CF yes or no?

Question

Hello,

My 4 month old daughter have F508del and R117H (7T,9T)
What are the risks to have CF?

Thank you

Answer

Dear Questioner
Many thanks for your question. You say that your daughter has two mutations of the CFTR gene (F508del and R117H on a background of a poly T genotype of either 7T or 9T). There are many mutations that can cause cystic fibrosis. Some can cause mild dysfunction of the CFTR protein and therefore cause milder disease. And there are others that cause greater dysfunction of CFTR protein and generally more severe disease. It is however difficult to predict with certainty, the clinical presentation and future course of a patient’s condition. People with the same two copies of the mutated CFTR gene may experience very different symptoms. There are many factors that can influence cystic fibrosis disease. These can include factors from the patient’s environment (for example, exposure to tobacco smoke and nutrition). They can also include modulator genes such as the poly T genotype that your daughter has.

Whether or not your daughter’s R117H mutation is on a background of either 7T or 9T may be important. According to a large database of CFTR mutations these can have different outcomes (www.cftr2.org/r117h.php). There are cases of patients identified with the R117H and 7T having pulmonary disease (Peckham et al 2006). This appears to be milder disease and often presents later in life when there is no newborn screening program. It would appear that having R117H on a background of 9T is very unlikely to cause CF disease. It may be worthwhile to clarify whether your daughter has a 7T or 9T with the team that conducted the genetic analysis. It may also be worthwhile to check if these are on the same gene as the R117H.

If you have not already talked to a cystic fibrosis specialist about your concerns, we would recommend doing so. They would be able to give you more specific advice after face-to-face consultation with you and your daughter. They may recommend further tests. For example, the sweat test looks at the amount of salt (chloride levels) in the sweat. Another test is nasal potential difference which looks at the function of the CFTR protein in the nasal passage. These tests can also help to indicate if cystic fibrosis is likely. Depending on these tests they may also recommend regular follow up in order to maintain contact with the CF team should clinical problems arise.

It might also be helpful to seek genetic counselling, not only to discuss risk, but also for other family members that may want to be tested.

Best wishes
Lisa Kent + Damian Downey
(Belfast)

References:
PeckhamD, Conway SP, Morton A, Jones A, Webb K. Delayed diagnosis of cystic fibrosis associated with R117H on a background of 7T polythymindine tract at intron 8. J Cystic Fibrosis 2006; 5(1):63-65

30.04.2013

The answer is edited by: PhD Lisa Kent

6.5.13
There is a article with concrete data on the risk for patients with the combination deltaF508 and R117H-7T based on French registry data (C. Tauvin-Robinet,
J Med Genet 2009;46:752-758 doi:10.1136/jmg.2009.067215: "The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening").
From the data,..." the theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%."

D. d'Alquen