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Clinical significance

Fragile X syndrome (FXS) is the most common cause of hereditary intellectual disability and also the second most common intellectual disability disorder after Down syndrome. It is an X-chromosome-linked genetic disorder caused by the abnormal amplification of CGG trinucleotide repeat sequences located in the 5′-UTR of the fragile X mental retardation 1 (FMR1) gene, situated at Xq27.3.

Diagnosis is based on the number of CGG repeats, with the following criteria:

1) 6-44: Normal

2) 45-54: Gray zone

3) 55-200: Premutation

4) >200: Full mutation

In the case of a premutation (55-200 repeats), it is not associated with intellectual disability, but there is a risk of the CGG repeat expanding when passed on to offspring. Associated conditions include Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) and Primary Ovarian Insufficiency (POI). A full mutation (>200 repeats) leads to a diagnosis of FXS.

** FXS screening can confirm up to an average of about 150 repeats using PCR and fragment analysis. FXS confirmation testing can identify FXS patients using methylation PCR and southern blot methods.