A FRAGILE-X MOSAIC MALE WITH A CRYPTIC FULL MUTATION DETECTED IN EPITHELIUM BUT NOT IN BLOOD

Individuals with developmental delay who are found to have only fragil e X premutations present an interpretive dilemma. The presence of the premutation could be an unrelated coincidence, or it could be a sign o f mosaicism involving a full mutation in other tissues. To investigate three cases of this type, buccal epithelium was collected on cytology brushes for Southern blot analysis. In one notable case, the blood sp ecimen of a boy with developmental delay was found to have a premutati on of 0.1 extra kb, which was shown by PCR to be an allele of 60 +/- 3 repeats. There was no trace of a full mutation. Mosaicism was investi gated as an explanation for his developmental delay, although the cond ition was confounded by prematurity and other factors. The cheek epith elium DNA was found to contain the premutation, plus a methylated full mutation with expansions of 0.9 and 1.5 extra kb. The three populatio ns were nearly equal in frequency but the 1.5 kb expansion was the mos t prominent. Regardless of whether this patient has clinical signs of fragile X syndrome, he illustrates that there can be gross tissue-spec ific differences in molecular subpopulations in mosaic individuals. Be cause brain and epithelium are more closely related embryonically than are brain and blood, cryptic full mutations in affected individuals m ay be evident in epithelial cells while being absent or difficult to d etect in blood. This phenomenon may explain some atypical cases of the fragile X phenotype associated with premutations or near-normal DNA f indings. (C) 1996 Wiley-Liss, Inc.