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Please note: While some information will still be current in a year, other information may already be out of date in three months time. If you are in any doubt, please feel free to ask.

3849+10 kb c / 5T

Hello, can you tell me the phenotype of the mutation 3849 + 10 kb c facing the variant T5 please. Thank you in advance. Best regards

regarding the mutation 3849 + 10kb C-> T:
- on a biological level it causes the creation of a splice site in the intron 19, and the insertion, in a proportion of transcripts, of a novel exon of 84 pb containing a stop codon;
- on a practical level, in CFTR2 which is the largest international database of the cystic fibrosis gene, this mutation is classified as "CF causing", say it causes CF when combined with another CF causing mutation. However, it is a class V mutation which causes not a complete absence, but a decreased amount of functional protein at the cell membrane. It is "variable spectrum": pulmonary involvement is usually characteristic of CF but patients are often pancreatic sufficient. Finally, it is a rare mutation for which the sweat test may be normal.

Regarding the 5T variant, this variant located in intron 8 (variant IVS8 5T) is present in 5% of the general population. On a biological level, it can be associated with 10 to 13 times nucleotide TG repetition. These forms of variant, isolated or even associated with CF Causing mutations, are frequently found in individuals with phenotypes (clinical forms) called CFTR-Related Disorders (CFTR-RD) which are linked to a defect in the CFTR gene but do not meet all the CF diagnostic criteria. Specifically, in infertile men due to bilateral absence of vas deferens (CBAVD) the frequency of the isolated 5T variant (without other mutation Causing CF) is much higher than that of the general population.

When associated with CF Causing mutations:
- 3 variant forms TG10-T5, TG11-T5 and TG12-T5 are associated with CFTR-related disease phenotypes;
- The TG13-T5 variant has long been considered a causative mutation of CF phenotype but analysis of clinical cases shows that patients have a phenotype either CF atypical (pulmonary signs only) or CFTR-RD including CBAVD in men.
Finally, in practice the 3849 genotype + 10kbC-> T / ISV8 T5, is most often associated with CFTR-RD phenotype (bronchiectasis, male infertility with CBAVD), and more rarely to a "moderate" CF phenotype .

Hop this answer can help.
Best wishes

Gilles RAULT, MD, Roscoff CF Center
and Marie-Pierre AUDREZET, Molecular Genetic, Brest University Hospital