Two Recessive Risks in One Couple: Duchenne and Cystic Fibrosis
A 27-year-old woman and her 28-year-old partner seek preconception counseling. The woman's brother has genetically confirmed Duchenne muscular dystrophy (DMD) with a deletion in DMD; her mother is an obligate carrier. The woman has no muscle weakness and a serum creatine kinase of 85 U/L (reference <170). The man's sister has cystic fibrosis (CF) with F508del/G542X; his parents are healthy. He underwent a 50-mutation CF carrier panel, which detects about 90% of CF carriers in this population; the result is negative. The couple is not consanguineous. The local CF carrier frequency is 1 in 25. They plan one pregnancy and want to know the chance of an affected child, whether the woman's normal CK is reassuring, and whether the man's negative CF test can be trusted.
1. Calculate the woman's risk of being a DMD carrier and the risk that a future son is affected. Does the normal CK change your estimate?
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The woman's brother has DMD, an X-linked recessive disorder. Her mother must be an obligate carrier because she has an affected son and, in the absence of a new mutation, the mother transmitted the DMD allele. The woman has a 1/2 chance of inheriting the carrier state. If she is a carrier, each son has a 1/2 chance of being affected because he inherits one of her X chromosomes; each daughter has a 1/2 chance of being a carrier. A normal serum CK does not materially change the 1/2 prior: CK is elevated in only a minority of DMD carriers, and levels vary with age and skewed X-inactivation. Thus the risk that a future son is affected is 1/2 × 1/2 = 1/4, and the risk for any pregnancy to produce an affected son is 1/2 × 1/2 × 1/2 = 1/8. The 85 U/L CK is reassuring only in the weak sense that it does not suggest muscle disease in the woman herself; it is not a carrier exclusion test. Definitive risk refinement requires testing for the familial DMD deletion.
2. Calculate the man's residual CF carrier risk after the negative panel, and the couple's risk of a CF-affected child. State your assumptions.
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The man's prior carrier risk is 2/3, because both parents of an affected child are carriers and he is unaffected; among unaffected siblings of an autosomal recessive case, the genotype probabilities are 1/3 non-carrier and 2/3 carrier. The panel detects 90% of carriers, so a carrier has a 10% chance of testing negative, while a non-carrier has a 0% chance (assuming perfect specificity). Posterior carrier probability = (2/3 × 0.10) / [(2/3 × 0.10) + (1/3 × 1.0)] = 0.0667 / 0.4 = 1/6, or about 16.7%. The woman's population carrier risk is 1/25. If both are carriers, each child has a 1/4 risk of CF. Therefore the couple's risk of a CF-affected child is 1/25 × 1/6 × 1/4 = 1/600, about 0.17%. This assumes the panel's 90% sensitivity applies to this population and that the woman has no independent family history. Testing the man directly for the two familial CF variants (F508del and G542X) would be more informative than the panel: if he carries neither, his risk from those alleles is very low, though rare other alleles remain.
3. The couple asks whether they should have prenatal diagnosis or preimplantation genetic testing. What should be recommended first, and what is the main limitation of the man's negative carrier test?
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The first step is not to choose a procedure but to define the familial variants. The man's sister has CF with F508del/G542X, so targeted testing of the man for those two variants is more informative than a generic 50-mutation panel and should be done before counseling about prenatal diagnosis. The woman should be tested for the DMD deletion found in her brother; if she carries it, her risk is confirmed and prenatal diagnosis by CVS or amniocentesis, or preimplantation genetic testing for monogenic disease (PGT-M), can be offered. If she does not carry the deletion, her DMD risk falls to the new-mutation rate, and the reproductive plan changes. For CF, even if the man is negative on targeted testing, a small residual risk from rare variants remains, and the woman's 1/25 population risk means the couple's CF risk is low but not zero. The main limitation of the man's negative panel is that it excludes only common alleles; a negative result is not a guarantee of non-carrier status. Genetic counseling should present the two conditions separately, because DMD affects sons and CF affects both sexes.