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Lack of understanding of F508del-9T/Variant 5T

Hello my partner received his result of genetic analysis and it is noted that he is compound heterozygous F508del and 5T variant. Until then I understand but it is also noted (genotype [p.phe508del / 9T] + [- / 5T]) then why the 9T? Are theF508del and 9T located on the same chromosome? Does it mean that he has three CFTR genes? As for the 5T variant, it is not clear which one of the TG 11, the TG 12 or the TG13 is normal?

You ask a specific and pertinent question: it calls for a less clinical than technical response I can offer, thanks to the contribution of my colleague from the molecular genetics laboratory.

First of all, there are not 3 CFTR genes, there are only 2, one on each chromosome of pair no. 7.

Variant "T" is a variant that is always present on the CFTR gene upstream of the p.Phe508del mutation (commonly referred to as F508del). This variant is either 5, or 7, or 9T. The mutation F508del is always associated with a 9T located on the same chromosome.

Whatever the mutation carried by the gene, it is always associated with a repetition of T, usually a T7 which is considered as the reference sequence. Moreover, it is never specified, since we are content to talk about the mutation. Then, the number of repetitions of TG, which varies between 9 and 13, has no negative impact on the function except in the case of 5T. The 5T variant in fact regulates a certain percentage of RNA without exon 9 as a function of the TG. The longer it is (13TG), the more RNA will be without exon 9 and the more the dysfunction of the mutated CFTR protein will be. The variant TG13T5 is thus considered as a mild mutation of CFTR with no apparent signs of cystic fibrosis. However, in-depth examination often reveals an increased frequency of chronic sinusitis, a history of repeated bronchitis (or even radiological abnormalities related to bronchial dilatation), and limited or abnormal sweat test values.

The study of the 5T variant is justified only in CFTR Related Disorders (CFTR-RD), ie in clinical situations where there is a symptom suggestive of cystic fibrosis but which, isolated, is not sufficient for diagnosis of cystic fibrosis. This is the case of the bilateral absence of vas deferens (ABCD) which, when isolated, is frequently linked to an abnormality of the CFTR gene and thus corresponds to a form of CFTR-RD. In this case the study of the variant T and the number of repeats TG is necessary. However, not all genetics laboratories can analyze the TG associated with 5T, but it is the presence of p.Phe508del which is the most important for genetic counseling.

Hope this answer can help.
Best wishes
Gilles RAULT, MD, Roscoff CF Center
Marie-Pierre AUDREZET, PhD, Molecular Genetics, Brest University Hospital