Copy number changes on the X chromosome in women with and without highly skewed X-chromosome inactivation

Aim: To test the hypothesis that microdeletions or microduplications below the resolution of a standard karyotype may be a significant cause of highly skewed X-inactivation (HSXI) in women without a cytogenetically detected X-chromosome anomaly. Methods: Cases were women with HSXI, defined as ≥85% of cells in a blood sample with the same active allele at the HUMARA locus. The skewing in controls ranged from 50 to <75%. We performed an SNP microarray analysis using the Affymetrix 6.0 platform for 45 cases and 45 controls. Results: Cases and controls did not differ in the frequency of X-chromosome copy number changes ≥100 kb or in the frequency of copy number changes that contained genes. However, one woman with HSXI >90% in blood and left and right buccal smears had a 5.5-Mb deletion in Xp22.2p22.1. This deletion could affect the viability of male conceptions and may have led to the dysmorphology found in female carriers. Conclusion: HSXI in a blood sample is rarely due to X-chromosome copy number changes detectable by microarray.