A person with fragile X syndrome has a mutation in the FMR-1 (Fragile X Mental Retardation) gene on the X chromosome. That mutation causes the cell to turn off a region of the FMR-1 gene. With the FMR-1 gene in this state, the person can’t make Fragile X Mental Retardation Protein (FMRP). The lack of this protein triggers the syndrome. FXS is one of a small group of tri-nucleotide repeat disorders. This means that some of the DNA building blocks that make up the FMR-1 gene repeat themselves. In this case it is the “CCG” DNA sequence. A common feature of these disorders is that their impact increases over generations as the number of sequence repetitions increases. Everyone has the FMR-1 gene and it normally contains 5 to 40 “CCG” repeats. When the gene has between 55 to 200 “CCG” repeats, it is termed the premutation and the person with the gene is a fragile X carrier. People with fragile X have over 200 “CCG” repeats. This is termed the full mutation. The way this works is the number of repeats increases the length of the gene. When the length goes beyond the critical point the gene turns itself off by a process called methylation. For some people with the full mutation, the gene will be only partially turned off, or methylated. This allows some protein to be produced and so the person is less affected. New Zealand Genetic Services now provide an indication of methylation status as part of the results of the fragile X DNA test. For a female carrier, the number of repeats can increase to over 200 when the X chromosome is passed on to her children. The number of repeats does not increase when it is passed on by male carriers. Female carriers have a 50% chance of passing the full mutation on to their children. Male carriers never pass the syndrome onto their sons, but will always pass the premutation on to their daughters. The premutation often has no observable impact. However some females who are carriers will experience early menopause. They may also exhibit some of the symptoms of fragile X, although normally in a very mild form. Fewer females are affected by fragile X, and the degree of impact is usually less. This is because females have two X chromosomes and one normally functioning gene may partially compensate for the non-functioning gene. Only about a third of fragile X females have a significant intellectual disability.

More detailed information can be found under “Cause” on the US National Fragile X Foundation website.

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