Severe phenotypes associated with inactive ring X chromosomes

Mental retardation and congenital malformations in individuals with small r ing X chromosomes are often due to the functional disomy that results from failure of these chromosomes to undergo X inactivation. Such chromosomes ei ther lack the XIST locus or do not express it. We have carried out genetic analysis of the ring X chromosomes from two girls with a 45,X/46,X,r(X) kar yotype, mental retardation, and a constellation of abnormalities characteri stic of the severe phenotype due to X disomy. In each case the ring X chrom osome included an intact XIST locus which was expressed; the breakpoints me re distal to DXS128, and therefore outside the XIC region; transcription an alysis of alleles at the androgen receptor locus confirmed that these were inactive chromosomes. The characteristics of the XIST RNA were similar to t he wild-type. Additional studies in cultured fibroblasts showed a second ri ng in a small percentage of the cells. The association of severe phenotype with an inactive X chromosome most likely reflects the presence of a second ring X chromosome which was active at least in some tissues during embryog enesis, but is no longer prominent in the tissues we analyzed. Am. J. Med. Genet. 93:52-57, 2000.