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R668C and M348K mutations

Question
Good morning,
my husband has the R668C mutation (he is carrying the atypical form of CF) and I have the variation M348K. My cousin has the mutations M348K and S912X and he is healthy, but his son has the classical form of CF with the mutations delta508, S912X, M348K. Which are the risks that me and my husband have a baby with the classical/atypical form of the disease?
Thank you,
best regards
Answer
Dear Questioner
Many thanks for your question.
When a couple who are both carriers have a baby there are four possible combinations of genes:
-CF + CF (both the CF causing mutations/ “CF”)
-CF + NORM (one CF causing mutation and one normal gene/ “Carrier”)
-NORM + CF (one CF causing mutation and one normal gene/ “Carrier”)
-NORM + NORM (both the normal genes “Healthy non-carrier”)

There is a 1 in 4 chance of having both mutations and therefore have CF. There is a 2 in 4 chance of having just one mutation and therefore be a carrier. There is a 1 in 4 chance of having no mutations and therefore be a healthy non-carrier.

There are some cases reported in the literature which suggest that the mutation M348K does not cause CF. It is possible that it might cause CF disease if it is found on the same gene as another mutation. If M348K is present it has been suggested that the gene should be scanned for other mutations (d’Apice 2004; Deltas 1996; Hentschel 2012).

The mutation R668C does not appear to be very common and has been listed in the CFTR2 database (www.cftr2.org/) as a mutation of varying clinical consequence.

Since neither you nor your husband carries the other mutations you mentioned (deltaF508 or S912X) you do not need to worry about these.

It is important to note that making a prognosis based only on genotype is very difficult. People with the same two copies of the mutated CFTR gene may experience very different symptoms.

If possible I would recommend that you speak to someone who can provide you and your husband with genetic counselling and extended screening for mutations.

Best wishes
Stuart Elborn
Lisa Kent
Belfast

References
D’Apice et al Prenatal Diagnosis 2004; Volume 24: Pages 981-983
Deltas et al Molecular Cell Probes 1996; Volume 10: Pages 315-318
Hentschel et al European Journal of Pediatrics 2012; Volume 171: Pages 1039-1046
25.07.2012
The answer is edited by: Prof Stuart Elborn