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Negative for R117H, positive for 5T

Hello Doctor,
We are trying to find as many information possible about this, because we are going to do IVF in the next weeks. Both myself and my husband tested positive for the 5T allele, but negative for the rest. I was wondering what are our risks for our baby? All that I found is that we have some risk of having a boy with CBAVD but our CF risk is almost none. Am I correct?

Can you provide more info on this and what we can expect?

Thank you VERY much!

Dear Questioner
Many thanks for your question. It is good that you have already received some information, I presume from a genetic counselling service. It would be interesting to know what your reasons were for seeking out genetic testing for CF. For example, is there a family history?

In your question you say that you and your husband carry 5T, but do not carry any CF-causing mutations. You would be right therefore in saying that the risk of you having a baby with CF is almost none. We can never give 100% guarantee since there are very rare mutations that could be picked up on extended genetic screening, hence the use of the word “almost”. Different countries test for different CF mutations which are common in their population.

There is very little information on individuals with 5T on each chromosome, but no CF-causing mutations. Therefore the risks associated with two 5T alleles in the absence of a CF-causing mutation have not been well defined. The majority of information comes from research in individuals with 5T in combination with a CF-causing mutation.

The 5T allele is very common and is present in around 10% of the population (Groman et al 2004). The amount of normal protein that is produced from the CF gene is lower when there is a 5T present. However it is unclear if two 5T alleles in males are likely to lead to congenital bilateral absence of the vas deferens (CBAVD) (Department of Human Genetics Division of Medical Genetics, Emory University, School of Medicine – see link at end of this answer). In females, having two 5T in the absence of any detectable CF-causing mutation is unlikely to cause any health problems.

I hope this answer has given you some additional information. We would also advise you to speak to a genetic counselling service for more specific information and to discuss your concerns further.

Best wishes,
Lisa Kent, Belfast
Damian Downey, Belfast

Groman et al Variation in a Repeat Sequence Determines Whether a Common Variant of the Cystic Fibrosis Transmembrane Conductance Regulator Gene Is Pathogenic or Benign. Am J Hum Genet. 2004 January; 74(1): 176–179.

The answer is edited by: PhD Lisa Kent
More information can be found in:
- 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"
In summary:
The risk for the asking couple here to inherit both 5T alleles to the Baby is 1/4 and we describe only the possible consequences of this constellation.
In most T5 CFTR genes, the number of so-called TG repeats found on the same chromosome as the T5, determines whether the amount of functional CFTR protein falls above or below the critical level for normal function. While TG13-T5 or TG12-T5 together with another CF-causing mutation or possibly if present on both chromosomes (as in the case here with a chance of 25% for each coming child) will in general result in a CFTR-related disorder such as the mentioned male infertility. Some patients may develop mild lung symptoms, in exceptional cases there may be a mild form of CF. In contrast, a TG11-T5 CFTR gene is highly unlikely to cause disease.
So in this case, we have no information about the number of TG repeats (TG13, TG12 or TG11) but this is crucial to make a more precise prediciton.
Important to mention, that the genotype alone should never be used to predict the phenotype, as many other genetic and environmental factors influence the course of the disease and patients with the exact same mutations can show very different courses of the illness. Therefore a good clinical surveillance is mandantory.
D. d'Alquen