Two Brothers and a Clotting Disorder
Two brothers, aged 8 and 11, both have prolonged bleeding after minor cuts and frequent nosebleeds. Their mother has no symptoms; their maternal grandfather also had a bleeding tendency. Clotting tests show the boys have low activity of a single clotting factor, and the pattern of affected males across generations through unaffected females is striking. A paternal cousin (son of the father's brother) is completely unaffected. A clinician says: 'Because the mother is healthy, the boys must have inherited the faulty gene from their father.' The family wants to know the recurrence risk for any future sons and whether the mother's sisters could be carriers.
1. State the most likely mode of inheritance and explain how the family pattern supports it, including why the paternal cousin is unaffected.
Read the worked answer
The pattern - affected males, unaffected carrier females, transmission through the maternal line, no male-to-male transmission - fits X-linked recessive inheritance.
Reasoning:
- The maternal grandfather was affected → he passed his single X to his daughters, making the mother an obligate carrier (she is phenotypically normal because the disorder is recessive and she has one normal X).
- Each son of a carrier mother has a 1/2 chance of inheriting the faulty X and being affected; both boys being affected is consistent.
- The father contributes his Y to sons, so he cannot pass an X-linked allele to them. The clinician's claim is wrong.
- The paternal cousin is unaffected because the faulty allele is on the mother's side; the father's X (which he passes to daughters, not sons) is normal, so the paternal branch carries no risk.
Note: 'healthy mother' is expected for an X-linked recessive carrier - absence of symptoms is not evidence against inheritance.
2. Calculate the probability that a future child of these parents is an affected son, and explain why the overall probability of an affected child is lower than that.
Read the worked answer
Mother is a carrier (X^A X^a); father is normal (X^A Y).
Punnett grid (mother's eggs × father's sperm):
| X^A (father) | Y (father) | |
|---|---|---|
| X^A | X^A X^A daughter | X^A Y son (normal) |
| X^a | X^A X^a daughter (carrier) | X^a Y son (affected) |
- Probability of a son = 1/2; given a son, probability he is affected = 1/2 → P(affected son) = 1/4 of all children.
- Daughters are never affected here (father supplies a normal X), but half of daughters are carriers.
- The overall probability of an affected child is also 1/4, but it is entirely borne by sons - so among sons the risk is 1/2, which is the number the family should be given for counselling.
Key distinction: '1/4 of all children' vs '1/2 of boys' - both are correct but answer different questions.
3. The mother's two sisters ask about their own carrier risk. What information would you need, and what can you say before testing?
Read the worked answer
The sisters' risk depends on their mother's (the boys' maternal grandmother's) genotype, which is not given.
Case analysis:
- The affected grandfather is X^a Y. He passes X^a to all his daughters. So if the sisters are daughters of this same affected grandfather, each sister is an obligate carrier (probability 1) - no testing ambiguity.
- If instead the affected relative is further back and the grandmother's status is uncertain, each sister's prior carrier probability is set by the pedigree (e.g. 1/2 if their mother was a known carrier).
What to say before testing:
- Clarify the exact relationship: are the sisters children of the affected grandfather? This single fact changes the answer from 'certain carrier' to 'probability'.
- Carrier status can be confirmed by DNA testing of the specific variant once it is identified in an affected boy; clotting-factor activity levels are less reliable in carriers.
- If a sister is a carrier, each of her sons carries a 1/2 risk, and she should be offered genetic counselling.
Lesson: the pedigree structure, not the label 'sister', determines the probability.