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Please help me understand CF mutations.


I previously asked this question which was not answered. I am hoping to receive some information.

My husband and I are in the process of electing PGD and would like to know what clinical symptoms, if any, we can expect in offspring with the following mutations:


one copy of F508 Del
one copy each of D443Y;G576A;R668C

one copy of M470V (no deletions or duplications, one benign sequence change)

My husband has CBAVD so we must elect IVF treatment. His sweat test was 40 and doctors are divided on a DX of CF.

Thank you.
Dear questioner,
Let me comment on the different mutation findings first, then on the risk to transmit them to a further child.
First of all the 7T/9T and 7T/7T finding of you and your husband; the 7T and 9T alleles are normal CFTR alleles, not causing CF.
Your husband carriers one copy of the deltaF508 mutation, the most common mutation in the CFTR gene. This mutation is a so-called class II mutation, leading to defective maturation of the CFTR gene product, which is a chloride channel that works in the cell membrane. With this mutation, not enough functionning chloride channel reaches the cell membrane, salt and water cannot be transported to the surface of the cell, resulting in too viscous secretions in many organs. However, as cystic fibrosis is an autosomal-recessive disease, clinical symptoms develop only, if there is a CF-causing mutation on both chromosomes. If one has only the deltaF508 and no other mutation on the second chromosome, one is a healthy carrier. If deltaF508 mutation combines with another deltaF508 mutation, for example, the classical clinical picture of CF results.
Your husband has furthermore “one copy each of D443Y;G576A;R668C”. Here, it is very important to know, if all those 3 mutations/variants are on the same chromosome and on the other chromosome than deltaF508. This can be investigated by a so-called segregation analysis. From the way you list the mutations, and because of the fact that D443Y;G576A;R668C are often found on the same chromosome, I assume here (I do not know for sure, please ask your geneticist about this) that those 3 mutations/variants are together on one chromosome, and the deltaF508 is on the other chromosome. G576A and R668C can be found in the CFTR2 database, there are about 42-48 patients described and from the data available one can draw the conclusion, that those mutations do not cause CF when combined with a CF-causing mutation, most people are healthy, only a small number may develop mild symptoms or CFTR-related disorder such as CBAVD. D443Y could be found in the CF mutation database from the sickkids hospital in Toronto; there are patients described with deltaF508 and D443Y, those suffered from CBAVD, were pancreatic sufficient, had mild respiratory symptoms and normal sweat chloride.
The variant found in your genetic analysis M470V can also be found in the CFTR2 database; it does not cause CF when combined with a CF-causing mutation, most people will be healthy, only a small number will develop mild respiratory symptoms or CFTR-related disorder.
So, what are the possibilities for a further child?
With the chance of 50% you will inherit the chromosome to your child, not carrying a CFTR sequence variant/mutation at all; so independently of the chromosome the father inherits, the child will be healthy, however with the chance of 25% be a healthy carrier of the delta F508 mutation and with the chance of 25% to be a carrier of the D443Y;G576A;R668C mutations.
With the chance of 50%, you will inherit the M470V variant to your child, so with the chance of 25% the child could inherit the combination M470V + deltaF508 and with the chance of another 25% it could inherit the combination M470V + D443Y;G576A;R668C from the chromosome of the father. For those cases it is impossible to predict the exact clinical course, however it is very unlikely, that a full clinical picture of CF develops; as the clinical picture is characterized by the less severe of two mutations, the child with M470V + deltaF508 will in most cases be healthy (you have been told that M470V is only a sequence variation) and only a small number could develop mild clinical symptoms or CFTR-related disorder. This is even more true for the child with M470V + D443Y;G576A;R668C, as there is no classical CF-mutation in combination here; maximally in exceptional cases one would expect mild respiratory symptoms, if the child is a boy, also sterility problems like the ones of the father (CBAVD) are possible.
Taken together, with the given mutations, you should not expect to give birth to a child suffering from CF; further children are expected to be healthy carriers, even if 2 mutations from both parents are inherited, they have a great chance to be healthy due to the type of mutations, developing mild respiratory symptoms or a kind of CFTR-related disorder (like CBAVD in males or chronic pancreatitis) is possible.
Hope to have helped you with this information.
Best regards,
Dr. Daniela d’Alquen (Coordinator of the Central English Archive of ECORN-CF)
The answer is edited by: Prof Stuart Elborn