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The X chromosome plays a vital role in numerous biological functions and is crucial for the development of various tissues, including those of the nervous system, blood, liver, bones, kidneys, retina, ears, heart, skin, and teeth. Mutations or alterations in its genes are associated with over 530 known disorders.[1] An X-linked trait or disorder occurs from a pathogenic variant in a gene on the X chromosome. In 1961, Mary Lyon proposed that in the cells of mammalian females, one of the two X chromosomes undergoes random inactivation during early embryonic development. As a result, both males and females effectively have a single active X chromosome. Lyon's hypothesis significantly advanced the understanding of the basic mechanisms underlying X-linked diseases.[2][3][4][5] Classically, X-linked inheritance is described as either X-linked recessive or X-linked dominant (see Image. Pattern of X-Linked Inheritance). X-Linked Recessive Inheritance Males who carry a pathogenic variant are affected, whereas females—who have a second nonpathogenic copy of the gene—are typically unaffected (or only mildly affected). A male with an affected allele on his single X chromosome is hemizygous and cannot transmit the disorder to his male offspring, but all his daughters are obligate carriers. Healthy heterozygous carrier females can pass the disorder to affected sons. Thus, from affected males, it can be transmitted to male grandchildren through a carrier daughter (diagonal or Knight's move transmission). The X chromosome from a male is transmitted to daughters, and the Y chromosome is transferred to sons. If an affected male has children with a healthy female, none of his male offspring are affected, but all of his female offspring are carriers. If a carrier female has children with a healthy male, each male offspring has a 50% chance of being affected, and each female offspring has a 50% chance of being a carrier. Variable expression: Heterozygous females carry one pathogenic allele on one X chromosome and one normal allele on the other. These females may exhibit variable expression of X-linked recessive disorders due to the random process of X inactivation. This variability results in mosaicism, where some cells inactivate the X chromosome with the mutant allele, whereas others inactivate the X chromosome with the normal allele.[1] X-Linked Disorders in Females

Variable expression: Heterozygous females carry one pathogenic allele on one X chromosome and one normal allele on the other. These females may exhibit variable expression of X-linked recessive disorders due to the random process of X inactivation. This variability results in mosaicism, where some cells inactivate the X chromosome with the mutant allele, whereas others inactivate the X chromosome with the normal allele.[1] X-Linked Disorders in Females Although X-linked recessive disorders typically affect males, females may occasionally be affected. This observation can be explained by one of the following possibilities: Heterozygosity: Inactivation is a random process that may involve either the X chromosome carrying the mutant allele or the one carrying the normal allele in a heterozygous female. This inactivation does not lead to complete silencing of one X chromosome, as approximately one-third of X-linked genes are expressed from both chromosomes to varying degrees across cells. The clinical significance of this incomplete inactivation is not yet fully understood.[PubMed PMID: 29022598] In cases where the X chromosome with the mutant allele remains active in the majority of cells (skewed X inactivation), disease expression can occur. This phenomenon has been observed in disorders such as Duchenne muscular dystrophy and hemophilia A.[6][7] Homozygosity: When both X chromosomes in a female carry a mutant allele, disease expression occurs. This phenomenon has been reported in conditions like hemophilia A and ichthyosis.[8][9] Translocations: If a female carries a translocation involving an autosome and one of the X chromosomes, and this translocation disrupts a gene on the X chromosome, the disorder may manifest. This phenomenon has been observed in cases of Duchenne muscular dystrophy.[10][11][10] In females with Turner syndrome (who have only one X chromosome), if the single X chromosome carries a mutant allele, the disorder may be expressed. Hemophilia has been reported in females with Turner syndrome.[12] X-Linked Dominant Inheritance

Translocations: If a female carries a translocation involving an autosome and one of the X chromosomes, and this translocation disrupts a gene on the X chromosome, the disorder may manifest. This phenomenon has been observed in cases of Duchenne muscular dystrophy.[10][11][10] In females with Turner syndrome (who have only one X chromosome), if the single X chromosome carries a mutant allele, the disorder may be expressed. Hemophilia has been reported in females with Turner syndrome.[12] X-Linked Dominant Inheritance Both males and females can be affected, but females are affected more frequently and usually less severely. Affected males can transmit the mutant allele to all their daughters but not to their sons. Affected females have a 50% chance of transmitting the mutant allele to each of their sons and daughters. Examples include vitamin D–resistant (hypophosphatemic) rickets and Charcot-Marie-Tooth disease.[13][14] Some X-linked dominant disorders, such as incontinentia pigmenti (Bloch-Sulzberger syndrome), show mosaicism in heterozygous females.[15] X-linked dominant lethals: X-linked dominant lethal disorders are incompatible with early embryonic survival in males. These disorders are observed only in females because the severe form typically results in the death of male embryos, whereas females, being less severely affected, can survive.[16] Current View Many female carriers of X-linked recessive disorders demonstrate mild phenotypes. This observation is attributed to the variable expressivity of X-linked disorders and the involvement of multiple mechanisms, such as skewed X-inactivation, somatic mosaicism, and others. Recently, studies have proposed discontinuing the terms dominant and recessive and classifying all such conditions simply as X-linked disorders.[17][18][19]