Phenotypic expression of genotype-phenotype correlation in cystic fibrosis patients carrying the 852del22 mutation

Abstract

Currently, more than 1,000 mutations have been identified in the cystic fibrosis transmembrane regulator (CFTR) gene. While some mutations are common worldwide, the majority are restricted in certain ethnic groups. We have found that in Southern Italy, the 852del22 mutation is well represented with a frequency of 3.5%. We have screened, by reverse dot blot, denaturing gradient gel electrophoresis (DGGE), and gene sequencing, the entire coding regions of CFTR gene in 371 consecutive cystic fibrosis (CF) patients from Southern Italy and have identified 17 patients carrying rare genotypes, among which 13 [6 M; median age 21.7 years (range: 4.5-47.7 years)] carry the 852del22 mutation. To assess the phenotypic expression of CF in patients with the 852del22 mutations we have compared these patients with a group of age and gender matched patients homozygous for the DeltaF508 mutation [n = 34; 19 M; median age 19.9 years (range: 3.8-34.6 years)]. Overall, we found no difference in terms of complications, patient survival (17.6% vs. 30.7%; P = NS), estimated time needed to develop a severe lung disease (22.1 vs. 24.5 years; P = NS), nutritional status, and rate of infection or colonization by most common pathogens between patients in the two groups. Finally, we have found that a late diagnosis was associated with a poor outcome (severe lung disease) regardless of genotype. Our data show that 852del22 mutation results in a phenotypic expression of disease as severe as that determined by the more typical DeltaF508 and, as in the latter case, there is no strict genotype/phenotype correlation.

Heterozygous variant at nucleotide position 875+11A>T in exon 6A cystic fibrosis transmembrane conductance regulator gene induces 852del22 mutation false-positivity by line probe assay

“…The phenotype found in our patient, which is associated with a compound heterozygosity for the F508del and 852del22 mutations, was in contrast with previous clinical observations (5,9). This highlights the possibility of false-positive results obtained by preliminary molecular screening.…”

“…They found no difference between these patients in terms of pathological complications, nutritional status, and progression of disease. The phenotypic expression of the disease in compound heterozygotes for the 852del22 and F508del mutations proves to be as severe as in F508del homozygotes (9).…”

“…To assess the severity of the phenotype associated with the 852del22 mutation, Polizzi et al (9) compared patients carrying this mutation (four patients homozygous and nine patients compound heterozygous) with patients homozygous for the F508del mutation. They found no difference between these patients in terms of pathological complications, nutritional status, and progression of disease.…”

Genotype-phenotype correlation in cystic fibrosis patients bearing [H939R;H949L] allele

“…The mutations G542X, 1259insA, G1349D, F508del have already been described as severe CF-asssociated mutation (Casals et al , 1993; Morral et al , 1993; Morral et al , 1994; Kerem et al , 1995; Estivill et al , 1997; Shrimpton et al , 1997; Rowntree and Harris 2003; Bompadre et al , 2007; Castellani et al , 2008). Particularly, 1259insA and G1349D represent with few other mutations, 4382delA, I502T, 852del22, 4016insT, D579G, R1158X and L1077P, almost 20% of the CF alleles found in the Apulian population (Castaldo et al , 2005; Polizzi et al , 2005). The 1259insA results in the increase of a string of four As into five, which leads to the premature termination of product due to the formation of a stop codon, as described by Shrimpton et al (defective protein production, class I mutation) (Shrimpton et al , 1997).…”

A self-contained fluorescent fiber optic DNA biosensor

“…1 The relative simplicity and selectivity of analysis of nucleotide sequences provides for a wide range of applications such as detection of diseases and pathogens, genome sequencing, forensic DNA profiling and ecological control. [2][3][4] With the completion of the human genome sequencing project, 5 the focus has changed from the collection and archiving of genomic data, to analysis and use in prediction and discovery. Nucleic acids can be used as selective biomolecular reagents.…”