How can X chromosome inactivation cause symptoms in some female carriers of X-linked disorders?

In females, X chromosome inactivation—also known as lyonization—is a process occurring early in embryonic development where one X chromosome in each somatic cell is randomly inactivated to balance gene expression. This process typically results in a mosaic state, where roughly half of a female's cells express the maternal X chromosome and the other half express the paternal X chromosome.12

For female carriers of X-linked disorders, this random process usually ensures that enough cells express the normal gene to maintain health, keeping the carrier asymptomatic. However, symptoms can arise in some carriers, known as manifesting heterozygotes, due to nonrandom X inactivation. If a higher proportion of cells happen to inactivate the X chromosome carrying the normal gene, the cells expressing the mutant gene may predominate. Depending on the extent of this skewed inactivation and the specific tissue involved, the individual may exhibit symptoms of the disorder in varying degrees of severity.13