X-Linked Inheritance

X-linked inheritance involves genes on the X chromosome. Because males are hemizygous (only one X), a single pathogenic variant causes full disease expression. Females with two X chromosomes may be carriers (X-linked recessive) or affected (X-linked dominant), with clinical expression influenced by X-inactivation patterns.

For the carrier-risk math (Bayesian updates with unaffected sons, Haldane's 1/3 de novo rule, worked Bayesian tables), see X-Linked Risk Assessment.

• Hemizygosity: Males have only one X chromosome, so any pathogenic variant is fully expressed. There is no "carrier" state for males: they are either affected or unaffected.
• X-linked recessive: Primarily affects males. Carrier females are usually unaffected but can be manifesting carriers due to skewed X-inactivation. No male-to-male transmission (fathers pass Y to sons, X to daughters).
• X-linked dominant: Affects both males and females with a single pathogenic allele, but females are often less severely affected due to having a second normal X. Affected fathers transmit to all daughters but no sons.
• X-linked dominant male lethal: Some X-linked dominant conditions are so severe that hemizygous males do not survive (e.g., Rett syndrome from MECP2, incontinentia pigmenti from IKBKG). Pedigrees show affected females and increased male miscarriages.
• Manifesting carriers: Females heterozygous for X-linked recessive variants who show symptoms due to unfavorable (skewed) X-inactivation. Example: ~5-10% of female DMD carriers develop cardiomyopathy.
• Obligate carriers: Females who must carry the pathogenic variant based on pedigree analysis (e.g., a woman with an affected father and an affected son).
• New mutations: A significant fraction of severe X-linked recessive conditions arise as de novo variants, especially when they reduce reproductive fitness (e.g., ~1/3 of Duchenne muscular dystrophy cases).

• Duchenne/Becker muscular dystrophy (DMD): X-linked recessive; Duchenne is severe (frameshift/nonsense), Becker is milder (in-frame deletions preserving partial dystrophin). CK levels elevated in affected males and some carrier females.
• Hemophilia A and B (F8, F9): X-linked recessive clotting disorders. Female carriers may have reduced factor levels and mild bleeding symptoms.
• Rett syndrome (MECP2): X-linked dominant, typically lethal in males. Affected females show normal early development followed by regression at 6-18 months.
• Fragile X syndrome (FMR1): X-linked with unique features, including trinucleotide repeat expansion and premutation carriers at risk for FXTAS (males) and FXPOI (females).