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: 25%

Step-by-step solution

Understanding Cystic Fibrosis Mutations

Cystic fibrosis is caused by mutations in the CFTR gene, which codes for a protein that regulates the movement of ions across cell membranes. There are many different mutations in the CFTR gene that can cause cystic fibrosis, but some of the most common mutations are Δ508 and R117. For a child to have cystic fibrosis, they need to inherit two copies of a CFTR gene mutation, one from each parent.

Determine the Possible CFTR Gene Combinations in the Offspring

Since the husband carries the Δ508 mutation and the wife carries the R117 mutation, there are four possible combinations of CFTR genes that they could pass on to their offspring: 1. Normal CFTR gene from both parents: No CF 2. Normal CFTR gene from the husband, R117 mutation from the wife: Carrier of R117 mutation 3. Δ508 mutation from the husband, normal CFTR gene from the wife: Carrier of Δ508 mutation 4. Δ508 mutation from the husband, R117 mutation from the wife: Compound heterozygous for CF

Explain the Risk of Having a Child with Cystic Fibrosis

The couple's belief that they cannot have a child with cystic fibrosis because they each carry different mutations is incorrect. Although it is true that their child cannot be homozygous for either mutation, they can have a child who is compound heterozygous for both mutations, inheriting one Δ508 mutation from the husband and one R117 mutation from the wife. A compound heterozygous individual can still develop cystic fibrosis, as both CFTR gene copies have mutations that prevent the protein from functioning properly.

Calculate the Probability of Having a Child with Cystic Fibrosis

Since there are four possible CFTR gene combinations, and one of them results in a compound heterozygous individual, the probability of them having a child with cystic fibrosis is 1 in 4, or 25%. In conclusion, the couple should be informed that they are at risk for having a child with cystic fibrosis since their child could inherit a combination of the Δ508 and R117 mutations. This would result in a compound heterozygous child with cystic fibrosis with a 25% probability. They should be provided with appropriate resources and support to help them make informed decisions about family planning and prenatal care.

Key concepts

CFTR Gene Mutations

Cystic fibrosis (CF) is a genetic disorder primarily affecting the lungs and digestive system. It's caused by mutations in the CFTR gene, which plays a crucial role in regulating the movement of chloride and sodium ions across cell membranes. If the CFTR protein is dysfunctional due to mutations, the transport of these ions is hindered, leading to thick, sticky mucus buildup in various organs.

There are over 1,700 different mutations identified in the CFTR gene that can contribute to cystic fibrosis, but the \(\Delta 508\) mutation is the most common, followed by others like the \(R117H\) mutation. It is important to note that not all mutations have the same effect on the protein's function. Some may completely abolish its function, while others only partially impair it, resulting in various CF severity levels.

Compound Heterozygous

The term 'compound heterozygous' refers to an individual who has inherited two different mutations, one from each parent, which affect the same gene but at different locations. In the context of cystic fibrosis, a compound heterozygous person has two distinct CFTR gene mutations that can lead to the development of the disease.

This differs from being 'homozygous', where two identical gene mutations are inherited. Although compound heterozygotes for CFTR mutations carry different mutations, each can still disrupt the gene's function enough to cause CF symptoms. It's essential to understand that having two different mutations can be just as impactful as having two copies of the same mutation when it comes to diseases like CF.

Genetic Counseling

Genetic counseling is a process that provides support and information to individuals or families who may be at risk for hereditary conditions, such as cystic fibrosis. In the case of the couple concerned about CF in their future children, a genetic counselor would explain the significance of CFTR gene mutations and the implications for their offspring. The counselor would also provide guidance on the range of possible genetic outcomes for their children and discuss the associated risks.

In addition to offering emotional support, genetic counselors can aid in decision-making about family planning, provide information on genetic testing and prenatal diagnosis options, and connect families with resources and support networks. They play a pivotal role in helping individuals understand complex genetic information and its impact on their lives.

Inheritance Patterns

Cystic fibrosis inheritance follows an autosomal recessive pattern. This means that an individual must inherit two copies of the mutated CFTR gene, one from each parent, to exhibit symptoms of the disease. Carriers of CF, who possess only one copy of a mutated gene, typically do not show symptoms.

When both parents are carriers of CFTR mutations, there's a 25% chance of having a child with CF, a 50% chance of having a carrier child, and a 25% chance of having a child with no mutations. In the case of the mentioned couple, with both being carriers of different CFTR mutations, there is a 25% probability that their child will be compound heterozygous for CF. Detailed genetic counseling and understanding these inheritance patterns are crucial for accurate risk assessment and informed family planning.