The Fragile X premutation: new insights and clinical consequences

The Fragile X syndrome (FXS, MIM 309550) is still the most prevalent cause of heritable mental retardation, with a frequency of 1/4000 males and 1/6000 females. The syndrome and its particular pattern of heredity are caused by a dynamic mutation, involving an unstable expansion of a trinucleotide (CGG) repeat at the 5′ UTR of the FMR1 gene, located at Xq27.3. Expansion of this repeat region greater than 200 repeats leads to methylation-coupled silencing of the gene and absence of the Fragile X mental retardation protein (FMRP), causing the classical FXS. Individuals with expanded repeat lengths varying from 50 to 200 repeats do not exhibit the classical FXS phenotype, but are considered as fragile X premutation (PM) carriers. These premutation alleles may become unstable, only through maternal transmission, with further expansion in the next generations. For long-time, male and female premutation carriers were considered as asymptomatic. This view was, however, gradually challenged with the description and reports of different premutation-associated clinical phenotypes over the last decade.