a lower frequency and at less extreme levels in most cases. Clinical significance Skewed X-inactivation has medical significance due to its impacts on X-linked diseases. X-chromosome skewing has an ability to amplify diseases on the X chromosome. In wildtype women, recessive diseases on the X chromosome are often unexpressed due to the roughly even inactivation process, which prevents mutated alleles from becoming heavily expressed. However, skewed inactivation can lead to a more severe expression of the disease. The diseased X-linked allele can also cause strong selection in a heterozygote for the cells with the diseased allele on the inactive chromosome. Therefore, strong skewing in female members of a family can suggest they are carriers of an X-linked disease. Cancer predisposition Skewed X-inactivation has also been found to correlate with a higher rate of ovarian cancer, although the mechanism behind this is unknown. A 2013 study also found skewed X-inactivation to be a factor that predisposes individuals to esophageal carcinomas. It has been postulated that skewed X-inactivation might lead to a decrease in the expression of X-linked tumor suppressor genes in an individual who also has a germline mutation in the expressed chromosome. This would cause the gene on that chromosome to become under-expressed, making it more difficult for cells to regulate themselves properly. Other researchers have contended that such a mutation would lead to higher rates of cancer among wild type females, as approximately half the cells would not express the gene due to random inactivation. One would also see a higher rate of cancer in males with the mutation. Instead, the researchers proposed that the cause of cancer and skewed inactivation could potentially be separate events, or both be caused by an unknown source. Rett syndrome Rett syndrome is a genetic disorder caused by a mutation of the MECP2 gene on the X chromosome. The disease occurs mostly in females and involves repetitive hand movements, frequent seizures and a loss of vocal skills and sometimes motor skills. Females with one copy of the mutated allele show symptoms of severe mental retardation. Asymptomatic carriers and patients with very mild symptoms have been described, who can show skewed X-inactivation that favors the inactivation of the mutated allele. Asymptomatic carriers can pass on the mutated allele to their daughters, who can show full symptoms if skewing does not occur. Most Rett syndrome cases show no skewing. Autoimmunity Skewed X-inactivation has been correlated