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p.Phe1078Ile

Question
My one year daughter was diagnosed with cf a year ago because of malnutrition, sweat test borderline and single Df508 (ex 11 CFTR). Direct sequencing test revealed another absolutely new mutation - p.Phe1078Ile (or c.3232t>a) in exon 20 cftr - which has never been described in any database before. I was told that it is not clear whether with this mutation - c.3232t>a - the cftr function is abolished or residual. It is also not clear whether this mutation is desease causing or not. This mutation was not found in 110 unrelated CF chromosomes and that is how the dx was confirmed genetically. The mutation has been entered into cftr database after that.

Anna's (my DD) clinical picture is unclear: slightly elevated IRT level, sweat test - one negative and one borderline, fluctuating level (high-low) of potassium in serum (low level of potassium is considered as pseudo-barter syndrome - which may be an atypical presentation of CF), plus some vomiting and malnutrition in the past (but all these things are quite common for new babies), she doesn't need enzymes. Other things went quite well. We are doing all treatments and preventive measures - and Anna is doing like a normal 1 (almost 2) y.o. girl (without CF).

Have you ever seen p.Phe1078Ile before?
Can you please point me in the direction of some resources for p.Phe1078Ile by itself, or in conjunction with single DF508?
Is it a rare missense mutation or it is a different category this mutation falls into?
How this can be that my DD is the only person with c.3232t>a in the world?
Answer
Dear Questioner
We do not have any CF patients with the p.Phe1078Ile mutation. It is quite plausible, and indeed likely, that there are many other CF subjects throughout the world who have this particular mutation, but the mutation itself has merely not been identified. Very often a diagnosis of CF is established without having identified any known culprit mutations (i.e. diagnosis made on the basis of sweat testing in conjunction with typical clinical findings). These rarer CF mutations are initially often not allocated to a specific class of mutation on CF Mutation databases. Furthermore, by virtue of being rare, it can also be challenging to be precise with regard to phenotype, or severity of disease, that the mutation renders in any given individual. In addition, the impact that any given CF mutation has on severity of disease is often determined by the combination of CF mutations, rather than any one mutation in isolation.[1] It is also important to keep in mind that there is a high variability in phenotype within identical CFTR genotypes.[2] As a definite modifier genes remains to be identified we support consensus statements advising that clinicians should not use genotype alone to predict clinical outcomes at the time of diagnosis.[3]
The fact that your daughter has a borderline sweat test result, is pancreatic sufficient with only a mildly elevated IRT level is very promising indeed. Collectively these findings would suggest that this new mutation belongs to a higher class of mutation. These particular mutations often confer only very mild CF symptoms and signs in adult life.[4]


Reference List

1. Comer, D.M., et al., Clinical phenotype of cystic fibrosis patients with the G551D mutation. QJM, 2009. 102(11): p. 793-8.
2. Loubieres, Y., et al., Association between genetically determined pancreatic status and lung disease in adult cystic fibrosis patients. Chest, 2002. 121(1): p. 73-80.
3. Castellani, C., et al., Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros, 2008. 7(3): p. 179-96.
4. Zielenski, J., Genotype and phenotype in cystic fibrosis. Respiration, 2000. 67(2): p. 117-33.


Best wishes

Dr David Cromer
03.07.2012