An overall very mild phenotype associated with the CFTR mutation R117H, irrespective of the second mutation. C. Thauvin-Robinet1,3, F. Huet2,3, M. P. Audrezet4, C. Férec4, M. Des Georges4, M. Claustres4, G. Lalau4, F. Cabet4, E. Bieth4, G. Bellis5, D. Hubert2, R. Nové-Josserand2, A. Munck2,3, G. Bellon2, C. Binquet6, L. Faivre1, M. Roussey2,3, E. Girodon4,7, R117H Collaborativ Group 1) Genetics Centre, Dijon,France; 2) CF Care Centres, France; 3) AFDPHE,Paris,France; 4) CF laboratory Network,France; 5) INED,Paris,France; 6) CIC-EC,Dijon,France; 7) Molecular Genetics Laboratory,Créteil,France.
Over 1500 CFTR sequence variations have been identified in cystic fibrosis (CF) and CFTR-related disorders (CFTR-RD), such as congenital bilateral absence of the vas deferens (CBAVD). They can be of severe, mild, or neutral clinical effect. R117H mutation, initially considered as a mild CF-causing mutation with pancreatic sufficiency and rare early pulmonary symptoms, was found predominantly associated with pure CBAVD, and incidentally observed in asymptomatic individuals. Out of a large French collaborative study collecting 278 patients until 2007 with two CFTR mutations including at least one R117H, we explored data from 179 patients recruited on the basis of symptoms or a positive family history. Median age at last follow-up was 31.5 years (IQR [27.3-35.7]). Clinical data available in 165 patients revealed 49% pure CBAVD, 40% other CFTR-RD, 8% totally asymptomatic individuals, and 3% with a severe pulmonary disease (FEV1 <60%) of late onset. 42 different mutations were identified: 95% of severe (F508del: 68%), 3% of mild and 2% of unknown effects. The IVS8 T5 variant was found in only 5 patients. Phenotype-genotype correlation studies showed no significant clinical difference between patients, according to the mutation class of the 2nd allele. This study confirmed the overall mild phenotype associated with compound heterozygosity for R117H and a severe mutation, irrespective of the mutation class. Even if the numbers were too small to obtain a significant difference, we observed that the 8 patients with mild mutation of the 2nd mutation had CBAVD, and only 3 also presented mild asthma. The very low frequency of mild mutations on the 2nd allele (3%) let to suggest that the clinical penetrance of genotypes combining R117H and a mild mutation is very low.