Skewed X Inactivation in X-Linked Disorders

ABSTRACT X chromosome inactivation is a process by which the dosage of proteins transcribed from genes on the X chromosome is equalized between males (XY) and females (XX) through the silencing of most genes on one of the two X chromosomes in females. Although the choice of which of the two X's is inactivated is entirely random, not all women have a 50:50 ratio of cells with one or the other X chromosomes active. A number of different mechanisms lead to extremely skewed ratios and this can result in expression of the phenotype of X-linked recessive disorders in females. Nonrandom X inactivation patterns are also associated with selective female survival in male-lethal X-linked dominant disorders or with variable severity of the phenotype in women carrying X-linked dominant mutations. These features are important for the study and gene identification of X-linked disorders and for counseling of affected families.