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Heterozygous mutation

Question
Hi, I have a daughter that was Diagnosed with DeltaI507 from mother's side and 3272-26A>G from fathers side, she has never had an symptoms and is perfectly healthy at 7 years old. Nevertheless, I am pregnant and would like to know if you have any record of this combination and what the expression is like.
Answer
Thank you for your question regarding your daughter’s CF genetics and their clinical consequences.

In CF there is often not a good correlation between the mutations in the CFTR gene (genotype) and how the person actually is (phenotype). There is high variability in phenotype within identical CFTR genotypes (1). Modifier genes and non genetic environmental factors e.g. level of care and exposure to cigarette smoke affect lung function and disease progression.

Both deltaI507 (can also be found under I507del) and 3272-26A>G are known to be disease causing mutations in CF.
Some studies have looked at groups of patients with one 3272-26A>G and one of the 23 common mutations (which includes deltaI507) and compared them to patients with two of the 23 common mutations. Clinical phenotypes of CF patients with 3272-26A>G were found to be milder with a lower incidence of Pseudomonas, lower occurrence of pancreatic insufficiency and better lung function. (2)

Similar findings were reported in a large European Study comparing patients with the genotype 3272-26A>G/ any mutation with those who had two F508del mutations, although they did see an unexpected increased incidence in nasal polyps. (3)

Information on different genetic combinations seen in CF is readily available on line through the cftr2 website.

It is encouraging your daughter has no symptoms and is perfectly healthy at 7 years. Regardless of the underlying combinations of mutations it is important to mitigate the progression of disease with appropriate treatment.
Please discuss with your CF centre for advice specifically for your child.

References
1.McKone,E.F., et al., Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study, Lancet, 2003.361 (9370):p. 1671-6
2.(www.cftr2.org/)
3.Amaral, M.D., et al., Cystic Fibrosis patients with the 3272-26A>G splicing mutation have milder disease than F508del homozygotes: a large European study,J Med Genet,2001;38:783-784


Hazel Mills
CF Nurse Specialist
13.11.2012
The answer is edited by: Hazel Louise Mills
20.11.12
Here is some more informtaion why is the phenotype of the 3272-26A>G mutation is extremely variable.
3272-26A>G is a so called "splicing mutation", that means it affects the "splicing" process which is an important "cutting and reconnecting" process of the transcribed CFTR m-RNA on its way from the chromosome to be translated into a functional protein. Further additional information can be found in the guidelines from 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":
"Splicing mutations [such as 3272-26A>G] that still result in a fraction of correctly spliced transcripts, together with aberrant spliced transcripts, may belong to the CF-causing or CFTR-related disorders associated group. ...Patients carrying these mutations often have relatively mild phenotype, yet with variable disease expression, from minimal lung disease, pancreatic sufficiency and male fertility to a relative severe disease in all the involved organs..."
D. d'Alquen