Mutation c.3718-3T>G and deletion of exon 16 to exon 20 heterozygous found

Question

Hello dear experts,

my daughter (today 12 weeks old) has been diagnosed to suffer from CF after she had a sweat test at the age of 5 weeks.
A molecular genetic investigation had been done.
Via this investigation, a heterozygous c.3718-3T>G-mutation in combination with a heterozygous deletion of exon 16 to exon 20 of the CFTR gene has been found. Additionally the rare change c.224G>A,p.ArG75Gln has been found heterozygously.
Now my question: What does this mean and can one make a statement on the clinical course of the illness due to this mutations?

Answer

Hello,

every human being has 46 chromosomes, which are arranged in 22 autosome pairs (similar in men and women) and a gonosome-pair (XY in men, XX in women) and which come partly (50%) from the mother (23 chromosomes) and 50% from the father (23 chromosomes).
The CFTR-gene is on chromosome 7 and each human being carries a maternal and paternal CFTR-gene. In your daughter 3 sequence variants in the CFTR gene had been found, i.e. either all 3 changes are on the maternal respectively on the paternal chromosome (in cis) and the other gene would then be intact, or one of the parental genes has one and the other parental gene the other two changes, then the changes are in trans and if they are pathogen, i.e. they cause a loss of function of th CFTR protein (chloride channel), the person will suffer from CF.
The seuqence variation c.224G>A, p.Arg75Gln (R75Q) found in your daughter, is known to be a wide-spread variant in the population and does not cause the illness. The two other genetic changes, however, are pathogen and cause, if they are found in trans, the illness of CF. As your daughter has shown a pathologic sweat test, one can assume, that both mutations CFTRdele16-20 und c.3718-3T>G are on one of the parental genes each, therefore are in trans. In spite of this, the parents should undergo an investigation for a carrier status (if not alreday done), as the risk is 25% for further children to have the illness if the parents are identified to be carrier. The risk of the siblings of the parents would be 50% to be also carriers.
With the underlying mutations of your daughter a priori a classical course of the illness with the risk to become pancreatic insufficient can be expected. It has to be taken into account, however, that the clinical course and especially the degree of lung involvement, is not only determined by the mutation, the patient carries, however that many other genetic (modifier genes, individual genetic background) and environmental factors play a role. Therefore the severity of the illness and the course are not precisely predictable, as those can even vary markedly between patients with the exact same mutations. Therefore, it is very important, that your daughter is seen regularly in a certified CF center and takes part in her individual therapy program.
I hope to have answered your question satisfyably and stay with my best regards,

Prof. Dr. Sabina Gallati

29.07.2016