FXS is the most commonly inherited cause of intellectual disability (including autism), affecting approximately 1:4,000 males and approximately 1:8,000 females. Over 99% of cases of FXS are caused by the expansion of a trinucleotide CGG repeat in the FMR1 gene and is inherited in an X-linked dominant pattern.1 Other FMR1-related disorders include FXTAS and fragile X–associated primary ovarian insufficiency syndrome (FXPOI).
This test is used to detect the presence of expanded CGG repeat alleles in the FMR1 gene. FMR1 repeat size is classified as follows: normal (5-44 repeats), gray zone (45-54), premutation (55-200), or full mutation (>200). The distinction between these ranges is not absolute. Expansions to the full mutation size are associated with hypermethylation of the FMR1 gene and loss of FMR1 gene activity, which leads to FXS. If a full mutation is detected, individuals with 1 X chromosome would be expected to have FXS; individuals with 2 X chromosomes have a more variable presentation, ranging from normal to affected. Female premutation carriers are at an increased risk of POI. Each offspring is at an increased risk of inheriting an FMR1 allele that is in the full mutation range. Males with a premutation are at risk for developing symptoms associated with FXTAS (onset middle-age). See below for more information regarding gray zone and negative results.