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It is often challenging for the clinician interested in cystic fibrosis (CF) to interpret molecular genetic results, and to integrate them in the diagnostic process. The limitations of genotyping technology, the choice of mutations to be tested, and the clinical context in which the test is administered can all influence how genetic information is interpreted. This paper describes the conclusions of a consensus conference to address the use and interpretation of CF mutation analysis in clinical settings. Although the diagnosis of CF is usually straightforward, care needs to be exercised in the use and interpretation of genetic tests: genotype information is not the final arbiter of a clinical diagnosis of CF or CF transmembrane conductance regulator (CFTR) protein related disorders. The diagnosis of these conditions is primarily based on the clinical presentation, and is supported by evaluation of CFTR function (sweat testing, nasal potential difference) and genetic analysis. None of these features are sufficient on their own to make a diagnosis of CF or CFTR-related disorders. Broad genotype/phenotype associations are useful in epidemiological studies, but CFTR genotype does not accurately predict individual outcome. The use of CFTR genotype for prediction of prognosis in people with CF at the time of their diagnosis is not recommended. The importance of communication between clinicians and medical genetic laboratories is emphasized. The results of testing and their implications should be reported in a manner understandable to the clinicians caring for CF patients. © 2008 European Cystic Fibrosis Society.

An abbreviated tract of five thymidines (5T) in intron 8 of the cystic fibrosis transmembrane conductance regulator ( CFTR) gene is found in similar to 10% of individuals in the general population. When found in trans with a severe CFTR mutation, 5T can result in male infertility, nonclassic cystic fibrosis, or a normal phenotype. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, we determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals ( fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% ( 21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% ( 10 of 107) of affected individuals. Conversely, 91% ( 97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% ( 6 of 27) of unaffected individuals (P < .00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats ( odds ratio 34.0, 95% CI 11.1 - 103.7, P < .00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles.

The increase in genome scanning data, derived from clinical genetics practice, is producing a wealth of information on human sequence variability. The critical issue is to identify if a given nucleotide change results in a benign polymorphism or a disease-causing mutation. We have focused on one specific gene expression step, pre-mRNA processing, where we can functionally define the effect of nucleotide changes and in turn the patient’s mutation can shed light on the basic pre mRNA splicing mechanisms. Our results show that several nucleotide changes in CFTR exon 12 induce a variable extent of exon skipping that leads to reduced levels of normal transcripts. This is the case in both natural mutations D565G and G576A (the latter having previously considered a neutral polymorphism) and several site-directed silent substitutions. We demonstrate here that this phenomenon is due to the interference with a new regulatory element that we have named composite exonic regulatory element of splicing (CERES). The effect of single nucleotide substitutions at CERES cannot be predicted by neither SR matrices nor enhancer identification. The recognition and characterization of splicing abnormalities, caused by exon sequence variations at CERES elements, may represent a frequent disease-causing mechanism that also relates to the phenotypic variability. Our results indicate that even the most benign looking polymorphism in an exon cannot be ignored as it may affect the splicing process. Hence, appropriate functional splicing assays should be included in genotype screenings to distinguish between polymorphisms; and pathogenic mutations.

Editor,—In up to 30% of patients with idiopathic pancreatitis (IP) a mutation of at least one or both alleles of the cystic fibrosis transmembrane conductance regulator (CFTR) gene can be identified.1-3 The study by Malats et al ( (2001) Gut 48:70–4; [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] ) addressed the question of whether CFTR mutations, possibly together with environmental factors such as alcohol, may be associated with chronic pancreatitis or pancreatic cancer. The vast majority of the pancreatic patients (86.4%) investigated by Malats et al were diagnosed as having alcoholic pancreatitis (AP), and 75.4% of the cancer patients were daily drinkers. The authors found no statistically significant difference in the prevalence of delta-F508 (0%; 2.4%) and the 5T allele (10.5%; 5.5%) in the AP or cancer groups compared with the expected prevalence in the general population. The lack of a positive association of both delta-F508 and the 5T allele with AP is neither surprising nor argues against involvement of CFTR variations in the development of AP, considering the following. In cystic fibrosis (CF), the degree of correlation between CFTR genotype … Dr Malats. nuria{at}imim.es Dr Malats. nuria{at}imim.es Dr Malats. nuria{at}imim.es Dr Malats. nuria{at}imim.es [1]: {openurl}?query=rft.jtitle%253DNew%2BEngland%2BJournal%2Bof%2BMedicine%26rft.stitle%253DNEJM%26rft.issn%253D0028-4793%26rft.aulast%253DCohn%26rft.auinit1%253DJ.%2BA.%26rft.volume%253D339%26rft.issue%253D10%26rft.spage%253D653%26rft.epage%253D658%26rft.atitle%253DRelation%2Bbetween%2BMutations%2Bof%2Bthe%2BCystic%2BFibrosis%2BGene%2Band%2BIdiopathic%2BPancreatitis%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJM199809033391002%26rft_id%253Dinfo%253Apmid%252F9725922%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1056/NEJM199809033391002&link_type=DOI [3]: /lookup/external-ref?access_num=9725922&link_type=MED&atom=%2Fgutjnl%2F49%2F2%2F312.2.atom [4]: /lookup/external-ref?access_num=000075688100002&link_type=ISI

