X-Linked Risk Assessment

X-linked risk assessment requires tracking the X chromosome through the pedigree. Males are hemizygous (one X), so a single pathogenic variant causes disease. Females are typically carriers but may be variably affected due to X-inactivation.

For the underlying biology and pedigree pattern (hemizygosity, manifesting carriers, X-linked dominant male lethality, no male-to-male transmission), see X-Linked Inheritance.

• Carrier mother x unaffected father: Each son has 1/2 chance of being affected; each daughter has 1/2 chance of being a carrier
• Affected father x unaffected mother: All daughters are obligate carriers; no sons are affected (father passes Y to sons)
• De novo mutations: About 1/3 of X-linked recessive cases in males are de novo (Haldane's rule for severe X-linked lethal conditions)

Example 1: Carrier risk through pedigree

Problem: A woman's brother has hemophilia A. Her mother is an obligate carrier. What is the woman's risk of being a carrier? If she is a carrier, what is the risk her son will be affected?

Solution:

• Woman's carrier risk: 1/2 (she got one of her mother's two X chromosomes)
• If carrier, risk to each son: 1/2
• Combined risk that her son is affected: 1/2 x 1/2 = 1/4

Example 2: Bayesian modification with unaffected sons

Problem: Same woman as above, but she has 3 unaffected sons. What is her updated carrier risk?

Solution (Bayesian):

• Updated carrier risk: 1/9 (down from 1/2)
• Each unaffected son reduces her carrier risk because it is more likely she is not a carrier

Example 3: Haldane's rule (isolated case)

Problem: A boy is the first person in his family diagnosed with Duchenne muscular dystrophy. His mother has no family history. What is the probability the mother is a carrier?

Solution:

• For X-linked lethal conditions, Haldane's rule states that 1/3 of cases are de novo
• Therefore, 2/3 of mothers of isolated cases are carriers
• Mother's carrier risk: 2/3
• This can be further modified by Bayesian analysis using CK levels, number of unaffected sons, etc.

• Forgetting carrier females can be affected: Skewed X-inactivation can cause symptomatic carriers (e.g., manifesting carriers of DMD with cardiomyopathy)
• Applying Haldane's rule to non-lethal conditions: The 1/3 de novo rule applies specifically to severe X-linked conditions where affected males do not reproduce
• Not updating with Bayesian analysis: Always update carrier risk with available information (unaffected sons, CK levels, molecular testing)