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Quantitative Genetics

Autosomal Recessive Risk Assessment

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Personalized Risk Assessment/Inheritance Patterns

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Autosomal recessive (AR) risk assessment involves calculating the probability that an individual is a carrier or will have an affected child, based on family history, population carrier frequencies, and pedigree analysis.

For the underlying biology and pedigree pattern (horizontal transmission, carrier state, manifest in homozygotes), see Autosomal Recessive Inheritance.

  • Both parents must be carriers (heterozygous) for an affected child
  • Each child of two carriers has a 1/4 chance of being affected, 1/2 chance of being a carrier, 1/4 chance of being homozygous unaffected
  • An unaffected sibling of an affected individual has a 2/3 chance of being a carrier (not 1/2, because we exclude the 1/4 who are affected)

Example 1: Carrier risk for an unaffected sibling

Problem: A couple has a child with cystic fibrosis. What is the probability that their unaffected daughter is a carrier?

Solution:

  • Both parents are obligate carriers (Aa x Aa)
  • Offspring ratio: 1/4 AA, 2/4 Aa, 1/4 aa
  • The daughter is unaffected, so she is either AA or Aa
  • P(carrier | unaffected) = (2/4) / (3/4) = 2/3

Example 2: Couple risk when one partner is a known carrier

Problem: A woman is a known CF carrier. Her partner has no family history. The population carrier frequency is 1/25. What is their risk of having an affected child?

Solution:

  • Mother: carrier (1)
  • Father: carrier probability = 1/25 (population frequency)
  • Risk of affected child = 1 x 1/25 x 1/4 = 1/100

Example 3: Couple risk with an affected sibling

Problem: A man's brother has sickle cell disease. His partner has no family history. Carrier frequency in their population is 1/12. What is their risk of having an affected child?

Solution:

  • Man's carrier risk: 2/3 (unaffected sibling of affected)
  • Partner's carrier risk: 1/12 (population frequency)
  • Risk = 2/3 x 1/12 x 1/4 = 2/144 = 1/72
  • Forgetting the 2/3 rule: An unaffected sibling of an affected person has a 2/3 carrier risk, not 1/2
  • Using wrong population frequency: Carrier frequencies vary by ethnicity. Always use the population-specific frequency.
  • Forgetting to multiply by 1/4: The 1/4 is the chance that two carriers produce an affected child

"2/3 of the unaffected": when you know both parents are carriers, unaffected children have a 2/3 chance of being carriers. The key: you are conditioning on being unaffected, which removes the 1/4 affected from the denominator.