Asymptomatic carrier of two CFTR mutations: Consequences for prenatal diagnosis?

Abstract

The cystic fibrosis (CF) gene has been observed to have the highest frequency of mutations in the Caucasian population. Prenatal diagnosis can now be performed with a high degree of accuracy since the identification of most of the gene's mutations, as well as the characterization of intragenic markers. However, the observation of a distribution of clinical phenotypes increases the need to identify a mild phenotype and avoid false-negative diagnosis. By screening most of the exons of the CFTR gene, we showed that a supposed obligate carrier of CF was in fact an asymptomatic affected woman.

Two Mild Cystic Fibrosis-associated Mutations Result in Severe Cystic Fibrosis When Combined in Cis and Reveal a Residue Important for Cystic Fibrosis Transmembrane Conductance Regulator Processing and Function

“…2A, there was little or no current under basal conditions, and application of CPT-cAMP activated large currents that reversed at the Cl Ϫ equilibrium potential (close to 0 mV with the solutions used). The currents were glibenclamide-sensitive and DIDS-and TS-TMcalix [4]arene-insensitive as expected for CFTR Cl Ϫ current (data not shown). These currents were activated a few seconds after stimulation and were slowly reversible after washout of CPT-cAMP.…”

“…The number of complex CFTR genotypes identified, including double-mutant alleles where two missense mutations are carried by the same chromosome, has been growing (2)(3)(4)(5)(6). It is difficult to evaluate the contribution of each mutation/or polymorphism to the phenotype as mutations in cis may act in concert to alter or reverse defective CFTR function and thus modify the CF phenotype (2).…”

Complex cystic fibrosis allele R334W-R1158X results in reduced levels of correctly processed mRNA in a pancreatic sufficient patient

“…The same seems to apply to the AF508-V1212I allele (Macek et al, 1993). Other in cis missense mutations have been reported, namely F508C-Sl251N (Kalin et al, 1992), G628R-S1235R (Mercier et al, 1995) and R74W-D1270N (Verlingue et al, 1993). The latter was also detected by us in compound heterozygosity with AF508 in a Portuguese patient with a very mild CF phenotype (to be reported elsewhere).…”

“…Since the gene and the major mutation responsible for CF (AF508) were identified in 1989 , more than 500 presumed pathogenic mutations and more than 100 DNA normal sequence variations have been identified in the CFTR gene (Newsletter from the CF Genetic Analysis Consortium, March 22, 1995). However, to our knowledge, only five complex alleles containing more than one mutation, mostly missense mutations, have been described in the CFTR gene (Dork et al, 1991, Kalin et al, 1992, Verlingue et al, 1993Macek et al, 1993;Mercier et al, 1995). We describe here another complex CFTR allele containing a missense mutation in exon 7 and a nonsense mutation in exon 19.…”

DGGE screening of PKD1 gene reveals novel mutations in a large cohort of 146 unrelated patients

“…Our patients were screened for all exons, from exon 34 to exon 46, even if a causative mutation was identified, in order to localize a possible second nucleotide variation which could have a phenotypic effect on the severity of the disease, as has been the case with other genes (Verlingue et al 1993;Savov et al1995) In this cohort we have identified novel mutations. Most of these mutations are point mutations except those with the insertion of 9 or 23 nucleotides: 5 of them are ins/del or nonsense mutations that are clearly deleterious, 2 are missense mutations, 1 is an in-frame insertion of 3 amino acids and 3 are possible splicing mutations.…”