Fragile X Syndrome, FMR1 Gene
Definition
The most common genetic cause of inherited intellectual disability, arising from an increase in the number of CGG triplet repeats in the 5' untranslated region of the FMR1 gene. In alleles exceeding 200 repeats the gene becomes methylated and is silenced.
Inheritance
X-linked dominant
Categories by repeat number:
| Category | CGG repeat number | Meaning |
|---|---|---|
| Normal | ~5 to 44 | No problem |
| Intermediate (gray zone) | ~45 to 54 | Uncertain range |
| Premutation | ~55 to 200 | Carrier, does not develop Fragile X syndrome themselves, but can expand to a full mutation in the next generation; also carries a risk of FXTAS and FXPOI |
| Full mutation | >200 (often several hundred to thousands) | Fragile X syndrome |
Why it is examined by repeat counting rather than sequencing:
Typical multigene panels and comprehensive genomic tests (exome or genome sequencing) are useful only if Fragile X is still suspected even though no CGG repeat expansion has been detected.
Standard sequencing cannot reliably read triplet repeats; PCR and Southern blot analysis is required to accurately measure the repeat number and the methylation status, and this information is critical both for diagnosis and for genetic counseling.
Risks and Limitations
Important for women who carry a premutation: the repeat number can expand as it is passed to the next generation, meaning a premutation in the mother can become a full mutation in the child. The likelihood of expansion increases with the repeat number.