Clinical, cytogenetic, and molecular description of a FRAXE French family.

Background: FRAXE is a second locus associated with X chromosome fragility. Similar to FRAXA, the common mutation is a GCC expansion located in the 5' untranslated region, leading to the hypermethylation of the region and to the subsequent inactivation of specific genes (FMR1 and FMR2, respectively). Unlike FRAXA, FRAXE has a rare occurrence and is less currently studied in routine analyses. The phenotype associated with FRAXE is usually considered as mild or moderate mental retardation, with incomplete penetrance. However, phenotype/genotype relations have been less characterized.

Objective: We report a French family with three members affected with mental retardation, including a female suffering from West syndrome, and two mentally retarded males.

Methods: After exclusion of the FRAXA expansion by Southern blot analysis, we performed a karyotype using folate-thymidine-deficient medium and a southern blot to search for FRAXE expansion.

Results: All three mentally retarded patients had a number of repeats over 800 GCC and expressed more than 20% of fragile sites in their leukocytes. Another carrier female with a full expansion had a subnormal mental impairment.

Conclusions: Clinical features and both the cytogenetic and molecular findings seem to correlate in this family. We discuss the bias encountered when studying such families and some of the mechanisms that may explain part of the clinical variability.