FXS is the most prevalent inherited cause of mild-to-severe intellectual disability and the most common monogenic cause of autism spectrum disorder.
Overview
- Fragile X Syndrome (FXS), also known historically as Martin-Bell syndrome, is a non-Mendelian trinucleotide repeat disorder.
- Most common inherited cause of mild-to-severe intellectual disability and the leading monogenic cause of autism spectrum disorder.
- Accounts for about half of X-linked intellectual disability cases and is second to trisomy 21 in mental impairment causes.
Etiology
- Genetic Basis: Caused by an expansion of the CGG triplet repeat in the FMR1 gene on the X chromosome, leading to reduced or absent fragile X mental retardation protein (FMRP).
- Normal: 5–44 repeats
- Intermediate: 45–54 repeats
- Premutation: 55–200 repeats
- Full mutation: >200 repeats (results in hypermethylation and silencing of the gene).
Epidemiology
- Variable expressivity and incomplete penetrance.
- Females have a milder phenotype due to the protective effect of the second X chromosome.