fragile X syndrome
Fragile X syndrome is the most common inherited cause of intellectual disability, and a common single-gene cause of autism spectrum features. It gets its name from an old laboratory observation: under certain conditions, the tip of the X chromosome looked pinched or fragile, as if it might snap off. The cause turned out to be a runaway repeat in a single gene.
The disorder comes from a CGG trinucleotide repeat expansion in the FMR1 gene on the X chromosome. When the repeat grows beyond a few hundred copies (a full mutation), the gene is switched off by methylation and stops making its protein, FMRP, which is needed for normal brain-cell connections. People with a smaller, intermediate expansion (a premutation) usually do not have the syndrome but can pass on a larger, full expansion to their children.
Because the gene is on the X chromosome, boys, with a single X, are more often and more severely affected than girls, whose second X partly compensates. The repeat tends to expand mainly when passed through the mother, so inheritance does not follow a simple recessive pattern. This entry is educational, not medical advice.
A boy with developmental delay is tested for FMR1; he has over 200 CGG repeats with the gene methylated and silenced, while his mother carries a premutation that expanded when she passed it on.
A silent premutation in a mother can become a full, disease-causing mutation in her child.
Fragile X shows how an expansion can act not by making a toxic protein but by silencing a needed gene, here through DNA methylation that switches FMR1 off once the repeat is long enough.