Interpreting a Pedigree with Incomplete Information
A family is referred to a genetics clinic because a 14-year-old boy, Sam, has a degenerative muscle condition. His parents are unaffected. Sam has an older sister, Maya, who is unaffected, and a younger brother, Tom, who is unaffected. The maternal grandfather had a similar condition and died at 52; the maternal grandmother is unaffected. Sam's father has no family history. A genetic test shows Sam carries a mutation in a gene on the X chromosome. The family asks whether Maya could pass the condition to her children, and whether Tom's children are at risk.
1. Explain the inheritance pattern and determine the most likely genotypes of Sam, his parents, and his grandparents.
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The gene is on the X chromosome and the condition affects males more severely, consistent with X-linked recessive inheritance. Let X^A be normal and X^a the mutant allele.
Sam (affected male) is X^aY. He inherited Y from his father and X^a from his mother. His mother is unaffected, so she must be a carrier: X^A X^a. His father is unaffected: X^A Y.
The maternal grandfather was affected: X^aY. He passed his X^a to all his daughters, so Sam's mother is a carrier - consistent with the pedigree. The maternal grandmother is unaffected; she could be X^A X^A or X^A X^a, but since her daughter is a carrier and her husband contributed X^a, the grandmother need not carry the allele. Sam's father's family history is irrelevant because fathers do not pass X-linked alleles to sons.
Note that an affected male cannot pass the condition to his sons (he gives Y), but all his daughters are carriers.
2. Assess the risk to Maya's future children and to Tom's future children. Include probabilities and reasoning.
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Maya: her father is X^A Y and her mother is X^A X^a. Maya is unaffected, so she is either X^A X^A or X^A X^a, each with probability 1/2. If she is a carrier (probability 1/2), each son has a 1/2 chance of being affected (inheriting X^a), and each daughter has a 1/2 chance of being a carrier. Overall, the chance that any given son of Maya is affected is 1/2 × 1/2 = 1/4. Genetic testing could determine her carrier status definitively, which would refine these odds.
Tom: he is unaffected male, X^A Y. He inherited Y from his father and X^A from his mother. He cannot pass an X-linked allele to his sons (he gives Y), so his sons are not at risk from him. His daughters receive his X^A, so they are not carriers from him; however, if his partner is a carrier, his daughters could still inherit an allele from the mother. Tom's own risk of being affected is zero because he inherited the normal X from his carrier mother.
3. A relative claims that because Sam's parents are unaffected, the condition cannot be genetic. Evaluate this claim.
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The claim is incorrect. Unaffected parents can have an affected child when the condition is recessive, because carrier parents each contribute a recessive allele without showing the trait. In X-linked recessive inheritance, the mother can be a carrier (heterozygous) and remain unaffected because the normal allele on her other X chromosome provides functional protein. Sam's father is unaffected because he has only one X and it is normal; he contributes Y to Sam.
The pedigree is consistent with this: the maternal grandfather was affected, which is exactly how the mother would have inherited the allele. The absence of the trait in the parents is therefore expected, not evidence against a genetic cause.
A genetic cause is supported by the family pattern, the male bias, and the identified X-linked mutation. Other explanations (e.g. environmental exposure) would not explain the grandfather's similar condition or the specific mutation found.