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Carrier Testing

Question
Dear Team,
Please can I ask your advice. I am worried that my 18 month old grandson may be showing signs of CF. I am not aware of any history of cystic fibrosis in the family, but know this does not have to be a necessary factor.
To avoid causing any unnecessary worry and stress to our daughter my husband and I are considering taking the 'carrier test'. We've been told we would each be tested for 40 mutations. My question is: Do you know if these 40 would be the same common mutations which are part of the 50 looked for in the heelprick test on newborns? If so would you think it pointless for us, because our grandson must have had a clear newborn result as our daughter wasn't informed otherwise.
Please can I have your answer as soon as possible, as my son has recently announced that he and his wife are expecting a baby in September and she would obviously have to undergo the relevant tests during her pregnancy should CF be found in our family.
Thank you so much for your time.
Sincerely,
Anxious Granny

Answer
Dear questioner,
You report about your grandson and your suspicion he might suffer from CF even there is no known CF history in your family. CF is suspected, if a child shows symptoms of the airways and digestive system: those children have fatty, smelly stools and a failure to thrive due to the lack of pancreatic enzymes. This is called “pancreatic insufficiency” as the pancreas is destroyed by chronic inflammation due to sticky secretions. However, there are courses of CF, without this “pancreatic insufficiency” so that the main symptoms address the airways: chronic cough, severe and repeated airway infections. If there is the clinical suspicion of CF (this is a point only the treating pediatrician can judge, I cannot make a diagnosis via the internet) the gold- standard to exclude CF is to perform a so-called “sweat test” to the child: this is a non-invasive (does not cause pain) test, that is done in 30 minutes, the result will be there immediatetly. It is important that this test is done at an experienced center (e.g. a CF center, find addresses for your nearest centers on the website of CF Trust) and that the chloride concentration of the sweat is measured by “pilocarpine ionotophoresis”. With that test, most cases can be excluded for sure, if the value is clearly negative. In borderline or positive cases, genetic investigation follows. But as you stated yourself, most genetic tests only test a panel of the most frequent mutations, and you cannot exclude CF for 100%, those test have a mutation detection rate of about 70-90%. The sweat test is more a functional test and therefore regarded as the first-line gold-standard.
I understand, that you do not want to worry your daughter unnecessarily, but to do a sweat test to the child would bring most clarity and avoid unnecessary testing for many of your family members in case it is clearly negative. You could explain your daughter, that this test is often done as a routine investigation in case of frequent airway infections (like in some centers in Europe, a sweat test is performed in all children presenting with asthma) and it would give relief to the whole family if one could exclude this disease by doing this easy test. Please talk to your pediatrician, about it, he will then initiate the diagnostic if necessary.
Now I will try to explain, why I do not consider your proposal sensible, to do a CF carrier screening in you both grandparents. If this carrier screening for the most frequent 40 mutations would be negative in both of you, you still do not know, if your grandson suffers from CF, as there are many more than 40 mutations and a certain rest risk remains, especially if you really suspect CF in your grandson. Your grandson had a newborn screening for CF; I found out, that the screening in UK measures first line the so-called IRT value, only if this value is pathological, mutation analysis for 33-35 mutations is done. This was obviously negative in your grandson and it is very probable that nearly the same mutations are tested during screening for newborns or adults, as they are the most frequent in a certain population. Of course, it may be possible that your grandson had normal IRT values, and his blood sample was therefore not tested for mutations, and it can of course not be 100% excluded, that the IRT value was falsely negative and so there is the possibility (it is small, however) to fall through the cracks.
In case one or even both of you would turn out to be carrier, your daughter could be also a carrier, but we do not know anything about her husband, so both of them would have to be tested, and we again do not know for which special mutation we are looking for in the father of your grandchild and if standard mutation panels cover his mutation. Then of course, your son has also to be tested, in case one of you carry a CF mutation.
So you see, the other way round is easier and helps to avoid unnecessary investigations of half of the family; in case the sweat test is unambiguously negative, there is no suspicion of CF still in your family as before, and there is no need to test the family members. If there should be a borderline or even positive result, extensive genetic investigation will firstly be done in the grandchild and if the underlying mutations are known, one can precisely search for those in the family of your daughter and in your son. As the result of the sweat test is there immediately, this should be in time for the decision about a mutation testing of your son and his wife. Your daughter and her husband would probably be calmed if they know that such a severe disease can easily be excluded by a simple test.
The concrete decision how to proceed here can of course only be made together with the physicians in charge.
Hope this helps a bit,
Best regards,
Dr. Daniela d’Alquen (Coordinator of the Central English Archive of ECORN-CF)
25.03.2014