XSense^®, Fragile X With Reflex

This test is helpful as part of genetic evaluation for individuals with intellectual disability and/or autism, individuals with a family history of fragile X syndrome (FXS) or other FMR1-related disorders, females with primary ovarian insufficiency (POI), and individuals with symptoms characteristic of fragile X-associated tremor/ataxia syndrome (FXTAS).

A polymerase chain reaction (PCR)-based test is used to determine CGG repeat number. If the CGG repeat size is under 85, the test will report out based on PCR data alone. If the CGG repeat size is 85 or greater, the test will reflex to methylation PCR to assess the methylation status of the FMR1 gene. Methylation PCR confirms whether an FMR1 expanded allele is hypermethylated, which would be expected in individuals with FXS. There is an additional charge (and CPT code) for the methylation PCR test.

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. 

Female gray zone (also known as intermediate) allele carriers have 1 FMR1 allele with a CGG repeat in the normal range, and the other with a CGG repeat size between 45 and 54. The stability of the allele with 45 to 54 CGG repeats is variable and cannot be predicted in an individual; it may be stable from generation to generation in some families. There have been no reported cases of a gray zone allele expanding to a full mutation in 1 generation. There have been a few reports of a gray zone allele expanding to a full mutation within 2 generations, but the likelihood is low.²

Male gray zone allele carriers have 1 FMR1 allele that has between 45 and 54 CGG repeats. The stability of this allele is unknown; the allele may be stable when passed to daughters or may expand to a premutation.

The vast majority of female patients with a negative result (ie, 2 normal-range CGG repeats in the FMR1 gene) are not affected by FXS and are not carriers. A male patient with an FMR1 allele in the normal size range would not be expected to have FXS; this is true even if the patient has an intellectual disability. There are rare cases of mosaicism or FXS caused by a mutation other than a CGG expansion. If other potential causes of the clinical presentation have been excluded and the patient has features of classic FXS, or a family history of FXS, please call a genetic counselor at 1.866.GENE.INFO to discuss.