What causes Fragile X Syndrome?

Fragile X syndrome is caused by genetic mutations in the FMR1 gene which affect the production of FMRP (Fragile X Mental Retardation Protein). Insufficient FMRP disrupts normal functioning of nerve cells, leading to severe learning deficits, mental retardation and physical abnormalities seen in people with fragile X syndrome. The severity of the fragile X syndrome depends on the gender and amount of FMRP protein produced. The amount of FMRP produced depends on the specific FMR1 genetic mutation. FMR1 is located on the X chromosome and only one copy of the defective FMR1 gene is required to develop fragile X syndrome. Males have one copy of the X chromosome and one copy of the Y chromosome. Males experience more severe symptoms of fragile X syndrome than females, as they will manifest all the symptoms associated with Fragile X syndrome when a defective FMR1 gene is inherited. Females have two copies of the X chromosome, but only one of them remains active in a cell in the X inactivation process. In this process, one of the two X chromosomes becomes inactivated during development in a random fashion. Therefore, if a female inherited one normal FMR1 and one defective FMR1 gene, there is a 50% probability that the defective FMR1 is turned off. This is the reason why fewer females than males are affected by severe symptoms of fragile X syndrome. The genetic mutation that commonly causes fragile X syndrome is an abnormal number of CGG tri-nucleotide repeats in the FMR1 gene. CGG is repeated 5-44 times in a normal person. When the CGG repeats are over 200, the FMR1 gene is silenced by methylation and no FMRP is produced. Other genetic mutations in the FMR1 gene that can cause fragile X syndrome are rare, and can involve partial or full gene deletions, or amino acid changes in FMRP. These mutations can inhibit FMRP protein from being produced or disrupt the 3D shape of the protein. FMR1 genetic mutations are classified into three groups: Intermediate – 45-54 repeats of CGG. These individuals have only mild or borderline change in FMR1, and typically do not show symptoms. Premutation – 55-200 repeats of CGG. These individuals are known as carriers. They are intellectually normal and do not have the fragile X syndrome. However, they have increased risk of developing psychological and other fragile X-associated symptoms. Females with a premutation are at risk of passing a full mutation to their children if the repeat expands to >200 during egg production. Full mutation – >200 repeats of CGG. These individuals have fragile X syndrome. They are affected by the symptoms, involving intellectual disabilities and physical abnormalities. References: Fragile X-associated Disorders. National Fragile X Foundation Saul RA, Tarleton JC (1998, Updated 2012 Apr 26). FMR1-Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews®