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Disease Causing or not?

Hi, my 18 month old son's CFTR renotyping results are back. He is heterozygous for;
c.[1521_1523delCTT] + c.[1584G>A]
they also found sequence variants of limited or no known clincal significance;
c.1210-12T[7]+[9] (poly T 7T/9T)

A short history is my boy screen positive due to DF508 (my 11old neice is DDF508 and my daughter is a carrier), after a sweat test at 6weeks was negative he was presumed negative. He is my fourth child and I noticed he was different straight away. He has had a cough since birth which is increasing with age. I went back to doctors after he was continually getting sick with URI and cultured Heamaphilis Influenzae. from a few months of age he had chronic diareah with tummy pains and mucus in stools. He had a continual runny or blocked nose. He was again tested and sent to CF centre. Second sweat test was negative so dismissed again. After continueing to get sick and have diareah, sinus issues I ordered a full DNA test. He has had surgery to remove his adenoids due to infection and the doctor said there was excessive mucus through his sinuses. Six weeks ago he started showing signs of protein deficiecy (edemas in his feet and constantly sleeping). He has been put on creon and is a different child. He still has his sinus issues and a constant cough but I am ensuring he receieves daily airway clearence. The results from the DNA tests says that the mutation 1716G/A (legacy name) was previously thought to be not disease causing, but is has been show to have mild CF symptoms. The genetic specialist said I will have to be a sit and wait before a diagnosis is made depending on his symptoms, therefore making a diagnosis unclear. This mutation is listed as one for the trial of Kalydeco as it has some residual function. I would have thought that if it has been listed in this trial then it must be disease causing in someone? Have you got any information on the pairing of these two mutations and if they together are disease causing?
Dear questioner,
In the case of your son, one mutation c.[1521_1523delCTT] or better known as deltaF508 has been found. This mutation is the most frequent CFTR mutation and is causing the classical clinical picture of CF with pancreatic insufficiency and variable degree of lung disease when combined with another CF-causing mutation belonging to the same class. You already know, that the delta F508 mutation is in your family as your daughter is a carrier and your son has also inherited it.

With the second mutation c.1584G>A (c-DNA name, legacy name 1716G/A) things are not as clear. It is not listed in the CFTR2 database, I found some information via the cystic fibrosis mutation database from the sickkids hospital in Toronto. Here, it is described as sequence variation, so one would expect probably no signs of an illness. However, there is a publication by Casals at al. (Pancreas. 2004 May;28(4):374-9. “Different CFTR mutational spectrum in alcoholic and idiopathic chronic pancreatitis?”) reporting that the 1716G/A variant could be found in a substantial percentage of patients suffering from chronic idiopathic pancreatitis. The symptoms of your son that you report hint at pancreatic insufficiency and at the same time several negative sweat tests – normally a very unusual combination, so one could only speculate, if this mutation has probably a special influence on the pancreas even if the function of the chloride channel (measured by the sweat test) seems to be not totally impaired. This is however just a theory, as until now, there is not enough known about the consequences of the mentioned “sequence variation? ” or “mutation?”.
Therefore, the finding of c.1584G>A as well as the other sequence variations cannot make a secure diagnosis of CF from the genetic standpoint, however, can neither exclude it. As your genetic specialist told you, a clear diagnosis is not possible due to the genetic findings.
The clinical signs of your son, however, fit somehow in the picture of CF, as he is suffering from airway infections, has sinus problems and seems to have pancreatic insufficiency that could be alleviated by Creon. At the same time you report about several negative sweat tests. This is indeed a very unusual combination, as one would expect a clear change in sweat electrolytes if the pancreas is already involved in that way. However, cases of CF patients with negative sweat test are described.
It would be interesting to know, if the pancreatic function has been tested before the therapy with Creon, e.g. via measurement of the stool fat excretion (gold standard) or of the pancreatic elastase. If the sweat test is not conclusive, the function of the chloride channel can also be assessed by measurement of the potential difference in the nasal mucosa (NPD test, problematic in young children) or in a biopsy of the rectum mucosa (ICM test, possible already at young age). Both tests, however are available only in a few specialized centers.
However, even more important for your son is the regular follow-up in a specialized CF center for supervision of his digestive and airway symptoms, in order to be able to intervene promptly in case of problems and initiate necessary therapies. Precisely because it seems not possible at them moment to make a clear diagnosis a good follow-up is important and the course of time will probably bring more clarification.

Yours sincerely,

Dr. Daniela d’Alquen (Coordinator of the Central English Archive of ECORN-CF)
Castellani et al in the Journal of Cystic Fibrosis 7 (2008) 179-196: "Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice"
The answer is edited by: Prof Stuart Elborn