ASYMMETRY OF METHYLATION WITH FMR-1 FULL MUTATION IN 2 45,X 46,XX MOSAIC FEMALES ASSOCIATED WITH NORMAL INTELLECT/

The full FMR-1 mutation is known to cause the fragile X syndrome [Fra( X)], but variable expression in females, including normal to deficient intellect, may be related to random X-inactivation (lyonization). We have evaluated 2 mosaic 45,X/46,XX females who are cytogenetically fra (X) positive, have an FMR-1 full mutation, and are of normal intellect . There were 50% fra(X) chromosomes in the 45,X cells of one of the fe males; this has not been reported previously. In both patients, there was a strong asymmetry of FMR-1 methylation with the normal allele bei ng totally or 90% unmethylated and the mutant allele being similarly m ethylated. Thus, the apparent selective in activation of the full muta nt FMR-1 allele appears to have resulted in limited expression with no rmal intellect. The presence of the fra(X) chromosome in 45,X cells is unique; however, there may be no relationship to the asymmetric inact ivation of the mutant allele which could be due to chance or a mechani sm yet to be delineated. (c) 1994 Wiley Liss, Inc.