MOLECULAR ANALYSIS OF THE (CGG)(N) EXPANSION IN THE FMR-1 GENE IN 59 SPANISH FRAGILE-X SYNDROME FAMILIES

The fragile X mental retardation syndrome is caused by an expansion of a trinucleotide repeat (CGG)(n) in the FMR-1 gene. Molecular genetic study of fragile X provides accurate diagnosis and facilitates genetic counseling in families with affected members. We present here the mol ecular study of 59 Spanish fragile X syndrome families using probe StB 12.3 and the polymerase chain reaction (PCR) of the (CGG)(n) repeat s equence of the FMR-1 gene. The results obtained have allowed us to cha racterize 455 individuals, including eight prenatal diagnoses. The cli nical diagnosis of fragile X in 89 affected males was confirmed, 137 f emale carriers were identified (48 of whom were mentally retarded), 17 6 individuals ''at risk'' were found not to have the expansion, and 12 cases of normal transmitting males (NTM) were detected. In the sample studied, no de novo mutations were detected, nor any mutation differe nt from that described for the (CGG), expansion. One nonmentally retar ded male was detected as having an unmethylated CpG island for the FMR -1 gene, but with more than 200 CGG repeats (high functioning male). T he analysis of the (CGG)(n) repeat in 208 normal chromosomes gave an a llele distribution similar to that in other Caucasoid population group s, with alleles of 29 and 30 CGG repeats accounting for 46% of the chr omosomes. The combination of Southern analysis and PCR of the (CGG)(n) repeat is highly efficient for diagnosis, compared with cytogenetic t echniques, especially in the detection of female carriers, NTMs, and p renatal diagnosis. enabling accurate genetic counseling to be provided in all cases.