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The Fragile X syndrome [MIM 309550] is the most common familial form of inherited mental retardation with an incidence of 1 in 4000 males and 1 in 8000 females. Most affected males have characteristic physical findings including large ears, prominent chin and macroorchisdism after puberty. The mutation causing Fragile X is an unstable polymorphic trinucleotide CGG repeat in the FMR1 gene. In normal individuals, this region ranges in size from 5-60 repeats. In patients with the Fragile X syndrome, this region shows considerable expansion to greater than 230 repeats, and the normal carrier mothers and transmitting males usually carry a premutation allele which is between 60-200 repeats. An inconclusive size range is defined between 45-58 repeats. Alleles in this range are stable in some families while in others these may be unstable and represent a premutation. In addition to this marked amplification, the full mutation is associated with abnormal methylation of a region adjacent to the FMR-1 gene. Those alterations found from the full mutation are thought to interfere with normal FMR-1 gene expression, thereby resulting in the Fragile X phenotype in males and in some females. DNA testing by both PCR amplification and Southern Blot offers the most sensitive and specific method to establish the genetic status at the FMR-1 gene locus for all the samples tested.
