B. Genetics. FXS is caused by a mutation in the fragile X mental retardation-1 gene (FMR-1), which is located on the bottom end of the X chromosome. The mutation causes a fragile site or break in the chromosome at that location. The FMR-1 gene was identified and sequenced in 1991. An unusual expansion of a cytosine, guanine, guanine (CGG) nucleotide repetitive sequence was found to be the mutation. Within the FMR-1 gene, normal individuals have a nucleotide CGG sequence that repeats up to 45 times, carriers with a premutation have an expansion of the CGG sequence between 55-200 repeats, and individuals affected with FXS have a CGG repeat number greater than 200 (termed a full mutation). When this occurs, the gene usually becomes methylated or turned off so that little or no FMR-1 protein (FMRP) is made, and the full FXS occurs.

A carrier male will pass only X chromosome to all of his daughters, who will be obligate carriers and pass the mutation to 50% of their offspring. A significant expansion of the mutation will often occur in their children so that males and females with intellectual disability are common. A detailed family tree must be drawn to sort out possible carriers and other extended family members who may be affected by FXS or by premutation involvement including FXTAS and POI.