FRAXA syndrome is usually caused by the expansion of a CGG repeat region in the FMR-1 gene. However, in a few patients deletions and single point mutations have also been described. The CGG repeat sequence is polymorphic in the normal population and varies in size from 6 to 52 repeats. Individuals carrying 53-200 repeats are known to have a premutation and are believed to be clinically unaffected. Individuals with ≥ 200 repeats have a full mutation. Most males with a full mutation coupled with methylation of the CpG island of the FMR-1 gene exhibit symptoms characteristic of the FRAXA syndrome. However, recent reports suggested that there might be a milder clinical involvement in mental impairment and learning disabilities in individuals carrying unmethylated premutated and intermediate alleles (40-55 repeats). Southern blot and polymerase chain reaction (PCR) analyses were employed to determine the methylation status and the repeat size of the FMR-1 gene in a 15 year old male. He was referred for developmental and motor delay and a family history of mental retardation and affective behavior disorders. High molecular weight DNA was prepared from peripheral blood and double digested with Eco RI and Eag I and hybridized with [P-32]-labeled StB12.3 probe (a generous gift from Dr. J.L. Mandel). PCR was performed using forward primer 1 and reverse primer 3. The amplified fragments were analyzed with a 6% polyarylamide-8M urea denaturing gel. PCR analysis revealed the presence of a 140 bp (26 repeats) band and a 214 bp (50 repeats) band. On the other hand, the father and the mother showed only a single band of 154 bp (29 repeats) and 157 bp (31 repeats), respectively. Southern blot analysis showed a 2.95 kb band for the patient and a 2.80 kb normal sized band and methylation status for the FMR-1 alleles of the mother and the father. The phenotype-genotype correlation in this patient may be explained by the phenomenon of somatic mosaicism among different tissues. It is also important not to exclude the possibility of a different type of mutation other than that of triplet repeat expansion. The observation of the occurrence of the intermediate allele in the patient but not in his mother is also potentially significant. This work was supported in part by NIH grant HD 31553.

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