Question

A couple with European ancestry seeks genetic counseling before having children because of a history of cystic fibrosis (CF) in the husband's family. ASO testing for CF reveals that the husband is heterozygous for the \(\Delta 508\) mutation and that the wife is heterozygous for the \(R 117\) mutation. You are the couple's genetic counselor. When consulting with you, they express their conviction that they are not at risk for having an affected child because they each carry different mutations and cannot have a child who is homozygous for either mutation. What would you say to them?

Short answer

Answer: The probability of the couple having an affected child is 25%, as the child could inherit one mutated allele from each parent resulting in a compound heterozygote for the disease. This occurs even though the parents carry different cystic fibrosis mutations (\(\Delta 508\) and \(R 117\)).

Step-by-step solution

Understanding cystic fibrosis mutations

Cystic fibrosis is an autosomal recessive genetic disorder, meaning that a person must inherit two copies of the mutated gene (one from each parent) to be affected. In this case, the husband is heterozygous for the \(\Delta 508\) mutation, and the wife is heterozygous for the \(R 117\) mutation. Being heterozygous means that they each carry one normal allele and one mutated allele.

Examine the possible outcomes for child's genotype

To understand the possible outcomes for the couple's potential children, we need to examine all possible combinations of the two alleles from each parent. Using the Punnett square, we can see the following possible genotypes for the couple's child: 1. Normal allele from both parents (unaffected) 2. Normal allele from father and \(R 117\) mutation from mother (unaffected carrier) 3. \(\Delta 508\) mutation from father and normal allele from mother (unaffected carrier) 4. \(\Delta 508\) mutation from father and \(R 117\) mutation from mother (affected)

Calculating the probability of having an affected child

From the four possible genotypes listed above, only one of them results in an affected child (combination of both mutated alleles). The probability of this outcome is \(\frac{1}{4}\), as there is a 50% chance for each parent to pass on their mutated allele, and to have an affected child, both mutated alleles must be inherited simultaneously (0.5 x 0.5 = 0.25).

Explaining the risk to the couple

Contrary to the couple's belief, they can indeed have a child who is affected by cystic fibrosis, even if they carry different mutations. Their child would inherit one mutated allele from each parent, resulting in a compound heterozygote for the disease. They have a 25% chance of having an affected child, a 50% chance of having an unaffected child who is a carrier of the mutation, and a 25% chance of having an unaffected child with no mutated alleles. It is important to discuss these risks with the couple and help them make informed decisions regarding family planning.

Key concepts

Cystic Fibrosis

Cystic Fibrosis (CF) is a genetic disorder that affects the respiratory, digestive, and reproductive systems. It results from mutations in the CFTR gene, which is responsible for regulating the movement of salt and water in and out of cells. In people with CF, thick and sticky mucus builds up in various organs, leading to severe complications.

Those affected by CF often experience:

• Chronic lung infections
• Breathing difficulties
• Poor growth and weight gain
• Digestive issues

Understanding this disorder's genetic nature is crucial for genetic counseling, especially for couples with a family history of CF.

Autosomal Recessive

Cystic Fibrosis is known as an autosomal recessive disorder. This means that for a person to have CF, they must inherit two copies of the mutated gene, one from each parent.

In an autosomal recessive inheritance pattern, several outcomes are possible:

• If both parents are carriers, there is a 25% chance their child will be affected.
• There is a 50% chance their child will be a carrier, just like the parents.
• There is a 25% chance their child will inherit two normal alleles, unaffected by CF.

It's important to understand that even if parents carry different mutations in the CFTR gene, a child can still be affected if they inherit one faulty allele from each parent.

Punnett Square

The Punnett Square is a useful tool for predicting the genetic outcome of a child based on the genotypes of the parents. It helps visualize all possible combinations of alleles that a child could inherit.

For example, in the case of CF where both parents are carriers:

• The father's alleles could be represented on one side of the square ( extending to create two columns).
• The mother's alleles go on another side (creating two rows).
• This forms a grid showing all possible combinations.

The resulting squares represent potential genotypes for their children, providing a probability for being affected, being a carrier, or having no mutation. Using the Punnett Square makes complex genetic probabilities more manageable to understand.

Heterozygous Mutations

Being heterozygous means carrying one normal allele and one mutated allele of a gene. For the couple in our scenario, each carries different mutations on their CFTR gene.

Heterozygous individuals typically do not show symptoms of CF but can pass the mutated allele to their offspring. When both parents are heterozygous, their child may inherit:

• Both normal alleles (unaffected)
• One normal and one mutated allele (carrier, like the parents)
• Two different mutated alleles (compound heterozygote, affected)

Understanding heterozygosity is crucial, as compound heterozygotes—those with two different CF mutations—can still exhibit the disease, contrary to some beliefs that only identical mutations lead to CF.