RESUMEN
The fragile X mental retardation syndrome is caused by the expansion of an unstable CGG repeat in a 5' exon of the FMR1 gene. Significant linkage disequilibrium between this mutation and flanking microsatellite markers has been observed previously in Caucasian populations, a very unusual finding for an X-linked disease which severely impairs reproduction fitness in affected males. This reflects the multistep process at the origin of the full mutation. We have analyzed the FRAXAC2 and DXS548 microsatellites in 26 fragile X families originating from various parts of Finland, and report a striking founder effect much stronger than the linkage disequilibrium observed previously in other more heterogeneous populations. One DXS548 allele was present on 92% of fragile X chromosomes and on 17% of normal chromosomes. A single haplotype accounted for 73% of fragile X chromosomes, and was found only once in 34 normal chromosomes, corresponding to a relative risk of about 90 compared to its absence. The broad geographic origin of the high-risk haplotype and its expected frequency suggest that it was present in initial settlers of Finland, and could thus have been carried silently through 100 generations.
Asunto(s)
Síndrome del Cromosoma X Frágil/genética , Genética de Población , Niño , ADN Satélite/genética , Femenino , Finlandia/epidemiología , Síndrome del Cromosoma X Frágil/epidemiología , Frecuencia de los Genes , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Epidemiología Molecular , Linaje , Polimorfismo Genético , Secuencias Repetitivas de Ácidos Nucleicos , Cromosoma XRESUMEN
Linkage analysis was performed in a family with nonspecific X-linked mental retardation (MRX). Affected individuals had no clinical characteristics other than mental retardation. Linkage was detected to the marker loci DXS477, DXS465, DXS52, DXS15 and F8C with maximum lod scores of 1.70, 1.32, 2.52, 1.70, and 1.09, respectively (theta = 0.0). The results strongly indicate that the gene for mental retardation in the family studied maps close to DXS52.
Asunto(s)
Ligamiento Genético , Discapacidad Intelectual/genética , Cromosoma X , Femenino , Humanos , Escala de Lod , Masculino , Linaje , Polimorfismo de Longitud del Fragmento de Restricción , Recombinación GenéticaRESUMEN
Prenatal diagnosis was performed in 81 cases at risk for the fragile X syndrome. There were 12 fra(X)-positive cases, two of which showed low expression in cultured amniotic fluid cells. FUdR and high thymidine were used for induction of fra(X) (q27.3) expression in all cases. In 21 cases linkage studies were performed, 7 with probes for the loci DXS52, DXS98 and DXS105, 13 with probes for DXS369 and DXS296, DXS304 or DXS374 and one with the probe Do33 for DXS465. In 11 of these cases linkage analysis gave risk figures higher than 95% or lower than 5%, all in concordance with the cytogenetic findings. Discordance was found in three cases studied earlier, the two cases with low expression mentioned above and one cytogenetically normal case, which were now restudied with the new probes. RFLP-studies and linkage analysis was also performed for 24 cytogenetically fra(X)-negative females having a 50%, 25% or 12.5% risk of being carriers according to pedigree data. In 15 cases the risk dropped to 1% or less. Six of these women were pregnant and had asked for prenatal diagnosis but after genetic counseling prenatal diagnosis was avoided.
Asunto(s)
Síndrome del Cromosoma X Frágil/diagnóstico , Tamización de Portadores Genéticos , Diagnóstico Prenatal , Citogenética , ADN/genética , Sondas de ADN , Femenino , Síndrome del Cromosoma X Frágil/genética , Expresión Génica , Ligamiento Genético , Humanos , Masculino , EmbarazoRESUMEN
An improved technique for inducing fra(X) expression in cultured cells was obtained by using diazepam for mitotic arrest and 5-fluorodeoxyuridine (FUdR) for the induction of fra(X) expression. The method was developed using cultured fibroblast and urinary cells from fra(X) patients. Prenatal studies were performed on cultured amniotic fluid cells in five pregnancies at risk for fra(X). In two cases the cultured cells showed a 46,XY, fra(X) karyotype. One of the pregnancies was terminated and the diagnosis was confirmed by chromosome studies on several fetal tissues including chorionic villi and by histopathologic changes in the lymphatic vessels of the fetal testes. The fra(X) was also demonstrated in chorionic villi in a case in which amniotic fluid cells were not studied. Chorionic villi were isolated after a spontaneous abortion, the cultured cells had a 45,X karyotype and in addition 5% of the cells were fra(X) positive.