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Fragile X syndrome is the most common inherited form of familial mental retardation. It results from a (CGG)n trinucleotide expansion in the FMR1 gene leading to the typical Martin-Bell phenotype. Clinical features vary depending on age and sex. Expansion of a (CCG)n repeat in the FMR2 gene corresponds to the FRAXE fragile site which lies distal to FRAXA and is also associated with mental retardation, but it is less frequent and lacks a consistent phenotype. Analysis of repeat expansions in these two genes allows the molecular diagnosis of these different entities. We report here the screening of the FRAXA and FRAXE mutations in 222 unrelated mentally retarded individuals attending Spanish special schools. PCR and/or Southern blotting methods were used. We detected full mutations in the FMR1 gene in 11 boys (4.9%) and 1 boy (0.5%) with a CCG repeat expansion in the FMR2 gene. The latter shows mild mental retardation with psychotic behaviour and no remarkable physical traits. Molecular studies revealed a mosaicism for methylation in the FMR2 gene. This case supports the observation that expansions greater than 100 repeats can be partially methylated and cause the phenotype.

Background: Huntington's disease (HD) is a neurodegenerative disorder with late age of onset, caused by (CAG), expansion in the IT15 gene. We present here the results of IT15 gene study in Spanish families in order to show the usefulness of diagnosis, genetic counseling and clinical-genetic correlation in Spanish population., Patients and Methods: We have studied the number of (CAG)n repeats in the IT15 gene by PCR analysis in 137 individuals from 79 Spanish families with HD., Results: The number of (CAG)n repeats in HD chromosomes varied from 35 to 85, while the range for the normal chromosomes was from 13 to 31. In four juvenile cases the number of (CAG)n repeats was above 50. In three of these cases the transmission was paternal. The (CAG)n expansion was demonstrated in 98.3% of the cases. We established the diagnosis in 15 uncertain clinical diagnosis. We made a presymptomatic diagnosis after psychological-psychiatric evaluation in 50 HD at risk individuals. We showed an inverse correlation between the number of (CAG)n repeats and the age at onset of the disease., Conclusions: The (CAG)n repeats study in the IT15 gene in Spanish populations allows the confirmation of diagnosis of HD as well as presymptomatic testing enabling the genetic counseling. There is an inverse correlation between the age of onset of the disease and the number of (CAG)n repeats in the IT15 gene.

Fragile X syndrome is the most common cause of inherited mental retardation. The incidence has been estimated to be 1 in 1250 males and 1 in 2000 females. Molecular studies have shown that 95% of fragile X syndrome cases are caused by the expansion of a CGG triplet in the FMR1 gene with hypermethylation of the adjacent CpG island. In spite of the high incidence of this syndrome, a female with both FMR1 genes in the expanded form has never been reported. We presenting mental retardation and attention problems. Molecular analysis has revealed that both of her FMR1 genes have the CGG expansion, one with a premutation and the other with a full mutation. We have studied the CGG repeat in the FMR1 gene in 64 members of her family and detected 33 normal individuals, 14 carriers with the premutation (1 male and 13 females), and 18 individuals with full mutations (8 males and 10 females). The index case illustrates that the possibility of both parents being carriers of the fragile X syndrome premutation should be considered in consanguineous families or in small communities.

Most cases of Down syndrome (DS) result from a supernumerary chromosome 21; however, there are rare cases in which DS is due to partial trisomy of chromosome 21, involving various segments of the chromosome. The characterization of cases of DS that are due to partial trisomy 21 allows the phenotype to be correlated with the genotype. We present a case with features of DS and a partial trisomy of chromosome 21 inherited from a paternal balanced translocation involving chromosomes 13 and 21. Fluorescence in situ hybridization analysis using yeast artificial chromosome (YAC) probes mapped the breakpoint to 21q22.1, within YAC 230E8, which contains markers CBR, D21S333 and D21S334. Further mapping using cosmids positioned the breakpoint proximal to CBR. The patient was also monosomic for the distal portion of chromosome 13 (q33-qter). Many phenotypic features of DS were present including hypotonia, flat occiput, flat facies, up-slanted palpebral fissures, epicanthic folds, flat nasal bridge, macroglossia, open mouth, small ears and a heart murmur. This case further supports the contention that the majority of the phenotypic features of DS map to 21q22-qter and further refines the location of some of them. In addition to the DS phenotype, the patient had a prominent upper maxilla with protruding upper incisors, and low levels of the coagulation factors VII and X, consistent with a syndrome resulting from monosomy 13q33-qter. Since some features overlap between the two syndromes, including severe mental retardation, it is unclear to what extent monosmy for 13q33-qter, trisomy for 21q22.1-qter, or a combination of both, contributed to the common features of the phenotype.

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.

The fragile X phenotype has been found, in the majority of cases, to be due to the expansion of a CGG repeat in the 5'-UTR region of the FMR-1 gene, accompanied by methylation of the adjacent CpG island and inactivation of the FMR-1 gene. Although several important aspects of the genetics of fragile X have been resolved, it remains to be elucidated at which stage in development the transition from the premutation to the full mutation occurs. We present two families in which discordance between two sets of MZ twins illustrates two important genetic points. In one family, two affected MZ brothers differed in the number of CGG repeats, demonstrating in vivo mitotic instability of this CGG repeat and suggesting that the transition to the full mutation occurred postzygotically. In the second family, two MZ sisters had the same number of repeats, but only one was mentally retarded. When the methylation status of the FMR-1 CpG island was studied, we found that the majority of normal chromosomes had been inactivated in the affected twin, thus leading to the expression of the fragile X phenotype.