Pedigree Puzzle: X-Linked or Autosomal Recessive?
A student analyzes a family in which a rare metabolic disorder appears in three males across two generations. Generation I includes unaffected parents with an affected son and an unaffected daughter. The unaffected daughter, II-2, marries an unaffected man and has two affected sons and one unaffected daughter. No females are affected. The student writes that the pattern is X-linked recessive because only males are affected and affected males come from carrier mothers, so II-2 must be a carrier and her daughters cannot pass the trait. The teacher asks the class to consider whether the data are sufficient and to calculate probabilities for II-2's next child. The family is large, but the disorder is rare in the population and no molecular testing has been done. Another student points out that II-2's father is unaffected and asks whether that matters.
1. Evaluate the student's claim that the pedigree proves X-linked recessive inheritance. Address the evidence for and against, and correct any error in the statement about daughters.
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The pedigree is consistent with X-linked recessive, but it does not uniquely establish it. Unaffected parents with an affected son fit both X-linked recessive, where the mother is a carrier, and autosomal recessive, where both parents are carriers. The absence of affected females is weak evidence in a small family: with X-linked inheritance, daughters of an unaffected father and a carrier mother have no affected phenotype, but autosomal recessive would produce affected females only when both parents carry the allele, and chance can explain zero affected daughters. The student's claim that daughters cannot pass the trait is incorrect. A daughter of a carrier mother can inherit the allele and become a carrier, and she can later have affected sons. The unaffected father of II-2 is not informative by himself under either model. Father-to-son transmission would rule out X-linked inheritance; an affected daughter from an unaffected father would strongly support autosomal recessive.
2. Calculate the probability that II-2's next child will be affected under each inheritance model. Show the reasoning and state what birth outcome would distinguish the models.
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If the trait is X-linked recessive, II-2 has two affected sons, so she is an obligate carrier, X^A X^a. Her husband is unaffected, X^A Y. Each son has a 1/2 chance of inheriting X^a and being affected; each daughter has a 1/2 chance of being a carrier and essentially 0 chance of being affected because the father contributes X^A. Thus P(next child affected) = P(son) × P(affected | son) = 1/2 × 1/2 = 1/4. If the trait is autosomal recessive, two affected sons make II-2 and her husband obligate carriers, Aa × Aa, so each child has a 1/4 chance of being affected regardless of sex. An affected daughter would distinguish the models: under X-linked recessive, an affected daughter would require an affected father, but the father is unaffected, so that outcome would contradict X-linked inheritance and support autosomal recessive. A son would not distinguish them because both models predict affected sons.
3. Describe two additional pieces of evidence, other than molecular testing, that would help resolve the mode of inheritance, and explain how each would shift the conclusion.
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First, look for father-to-son transmission. A son inherits his Y chromosome from his father and his X chromosome from his mother, so an affected father passing the trait to a son is impossible under X-linked inheritance but possible under autosomal recessive if the mother is a carrier. Such a transmission would rule out X-linked and support autosomal. Second, examine whether affected males have affected daughters. Under X-linked recessive, an affected father and an unaffected mother produce daughters who are obligate carriers but not affected; under autosomal recessive, an affected father and a carrier mother can produce affected daughters. The birth of an affected daughter from an unaffected father would also rule out X-linked. Population data can help: if the disorder is very rare, a cluster of affected males in one family is more likely under X-linked inheritance, but rarity alone does not prove it. Consanguinity in the family would raise the prior probability of autosomal recessive inheritance.