A couple with a family history of beta-thalassemia major in a distant relative has come for counseling. The husband has HbA2 of 4.8% and the wife has HbA2 of 2.3%. The risk of having a child with beta-thalassemia major is:

## Core Concept
Beta-thalassemia major, also known as Cooley's anemia, is a severe form of thalassemia that results from mutations in both alleles of the HBB gene, which codes for the beta-globin subunit of hemoglobin. The condition leads to reduced or absent production of the beta-globin chains, causing severe anemia. The genetic basis of beta-thalassemia involves autosomal recessive inheritance.

## Why the Correct Answer is Right
The husband has an HbA2 level of 4.8%, which is elevated (normal range is about 2.2-3.5%). Elevated HbA2 levels are indicative of beta-thalassemia trait (also known as beta-thalassemia minor), suggesting that the husband is a carrier of one mutated allele of the HBB gene. The wife has an HbA2 level of 2.3%, which is within the normal range, suggesting she is likely not a carrier of beta-thalassemia. However, without genetic testing, we can't be 100% certain, but based on the information given, we assume she is not a carrier. The risk of having a child with beta-thalassemia major (homozygous for the mutation) is significant if both parents are carriers. Given that only the husband is confirmed as a carrier, the chance that the child will inherit one mutated allele (beta-thalassemia trait) is 50%, but the chance of the child being a carrier and the other parent also being a carrier (to result in a major form) depends on the wife's status. Assuming she's not a carrier (based on normal HbA2), the risk of having a child with beta-thalassemia major is actually 0% because the child would at most inherit one mutated allele from the father.

## Why Each Wrong Option is Incorrect
- **Option A:** This option suggests a specific risk percentage without calculation. Given the scenario, this seems incorrect because if only one parent is a known carrier, the direct risk to offspring of being affected (having beta-thalassemia major) is actually 0%, not some higher percentage.
- **Option B:** Similarly, this suggests a calculation or risk assessment that does not align with the provided clinical scenario where only one parent's carrier status is confirmed.
- **Option D:** This option implies a higher risk that does not correlate with the genetic information provided, specifically assuming both parents' carrier status or a different scenario.

## Clinical Pearl / High-Yield Fact
A crucial point to remember is that beta-thalassemia major occurs in offspring when both parents are carriers (obligate carriers or known carriers), with a 25% chance of having an affected child, a 50% chance of having a carrier child, and a 25% chance of having a completely normal child. For genetic counseling, confirming carrier status via genetic testing is critical.

## Correct Answer Line
**Correct Answer: C.**