inactivated such that in any given cell only one of the two copies of FMR1 is active. This is important in how women can be less severely affected by mutations in the FMR1 gene.
The vast majority of Fragile X syndrome (>99%) is caused by an alteration (mutation) in the FMR1 gene where a DNA segment, known as the CGG triplet repeat, is expanded. Normally, this DNA segment has from 5 to about 54 of the CGG triplets. In people with Fragile X syndrome, however, the CGG triplet is repeated more than 200 times (known as a "full mutation"). The abnormally expanded CGG segment inactivates the FMR1 gene, which prevents the gene from producing a protein called fragile X mental retardation protein (FMRP). Loss of this protein leads to the signs and symptoms of Fragile X syndrome. Both boys and girls can be affected, but because boys have only one X chromosome in each cell, an FMR1 mutation will affect all their X chromosomes and they will be more severely affected. About 50 per cent of women with one copy of the full mutation will have some degree of learning problems that can range from mild to severe but most women are much less severely affected than men with a full mutation.
People with a medium-size repeat sequence of 55 – 200 repeats are said to have a premutation in the FMR1 gene. They will not have intellectual disability or Fragile X syndrome in childhood as enough FMRP protein is still produced. They are however, at risk of developing problems later in life. Both men and women with premutations are at risk of developing a neurodegenerative disorder after middle age with slowly worsening movement problems that may be misdiagnosed as Parkinson’s syndrome, with memory loss, reduced sensation in the lower limbs and behavioural changes (Fragile X associated tremor/ataxia syndrome, or FXTAS). Women with premutations also have a moderate risk of developing ovarian failure and going into menopause before the age of 40 (Fragile X associated primary ovarian insufficiency, or FXPOI).
For more information about the effects of Fragile X syndrome see our Fragile X Condition article.
Because the FMR1 gene is on the X chromosome it has a special pattern of inheritance called X-linked and is only partly since around 50 per cent of women do express the condition to some degree. The test results can show a short or normal repeat length, a medium or premutation repeat length or a long or full mutation repeat length. An important factor is how the gene behaves when it is passed down to children from either their mother or their father.
- Short repeats are stable and the length does not change when passed on to children.
- Medium repeats or premutations behave differently when passed on by the mother or the father.
- When the father passes his premutation into his sperm the length of repeats usually does not change. Because he will only pass his Y chromosome to his sons, none of them will receive the mutated gene and they will be unaffected. All of his daughters will receive the mutated gene on his X chromosome and will be carriers of the premutation and will be unaffected at least until middle age.
- When the mother passes her premutation on to her children the repeat length may increase in length to become a full mutation or it may remain unchanged in length. Any child has a 50 per cent chance of receiving the mutated gene from their mother. If the gene has become a full mutation then any sons receiving this full mutation will have Fragile X syndrome. Any daughters receiving the full mutation will become carriers and have approximately 50 per cent chance of having some intellectual disability. Any sons receiving an unchanged premutation will be unaffected at least until middle age and will be carriers of the gene. Any daughters receiving the unchanged premutation will be unaffected at least until middle age and will be carriers of the gene.
- Long repeats or full mutations are generally only passed on by mothers who are carriers. The risks are different for her sons and daughters. Any son has a 50 per cent chance of inheriting the full mutation and if he does he will have Fragile X syndrome. Otherwise he will be unaffected. Any daughter has a 50 per cent chance of inheriting the full mutation and being a carrier and if she does she has an approximately 50 per cent chance of having some intellectual disability. If she inherits the normal gene on the other X chromosome she will be unaffected.
Very rarely Fragile X syndrome can be caused by different types of mutations in the FMR1 gene in areas away from the CGG repeats. The usual tests for CGG repeat number will not detect these types of mutations.