GeneticsTier 2Medical Sciences concept

X-inactivation (Lyonisation) and X-linked disease expression in females

Core concept

One X chromosome is randomly inactivated per cell early in female embryogenesis (Lyon hypothesis) - silenced via XIST-mediated chromatin condensation and DNA methylation -> forms the Barr body
Inactivation is random but then clonally fixed - each cell's descendants retain the same inactive X
Result: females are functional mosaics - a patchwork of cells expressing either the maternal or paternal X

Skewed X-inactivation (non-random, e.g. 90:10 by chance or selection) explains why female carriers of X-linked recessive disease can be symptomatic ("manifesting carriers")
Explains variable severity in female carriers of haemophilia A/B, Duchenne muscular dystrophy, Fabry disease, X-linked SCID
Genes that escape X-inactivation (e.g. in pseudoautosomal regions) contribute to the Turner syndrome (45,X) phenotype despite the loss of only one X

Female haemophilia carrier with unusually low factor levels -> skewed X-inactivation, not a new mutation
Duchenne carrier mothers - check CK, consider cardiac screening (manifesting carriers can develop cardiomyopathy)
Explains why X-linked dominant conditions (Rett syndrome, incontinentia pigmenti) can be lethal in males but survivable (via mosaicism) in females

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