Variant I 1027 T

Question

I am a mother of two sons who have CF. The reason I am reaching out to you is that my sons' genetic combination is the Delta F508 and I1027T. During my research, I discovered that there are only 41 people worldwide with this particular combination and some of them are in Brittany, France. Therefore, I was encouraged by my CF Center to reach out to individuals in France who may know about this I1027T mutation and what has been successful with it. Please let me know how to access information appropriately about this.

Answer

Hello,
Information taken from the Laboratory of Molecular Genetics of the University Hospital of Brest headed by Professor Claude FEREC (one of four national expert laboratories for CF), the genetic feature that you report (I1027T) means that the amino acid isoleucine (I) normally present in position 1027 of the CFTR gene is replaced by the amino acid threonine (T). This feature does not correspond to a mutation but to a variation of a mutation, namely the F508del mutation, carried on the same chromosome from one of the two parents. This variation, in cis of the F508del mutation was actually identified on one of the 2 chromosomes #7 of patients living in Brittany, the other chromosome #7 bearing another CFTR mutation. It was found in Brittany because the genetic expert center frequently uses techniques for extensive study of the gene that can highlight it. This variant would be revealed far more frequently if it would be systematically sought.
According to the information you provided, it would mean that your two boys are not F508del/I1027T compound heterozygous (which does not correspond to a CF genotype) but F508del -variant I1027T / Unknown mutation.
Advances in technology made it recently possible to identify many previously unknown mutations, but in rare cases of cystic fibrosis, the second mutation remains undiscoverable presumably because it’s located in regions of the gene that are not explored.
I hypothesize that these techniques were not available when the molecular genetic analysis was carried out for your two boys. So I suggest you to get in touch with your boys' CF Center in order :
• to discuss the relevance of searching for CFTR mutations in a blood sample from you and from the father of your children (you did not write which mutation you are respectively bearing) ;
• and, possibly, to use the most recent techniques to identify the second mutation in your children and in the parent who bears it.
Finally, a more precise knowledge of the genotype of your children will not bring much for a reliable prognosis of the phenotype (the clinical evolution) of their course of cystic fibrosis. While the analysis of a large population of patients can show some correlations between genotype and phenotype, this approach is not applicable at the individual level. Each clinical evolution is unique since the phenotype determinants of cystic fibrosis are multiple and diverse, innate or acquired (genetic or environmental) and are not all known. This is the case of those genetic factors that are not limited to the genotype but may be related to modifier genes different from the CFTR gene.
Hope that answers your question.
Sincerely yours.
Gilles RAULT, MD,
CF Center Roscoff
With the kind assistance of
Ms. Marie- Pierre AUDREZET, PhD
Molecular Genetics Laboratory, CHU Brest

26.09.2013