The Pedigree with Two Unaffected Parents and an Affected Daughter
A genetic counselor reviews a family in which two unaffected parents have four children: one unaffected son, one affected son, and two unaffected daughters. The affected son has a metabolic disorder. The mother's brother is also affected, but her sister is not. The father's family has no history of the disorder across three generations. The counselor is asked whether the disorder could be X-linked recessive or autosomal recessive, and whether the parents' next child can be predicted. A colleague argues it must be autosomal recessive because 'two unaffected parents had an affected child, so both must be carriers.' The counselor notes that the affected child is male and that the mother has an affected brother.
1. Evaluate the colleague's claim that the disorder 'must be autosomal recessive.' Is that conclusion justified?
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No. Two unaffected parents having an affected child shows the trait is recessive, but it does not distinguish autosomal from X-linked inheritance. For X-linked recessive: the mother can be a heterozygous carrier (X^A X^a), the father is unaffected (X^A Y), and a son who inherits X^a from the mother and Y from the father is affected. The mother's affected brother is consistent with her being a carrier, since their mother could also be a carrier. The absence of affected females is also consistent with X-linked recessive, because daughters would need an affected father to be affected. So the data fit both models. The colleague has identified recessiveness but overstates the conclusion by fixing the mode of inheritance without excluding X-linkage.
2. If the disorder is X-linked recessive, what is the probability that the next child is an affected son? If it is autosomal recessive, what is the probability the next child is affected? Show the reasoning.
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X-linked recessive model: the mother is a carrier X^A X^a and the father is X^A Y. Sons receive Y from the father and either X^A or X^a from the mother, each with probability 1/2. So the probability that the next child is an affected son is (1/2 chance the child is male) × (1/2 chance he inherits X^a) = 1/4. Daughters cannot be affected in this cross. Autosomal recessive model: both parents must be carriers Aa × Aa. The probability of an affected child (aa) is 1/4, regardless of sex. So both models predict a 1/4 chance of an affected child overall, but they differ in which children can be affected: under X-linked recessive only sons can be affected, while under autosomal recessive either sex can be affected. The observed family (affected son, unaffected daughters) is consistent with both, so the counselor cannot choose between them on this pedigree alone.