Clinical and molecular studies in 15 females with ring X chromosomes: implications for r(X) formation and mental development

We report clinical and molecular findings in 15 Japanese mosaic females wit h r(X) chromosomes, 45,X/46,X,r(X), confirmed by fluorescence in situ hybri dization (FISH) analysis for DXZ1 and whole X chromosome painting. Cases 1- 3, 5-7, and 11-13 had mental retardation (MR), the remaining cases being fr ee from MR. FISH analysis showed that XIST was absent from the r(X) chromos omes in cases lit and was present on the r(X) chromosomes in cases 5-15. X- inactivation analysis for the methylation status of the AR gene indicated t hat, of eight cases with XIST-positive r(X) chromosomes in more than 10% (2 3%-62%) of lymphocytes (cases 5-12), cases 5-10 had selective X-inactivatio n, whereas cases 11 and 12 had active X disomy. Microsatellite analysis for multiple loci on the pericentromeric region revealed that, of 11 cases wit h r(X) chromosomes in more than 10% (13%-52%) of lymphocytes (cases 1, 2, a nd 4-12), cases i, 2, and 5-10 had heterozygous alleles for at least one lo cus, whereas cases 4, 11, and 12 had single alleles for all the loci examin ed. The results suggest that the r(X) and normal X chromosomes could be of biparental or uniparental origin, and that mental status in females with r( X) chromosomes is determined by multiple factors, including the presence or absence of XIST on the r(X) chromosomes and the size and frequency of acti ve r(X) chromosomes, in addition to co-incidental genetic and environmental factors.