Inheritance - sex-linked

Definition

Sex-linked inheritance refers to conditions caused by variants on the X or Y chromosome - X-linked conditions are far more clinically significant than Y-linked given the X chromosome carries far more genes, most Y-linked conditions affecting only male fertility
X-linked recessive conditions are collectively common and clinically important (haemophilia, Duchenne muscular dystrophy, fragile X syndrome, many forms of colour blindness)

Males are hemizygous for the X chromosome (only one copy) - a single pathogenic X-linked recessive variant is therefore sufficient to cause disease in a male, unlike the two copies needed for autosomal recessive disease
Females are XX - a single X-linked recessive pathogenic variant typically leaves them an unaffected (or, via skewed X-inactivation, sometimes mildly affected) carrier, since their second, usually normal, X copy provides partial compensation

Key pedigree clue: no male-to-male transmission in X-linked conditions (a father transmits his Y, not his X, to sons) - male-to-male transmission in a pedigree effectively excludes X-linked inheritance and points toward autosomal
A carrier mother transmits the variant to 50% of sons (affected) and 50% of daughters (carriers) on average - the classic "maternal uncle" pattern of affected males across generations, connected through unaffected carrier females

Genetic counselling for X-linked recessive conditions focuses particularly on maternal relatives (sisters, maternal aunts, and their daughters) as the relevant at-risk carrier line, since paternal relatives of an affected male are not at increased carrier risk through him

Haemophilia A/B, Duchenne/Becker muscular dystrophy, fragile X syndrome, X-linked forms of severe combined immunodeficiency

"No male-to-male transmission" is the single most useful pedigree clue for recognising X-linked inheritance, and its presence in a pedigree should prompt reconsidering the inheritance pattern rather than assuming X-linkage regardless

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