Molecular characterization of a deleted X chromosome (Xq13.3-Xq21.31) exhibiting random X inactivation

As a result of selection following random X chromosome inactivation in human females, X chromosomes with visible deletions are usually inactive in every somatic cell. We have studied a female with mental retardation and dysmorphic features whose karyotype includes an X chromosome with a visible interstitial deletion in the proximal long arm. Based on cytogenetic analysis, the proximal breakpoint appeared to be in band Xq13.1, and the distal one in band q21.3. However, molecular analyses show that less of the q13 band is missing than cytogenetic studies indicated, as the deletion includes only loci from the region Xq13.3 to Xq21.31. Unexpectedly, studies of chromosome replication show that the pattern of X inactivation is random. Whereas the deleted X chromosome is late replicating in some cells from all tissues studied, it is early replicating in the majority of blood lymphocytes and skin fibroblasts, and is the active X chromosome in many of the hybrids derived from skin fibroblasts. As this chromosome is able to inactivate, it must include those DNA sequences from the X-inactivation center (XIC) that are essential for cis X inactivation. Molecular studies show that the XIC region, at Xq13.2, is present, so it is unlikely that the lack of consistent inactivation of this chromosome is attributable to close proximity of the breakpoint to the XIC. Supporting this conclusion is the similarity of the breakpoints to those of the other chromosomes we studied, whose deletions clearly do not interfere with the ability to inactivate. Our results show that deletions distal to DXS441 in Xq13.2 do not interfere with cis X inactivation. We attribute the random pattern of X inactivation reported here to the fact that in the tissues studied, cells with this interstitial deletion are not at a selective disadvantage.