Fragile X Syndrome is an X-linked mutation in FMR1, which encodes an abundant neuron protein named FMRP. Almost every FMR1 mutation is an expansion of the CGG-repeat sequence in the 5' untranslated region of the gene. Normal individuals between 6 and 50 CGG repeats, while diseased patients have over 200 repeats. So many repeats does not happen within one generation; it takes several expansions (premutations) over several generations to acquire hundreds of CGG repeats (full mutation). Having over 200 CGG repeats leads to hypermethylation of the repeat region and the adjacent FMR1 promoter, leading to obliteration of FMRP expression. Mental retardation ensues, with a more severe phenotype in males than females. AGG triplets nestled between CGG repeats inhibit AGG expansion; thus, individuals with reduced AGG triplets are predisposed to become carriers of a diseased FMR1 allele.
Almost all males and ∼50% of females with a disease allele will have the Fragile X phenotype. Some patients have a mixture of premutant and full mutant cells (repeat length mosaicism) due to a worsening genotype with every round of mitosis. Patients with over 200 CGG repeats but lacking methylation in some of their cells (repeat methylation mosaicism) or none of their cells range from normal to fully affected. When analyzing a pedigree, increasing prevalence of the disease in successive generations and inheritance from unaffected mothers are both signs of fragile X syndrome.