Genetics

The fragile X syndrome increases in severity down the generations of an affected family. This is termed genetic anticipation.

The gene which is most commonly responsible is FMR-1 (familial mental retardation 1).

The expression of the FMR-1 gene (locus FRAXA) is disrupted by large numbers of trinuclotide (CGG) repeats. The number of repeats determines the phenotype:

• normal - less than 50 CGG repeats
• premutation - 50-230 repeats
• mutation - hundreds of repeats

The premutation does not impair intelligence but is unstable. During oogenesis, but not during spermatogenesis, the premutation may expand to form the full mutation.

Of the patients carrying the full mutation:

• 80% of males are mentally retarded
• 20% of males are normal and are termed "transmitting males"
• 30% of females are mildly mentally retarded (except if the gene is inherited from a transmitting male, in which case the daughter is unaffected but is an obligate carrier)

Two further loci for the fragile X syndrome have been discovered, both are caused by a CGG/CCG expansion:

• FRAXE
• FRAXF

Reference:

• 1) Annemieke, JMH. et al. (1991). Cell. 65, 905-14.
• 2) Knight, SJL. et al. (1993). Cell. 74, 127-134.
• 3) Parrish, JE. et al. (1994). Nature Genet. 8, 236-242.