EXPERIENCE WITH MOLECULAR AND CYTOGENETIC DIAGNOSIS OF FRAGILE-X-SYNDROME IN BRAZILIAN FAMILIES

We report on the cytogenetic and DNA analysis of 55 families with the fragile X (FMR-1 locus) mutation (318 individuals and 15 chorionic vil li samples). A total of 129 males were investigated, 54 mentally norma l and 75 presenting mental retardation. Among the 54 normal males, 11 had the premutation, and none expressed the fragile site. The full mut ation was detected in 73 retarded males, and 14 (18%) presented a prem utation along with the full mutation (mosaics). All of them manifested the fragile site. The frequencies of fragile site expression correlat ed Positively with the sizes of the expansion of the CGG repeats (Delt a). Among 153 normal females, 85 were found to be heterozygous for the premutation and 15 had the full mutation. In the premutated females t he fragile site was not observed or it occurred at frequencies that di d not differ from those observed in 53 noncarriers. Cytogenetic analys is was thus ineffective for the diagnosis of premutated males or femal es. Among the 51 heterozygotes for the full mutation, 36 (70%) had som e degree of mental impairment. As in males, a positive correlation was detected between the frequencies of fragile site manifestation and th e size of the expansion. However, the cytogenetic test was less effect ive for the detection of fully mutated females, than in the case of ma les, since 14% false negative results were found among females. Segreg ation analysis confirmed that the risk of mental retardation in the of fspring of heterozygotes increases with the length of Delta. The avera ge observed frequency of mental retardation in the offspring of all he terozygotes was 30%. There was no indication of meiotic drive occurrin g in female carriers, since the number of individuals who inherited th e mutation did not differ from the number of those inheriting the norm al allele. No new mutations were detected in the 55 genealogies studie d here.