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CFTRdele2, 3 (21kb)

Question
Our baby has 8 months and was diagnosticated at 6 moths with CF. Now we have received the results from the genetic test:" Heterozygous carrier of a 21 kilobase deletion in the CFTR gene, which leads to a loss of exons 2 and 3 (CFTRdele2, 3 (21kb) A second mutation was not found." also, he was diagnosticated with Severe exocrine pancreatic insufficiency. No lung bacteria was found, no other lung disease.

Since in Romania he is the only case, we don't have much information on this specific mutation. Could you please explain us how this mutation will affect him? It is "good" that he has only this mutation or it's a very severe one?

Thank you very much in advance
Answer
Thank you for your question.
CF subjects who have two CFTRdele2, 3 mutations (and so are homozygous for this mutation), tend to have pancreatic insufficiency, an early age at diagnosis and develop significant pulmonary disease. Thus, the CFTRdele2, 3 mutation has features similar to other CF alleles which may be regarded as “severe”, such as the most common CF mutation, F508del.[1]
It is important however to take both mutations into consideration when predicting the burden of disease for any given individual. For example, there is a report of a German adult having the CFTRdele2, 3 mutation and a R117H mutation who had no CF symptoms as a child, and initially was regarded as solely having isolated congenital bilateral absence of vas deferens, rather than overt CF.[2] In contrast, comparing subjects who had both CFTRdele2, 3 and F508del mutations with those who were homozygous for F508del had similar lung function parameters, sweat chloride concentrations and prevalence of Pseudomonas aeruginosa lung infection.[1] As these two cases illustrate, the impact of the second mutation is critical in terms of the ultimate severity of disease, or the clinical phenotype, for that subject. The fact that your child has established exocrine pancreatic insufficiency at this early stage at least suggests that the second mutation in this case is more likely to be “severe”.
Over 1800 disease associated mutations for CF have been identified.[3] The vast majority are individually rare, and it is not unusual for CF subjects to have unidentified mutations and yet still have typical CF symptoms. This makes accurate genotype-phenotype studies of these mutations challenging. Furthermore, environmental and lifestyle factors, access to specialist CF carers, along with additional genetic factors also contribute to disease phenotype and so the burden of disease incurred. As modifier genes remain to be identified, consensus statements advising that genotype alone should not be used to predict clinical outcome at the time of diagnosis need to be kept in mind.[4]
Reference List
1. Dork, T., et al., Characterization of a novel 21-kb deletion, CFTRdele2,3(21 kb), in the CFTR gene: a cystic fibrosis mutation of Slavic origin common in Central and East Europe. Hum Genet, 2000. 106(3): p. 259-68.
2. Dork, T., et al., Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet, 1997. 100(3-4): p. 365-77.
3. Cutting, G.R., Modifier genetics: cystic fibrosis. Annu Rev Genomics Hum Genet, 2005. 6: p. 237-60.
4. 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.

26.06.2011