Case History
Martha is 8 weeks pregnant and Southeast Asian. The father of the baby is not involved, but his ancestry is Northern European. Martha is highly anxious about her risk for severe genetic diseases.
Martha decides to proceed with ECS for all categories of conditions. Because Martha is interested in the most comprehensive testing available, you select a laboratory that uses sequencing, which has higher sensitivity than a mutation panel. A rare deleterious variant is found in the CFTR gene, associated with cystic fibrosis (CF). Unfortunately, because it is rare, the severity of disease in individuals with this variant is unknown.
Question
What can you tell Martha about this result?
Answer Summary
D. Her baby has a higher risk for CF than the general population.
Martha's baby has a higher risk for CF, but clinical outcomes for the baby are difficult to predict for the following reasons:
Lack of information about father's carrier status. Screening for autosomal recessive conditions is always more informative when both parents are available for testing. We cannot accurately predict the chance for CF because the carrier status of the father is unavailable, but we can make an educated guess based on the father's ancestry. You can work with the laboratory or a genetic expert to provide a rough estimate of the chance for CF in the baby. In this case, based on the father's Northern European ancestry, the chance for CF in the baby is approximately 1 in 100 (or 1%).
Impact of a rare variant. If we knew that the father is also a carrier of a CFTR variant, we could tell Martha that the baby has a 1 in 4 (or 25%) chance for CF. Any pathogenic variant in the father is of concern; the maternal and paternal variants do not have to be identical for the baby to have CF. Nevertheless, even if we knew the father is a carrier, we would have difficulty predicting the clinical outcomes for this baby. Like many genetic diseases, the severity of cystic fibrosis can be highly variable, due in part to the functional effects of specific genetic variants. Unfortunately, because Martha's variant is very rare, little is known about how it specifically impacts disease expression. This uncertainty may complicate prenatal decision-making.
Given Martha’s high anxiety level prior to testing and the limitations of testing in her circumstances (non-Caucasian ancestry and lack of paternal testing), ECS may not have been the best choice for her. While patients will make their own decisions about testing, it is important to facilitate informed decision-making, and, to the extent possible, prepare patients for all types of results.