Fragile X syndrome is caused by a mutation in the FMR1 (fragile X mental retardation 1) gene on the X chromosome, the CGG repeat is expanded within this gene. The FMR1 gene codes for the fragile X mental retardation protein, which plays a role in cognitive development in the brain.

It is X-linked, but it is unclear whether it is dominant or recessive. Males are always affected, but females can vary in how much they are affected. This is because females have a spare normal copy of the FMR1 gene on their other X chromosome. When the mother is phenotypically normal, the affected child may have inherited the X chromosome from their mother, or it may result from a de novo (random) mutation.

Epidemiology

Most common inherited cause of intellectual disability

1 in 7,000 males

1 in 11,000 females (note that it is sometimes more difficult when making a diagnosis in female patients)

Pathophysiology

underlying genetic abnormality - trinucleotide repeat

Premutation associations

• No intellectual disability/mild cognitive impairment
• Fragile X-associated primary ovarian insufficiency (FXPOI): 20%
• Fragile X-associated tremor/ataxia syndrome (FXTAS): 40% males, 16% females
• Fragile X–associated Neuropsychiatric Disorders (FXAND): 50%

Children: anxiety, ADHD, social deficits, ASD