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X-Chromosome Inactivation

Clinical Features

As a rule, one of the two X chromosomes in the cells of females is inactive. Whether the maternal or the paternal X chromosome is inactive is determined randomly at an early embryonic stage. All subsequent daughter cells carry the identical pattern of activation/inactivation.

Testing for uneven X inactivation is clinically important for two reasons:

• When an X chromosomal recessive inherited genetic defect is located on an active X chromosome but does not hinder the viability of the cell. In this case, X chromosomal recessive inherited diseases may also be manifest in females.

• When an X chromosomal dominant inherited genetic defect is located on the inactive X chromosome. In this case, a woman may show no signs of an X chromosomal dominant disease but may pass the genetic mutation on to her children.

In addition, some forms of X chromosomal recessive inherited mental retardation that normally affect only males are present in females in the form of an uneven distribution of X-inactivation. This serves as an indicator of carrier status.

Genetic Information

A genetic defect located on an X chromosome can be detrimental to the survival of a cell if, in this cell, it is the genetically defect X chromosome that is active.  The advantage or disadvantage of selection can lead to an apparently uneven distribution of X-inactivation favoring the X chromosome without the genetic defect.

The degree of X-inactivation changes over time; uneven distribution is thus more often found in adult women that in newborn girls. With regard to the extent of the uneven distribution, the following differentiation can be made:

• Non-random X-inactivation: In approximately 99% of cells, the same X chromosome is active or inactive

• Skewed X-inactivation: In approximately 10% of cells, the same X chromosome is active or inactive

Diagnostic