Splice mutation 1811+1.6kbA>G causes severe cystic fibrosis with pancreatic insufficiency: report of 11 compound heterozygous and two homozygous patients.

Cystic fibrosis (CF, OMIM 219700) is one of the most common severe hereditary diseases occurring in white populations. It is characterised by considerable heterogeneity in the mutational spectrum and a diverse phenotypic presentation, which justifies extensive studies on the correlation between the cystic fibrosis transmembrane regulator (CFTR) genotype and the CF phenotype. Genotype-phenotype data are available especially for common genotypes, but information remains scarce or lacking for genotypes of compound heterozygotes with a rare mutation and homozygotes for a rare mutation. Among rare CFTR gene mutations, 1811+1.6kbA>G is practically absent in CF patients from other parts of France, but it is not rare in patients genotyped in the south west of France, occurring in fourth place after F508del, G542X, and N1303K. Its frequency is 3.4% and higher than 5% with reference to the number of CF chromosomes with a south western geographical origin. The mutation 1811+1.6kbA>G, located in intron 11 of the CFTR gene, is (with the mutation 3849+10kbC>T) one of the only two splicing mutations of the CFTR gene that generates a new exon (1811+1.6kbA>G creates a donor site, 3849+10kbC>T an acceptor site). Furthermore, it was previously ranked by Chillon et al among class I mutations responsible for defective CFTR protein production and a severe CF phenotype. However, because it allows a reduced synthesis of normal protein, the mutation 1811+1.6kbA>G has also been reported in class V. 8 According to the recent classification proposed by Welsh et al, the mutation 1811+1.6kbA>G now belongs definitely to the “new” class I. The present report aims to study as well as possible the clinical severity of the mutation 1811+1.6kbA>G. The clinical data from 13 CF patients originating from the south west region of France and bearing 1811+1.6kbA>G (11 compound heterozygotes and two homozygotes) were collected.