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CF Diagnosis

My nephew has recently been diagnosed with cystic fibrosis. This has been devasting news for the entire family. The genetic report received reads as follows:

This individual is heterozygous for both the p.R1088C and p.G542X mutations in the CFTR gene. The combination of these mutations would be expected to cause cystic fibrosis or a CFTR related disease if they are on different chromosomes. (in trans). However the severity of the disease cannot be predicted. Family studies would be necessary to determine if these mutations are on the same chromosome (in cia or trans).

I would highly appreciate if you can shed some more light on this report or provide any recomendations.
Dear Questioner
Thanks very much for your question. You say that your nephew has had a diagnosis of CF or CFTR related disease and that family studies are yet to be done to explore if the detected mutations are in cis or in trans. In cis means that the two mutations are found on the same gene on one chromosome (i.e. inherited from the same parent) and in trans means the two mutations are found on opposite genes, each on one of the two parental chromosomes(i.e. inherited from both parents). CF is an autosomal recessive disease. This means that the mutations must be present on opposite genes to cause disease. Therefore, it is necessary to investigate both parents of the child. If one mutation is found for each parent, it is certain that the child has inherited the mutations in trans and therefore might suffer from CF or CFTR-related disease. In the other case, if both mutations are on the same chromosome and the CFTR gene of the opposite chromosome does not show any changes (exception a further undetected mutation), the patient is most probable a healthy carrier.

CF diagnosis will likely not just depend on the genetic results. Other tests that might be conducted include sweat test and nasal potential difference. These both test the function of the protein CFTR which is faulty in CF. The CF team will also observe any clinical signs and symptoms that your nephew has in order to build up a picture.

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 based only on their genetic information. 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).

There is a large database which gathers information on the clinical outcomes of patients with different mutations ( ). This database lists one of the mutations you mention in your question (G542X) which is a severe mutation (Class 1, nonsense mutation). This means that the CFTR protein building stops too early and the protein made does not function. This mutation is generally associated with lung disease and pancreatic insufficiency. However, as the illness only occurs if two mutations are present, the clinical outcome will mainly depend on the severity of the “less severe mutation”. In your nephew's case you mention R1088C which may or may not be on the opposite gene. Unfortunately, I am not able to find R1088C described in the literature or on the CFTR2 database as a CF causing mutation. There is a similar mutation listed on the database (R1066C) - If this is perhaps the mutation you mean then there is further information on the CFTR2 site. If the mutation is indeed named p.R1088C and it is so rare that there is hardly any information about it available, it is even more important to assess in detail the clinical picture of your nephew (sweat test, pancreatic elastase, fat excretion, assessment of lung disease, probably nasal potential difference) in order to be able to classify his status: pancreatic sufficient or insufficient Cystic Fibrosis, CFTR-related disorder (very mild form of the disease with only one or very few organs involved) or no disease at all. You should however, always discuss this information with your genetic counselor/ CF team. They will be able to give information specific to the patient.
We also sent a mail to a further expert, to see if there is any information on p.R1088C, but as it is holiday time, it will be a while until we get an answer. We will add any new information to the answer as soon as available (if any), please have a look at this answer again later to see this information.

Best wishes,
Lisa Kent, Belfast
Daniela d’Alquen, Würzburg
The answer is edited by: PhD Lisa Kent