FRAXE mutation in a mentally retarded subject and in his phenotypically normal twin brother

The FRAXE fragile site, 600 kb distal to the more common FRAXA, has been re ported to be expressed in subjects with mild non-syndromal mental retardati on (MR). Amplification of more than 200 GCC repeats, associated with methyl ation of the adjacent CpC island at Xq28, leads to the expression of the fr agile site. In 1996 a large gene, FMR2, transcribed distally from the CpC i sland and downregulated by repeat expansion and methylation, was identified . Among 232 mentally retarded patients, tested FRAXA negative, we identifie d an Italian family segregating a hypermethylated expansion at the FRAXE lo cus in two dizygotic twin brothers, their sister and their mother. The inde x case was referred at 23 years of age with severe MR, epilepsy, a dysmorph ic face with a high arched palate, marfanoid habitus and hyperreflexia of t he lower limbs. His brother was referred to as normal and psychometric test s confirmed he is not mentally retarded. All members of the family underwen t FRAXE molecular analysis, after cytogenetic expression of the fraX site a nd negative FRAXA test. Interestingly, an expansion and a hypermethylation at the FRAXE locus were found in all of them. Fibroblasts from the clinical ly normal brother were assayed for FMR2 expression and the transcription of the gene was found to be silenced. The presence of a phenotypically normal male with absent FMR2 expression in fibroblasts suggests that the relation ship between the FRAXE mutation, FMR2 expression and MR needs to be further investigated.