Carriers

Question

My husband and I just found out through gene sequencing that I am a carrier of deltaF508 and he is a carrier of 5T. He testing negative in every way except the 5t. What are the odds of our children having CF? To me the odds aren't clear, our councilor says they could have a "mild" form of CF or infertility in a male.
Thank you

Answer

Dear questioner,
you report, that you are carrier of deltaF508 and your husband of 5T. You want to know about the risk of your children of having CF. First of all, it has clearly to be stated, that we cannot make clear diagnosis statements via the internet, as we do not have the full genetic result. We will try to make some general statements on this issue, for detailed information genetic counseling will be recommendable.
The risk for you as a couple that a further child inherits your mutation and the one from your husband is 1:4. Only then, the child will be affected. With the chance of 3:4 your children will be healthy, 1:4 will statistically inherit no CF mutation from both of you, 2:4 will inherit only one mutation and be a healthy carrier as you and your husband are.
So what can be said about the child having inherited deltaF508 and 5T?
There are over 1800 known mutations of the CFTR gene (the cystic fibrosis gene) that are grouped into six classes according to the way they affect the synthesis or functioning of the CFTR protein which serves as an ion channel in the cell membrane. Class I-III mutations result in defective synthesis, processing, maturation and regulation of the CFTR protein with an abolished function of the ion channel. Class IV-VI mutations result in defective conductance, reduced function/synthesis and increased degradation of the CFTR protein, though still with a residual expression and function of the ion channel.
When a patient has a mutation of a different class in each of his/her two CFTR genes, the less severe mutation affects the functioning of the protein and therefore part of the clinical expression of cystic fibrosis. In general, patients with two mutations from class I-III exhibit a phenotype associated with pancreatic insufficiency and a more severe course of the disease compared to patients with at least one class IV-VI mutation. Class IV-VI mutations are usually associated with pancreatic sufficiency and milder lung disease. However, the classification of mutations is not always conclusive and possible.
In your case, deltaF508 belongs to class II, it is the most frequent mutation found in CF patients. In the produced protein one amino acid is missing, so that it is not folded correctly and destroyed too early.
With the 5T mutation found in your husband, it is more difficult. It belongs to a so-called “complex allele” and the degree how severely the produced protein is affected depends not only on the number of T, but also on the number of a so-called TG-tract, that is linked to the T-tract. The lower the numbers of T are (e.g. T5 and T3, while T7 and T9 are normal) and the higher the number of TG are (e.g. TG 12 and TG13), the more severely the protein is affected.
For example , for the 5T, the number of TG repeats found on the same chromosome determines whether the amount of functional CFTR protein falls above or below the critical level for normal CFTR function. A TG12-T5 or TG13-T5 gene together with a CF-causing mutation, like in your case deltaF508, will in general result in a so-called CFTR-related disorder; that means often only one organ system is involved, such as chronic pancreatitis or CBAVD (congential bilateral absence of the vas deferens (=spermatic ducts)) resulting in male sterility. Some of those patients may develop mild lung symptoms, but it is not the full picture of CF. If your husband has the TG11-T5 gene and this comes together with your deltaF508, it is highly unlikely to cause disease, the risk of developing CBAVD is also reduced compared to TG12 and TG13-T5. Thus in the worst case, your child could develop with the chance of 1:4 a mild form of CF or even only a CFTR-realted disorder, if we talk about TG12-T5 or TG13-T5. So it would be important for you to get detailed genetic counselling with all results that have been found via genetic sequencing.
Besides, mutation analysis only gives a rough direction but it has to be clearly stated that the individual clinical course and especially the degree of lung involvement cannot be predicted according to the genotype, as many other genetic (modifier genes, etc.) and environmental factors play a role and the severity of disease differs substantially even between patients with the exact same mutations. Therefore, it is very important that the individual patient is seen regularly in a certified CF center and follows his individual treatment program.
Best regards,
Dr. Daniela d’Alquen (Coordinator of the Central English Archive of ECORN-CF)

11.03.2014