We report a large genomic deletion of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, viz.. a deletion that is frequently observed in Central and Eastern Europe. The mutation, termed CFTRdele2.3(21 kb), deletes 21,080 bp spanning introns 1-3 of the CFTR gene. Transcript analyses have revealed that this deletion results in the loss of exons 2 and 3 in epithelial CFTR mRNA, thereby producing a premature termination signal within exon 4. In order to develop a simple polymerase chain reaction assay for this allele, we defined the end-points of the deletion at the DNA sequence level. We next screened for this mutation in a representative set of European and European-derived populations. Some 197 CF patients, including seven homozygotes, bearing this mutation have been identified during the course of our study. Clinical evaluation of CFTRdele2.3(21 kb) homozygotes and a comparison of compound heterozygotes for Delta F508/CFTRdele2,3(21 kb) with pairwise-matched Delta F508 homozygotes indicate that this deletion represents a severe mutation associated with pancreatic insufficiency and early age at diagnosis. Current data show that the mutation is particularly common in Czech (6.4% of all CF chromosomes), Russian (5.2%), Belorussian (3.3%). Austrian (2.6%), German (1.5%), Polish (1.5%), Slovenian (1.5%), Ukrainian (1.2%), and Slovak patients (1.1%). It has also been found in Lithuania, Latvia, Macedonia and Greece and has sporadically been observed in Canada, USA, France, Spain, Turkey, and UK, but not in CF patients from Bulgaria, Croatia, Romania or Serbia. Haplotype analysis has identified the same extragenic CF-haplotype: XV-2c/KM. 19 “A” and the same infrequent intragenic microsatellite haplotype 16-33-13 (IVS8CA-IVS17bTA-IVSI7bCA) in all examined CFTRdele2,3(21 kb) chromosomes, suggesting a common origin for this deletion. We conclude that the 21-kb deletion is a frequent and severe CF mutation in populations of Eastern- and Western-Slavic descent.

La terminologia i el concepte d'Error Congènit del Metabolisme (ECM), van ser establerts per A. Garrod a principis de segle. Avui día sabem que estan causats per errors o mutacions en els gens. Degut a la naturalesa del nostre codi genètic, segons el qual les instruccions del DNA són traduïdes a un producte gènic, les proteïnes, que seran les encarregades d'executar-lo; les mutacions del DNA es tradueixen en proteïnes anòmales amb la corresponent...

We report a large genomic deletion of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, viz. a deletion that is frequently observed in Central and Eastern Europe. The mutation, termed CFTRdele2, 3(21 kb), deletes 21, 080 bp spanning introns 1-3 of the CFTR gene. Transcript analyses have revealed that this deletion results in the loss of exons 2 and 3 in epithelial CFTR mRNA, thereby producing a premature termination signal within exon 4. In order to develop a simple polymerase chain reaction assay for this allele, we defined the end-points of the deletion at the DNA sequence level. We next screened for this mutation in a representative set of European and European-derived populations. Some 197 CF patients, including seven homozygotes, bearing this mutation have been identified during the course of our study. Clinical evaluation of CFTRdele2, 3(21 kb) homozygotes and a comparison of compound heterozygotes for deltaF508/CFTRdele2, 3(21 kb) with pairwise-matched deltaF508 homozygotes indicate that this deleton represents a severe mutation associated with pancreatic insufficiency and early age at diagnosis. Current data show that the mutation is particularly common in Czech (6.4% of all CF chromosomes), Russian (5.2%), Belorussian (3.3%), Austrian (2.6%), German (1.5%), Polish (1.5%), Slovenian (1.5%), Ukrainian (1.2%), and Slovak patients (1.1%). It has also been found in Lithuania, Latvia, Macedonia and Greece and has sporadically been observed in Canada, USA, France, Spain, Turkey, and UK, but not in CF patients from Bulgaria, Croatia, Romania or Serbia. Haplotype analysis has identified the same extragenic CF-haplotype XV-2c/KM.19 "A" and the same infrequent intragenic microsatellite haplotype 16-33-13 (IVS8CA-IVS17bTA-IVS17bCA) in all examined CFTRdele2, 3(21 kb) chromosomes, suggesting a common origin for this deletion. We conclude that the 21-kb deletion is a frequent and severe CF mutation in populations of Eastern- and Western-Slavic descent.