Fragile X Syndrome (FXS)

Fragile X Syndrome (FXS) is an X chromosome-linked dominant disorder caused by the amplification of a CGG repeat in the 5′ untranslated region of the fragile X mental retardation gene 1 (FMR1). It is the most common inherited cause of intellectual disability, after Down syndrome.^[1]

• There is a prevalence of 1 in 3600 to 4000.^[2]
• FXS is the most common inherited cause of intellectual disability (Down syndrome is the most common genetic cause of intellectual disability overall, but most cases occur sporadically and thus are not “inherited”).

• Individuals have very high rates of anxiety disorders (over 80%), attention-deficit/hyperactivity disorder (over 50%), autism (30 to 35%), and mood instability and aggression.^[3]

• Fragile X is an X-linked dominant inheritance disorder. It is caused by a full mutation in the FMR1 gene. The FMR1 gene normally contains 5 to 44 trinucleotide repeats. “Premutation” carriers have about 55 to 200 trinucleotide repeats, while individuals with Fragile X have over 200 repeats. The excessive repeats lead to hypermethylation and silences expression of the gene.
• Since FXS affects the X chromosome, FXS predominantly affects males (since males only have one X chromosome). Females are less affected and and have greater variability in their phenotypic presentation (because they still have a normal X chromosome, in addition to the X with the mutation).

FXS can overlap with other disorders, such as autism, Prader-Willi syndrome, and attention-deficit/hyperactivity disorder (ADHD).

On physical exam, individuals with FXS typically have:

• Long face with a large jaw, large everted ears
• Mitral valve prolapse
• Hypermobile joints
• Post-pubertal macroorchidism (enlarged testes)