No abstract

Very little is known about the phenotype of FRAXE‐positive individuals and the relation between the genotype/phenotype and genotype/cytogenetic expression. We describe three families with normal and mildly affected individuals and a severely retarded male expressing fragility at the FRAXE locus or presenting different expansions at the CGG FRAXE triplet. In addition, we analyze the FRAXE mutation in sperm DNA from a retarded male carrier with a handicapped daughter expressing fragility at the FRAXE locus. Mental status in FRAXE individuals is highly variable and, although mild mental retardation is observed in most cases, several carrier males are apparently normal. It seems that methylation is not as strictly associated with size of CGG triplets in the FRAXE locus as in FRAXA, and it is possible that normal carrier individuals with fully methylated increments in lymphocytes have a certain proportion of unmethylated alleles in the critical (i.e., neural) tissues. FRAXE mutation is apparently similar to FRAXA in that males with somatic large methylated increments are carriers of small unmethylated ones in germinal cells. © 1996 Wiley‐Liss, Inc.

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 molecular study of 59 Spanish fragile X syndrome families using probe StB 12.3 and the polymerase chain reaction (PCR) of the (CGG)n repeat sequence of the FMR-1 gene. The results obtained have allowed us to characterize 455 individuals, including eight prenatal diagnoses. The clinical diagnosis of fragile X in 89 affected males was confirmed, 137 female carriers were identified (48 of whom were mentally retarded), 176 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 different from that described for the (CGG)n expansion. One nonmentally retarded male was detected as having an unmethylated CpG island for the FMR-1 gene, but with more than 200 CGG repeats (high functioning male). The analysis of the (CGG)n repeat in 208 normal chromosomes gave an allele distribution similar to that in other Caucasoid population groups, with alleles of 29 and 30 CGG repeats accounting for 46% of the chromosomes. The combination of Southern analysis and PCR of the (CGG)n repeat is highly efficient for diagnosis, compared with cytogenetic techniques, especially in the detection of female carriers, NTMs, and prenatal diagnosis, enabling accurate genetic counseling to be provided in all cases.

In a Spanish region with a population of one million, we screened 371 mentally retarded males, who had no previous diagnosis for fragile X [fra(X))] syndrome. Fifty-three of the 371 males were fra(X) positive. Of these 44 of 362 or 12.1% were unrelated. Family studies identified a large number of obligate carriers and women at risk for being carriers who were given genetic counseling including prenatal diagnostic information. Considering the age of the carriers and the fertility rate, 23 affected males could be born to these women. The prevention potential of this program suggests that it is highly cost-effective.

We report a girl with a de novo interstitial deletion in the long arm of a chromosome 10. Clinical features are described.